Although cystinosis is affecting 1 of 200.000 newborns in Europe and the United States, as far as we know until 2007 no patients with cystinosis were known in Russia. Therefore cystinosis was considered to be a ot-Russian?disease. The first Russian case of cystinosis was diagnosed by a paediatrician Mikhail Kagan in Orenburg, a large industrial city on Oeral, on the border between European and Asian parts of Russia. The same year two more patients were diagnosed. M. Kagan, together with a Moscow professor of paediatric nephrology Alexey Tsygin wrote a paper in the Russian Medical Newspaper aimed to reach as many as possible Russian physicians for informing them about cystinosis, which is most likely remains undiagnosed and untreated in the majority of Russian patients. We hope that this Internet page will help to spread information on cystinosis among Russian physicians and draw their attention to this rare, but potentially well-treatable disorder.
The Cystinosis Foundation has been working with Dr. Mikhail Kagan, M.D. of the Orenburg Regional Children's Hopsital in Orenburg, Russia, to help diagnose more children that may have Cystinosis and get information out to other hospitals and doctors throughout Russia
Wednesday
Cystinosis
Introduction
Background
Nephropathic cystinosis is an inherited (autosomal recessive) lysosomal storage disorder caused by defective transport of the amino acid cystine out of lysosomes. The stored cystine is poorly soluble and crystallizes within the lysosomes of many cell types, leading to widespread tissue and organ damage.
Three types of cystinosis have been described based on the age at diagnosis and magnitude of cellular cystine deposition: infantile onset, adolescent onset, and adult onset. Patients with the infantile nephropathic form of cystinosis (the most common and the most severe) develop symptoms early in life and develop end-stage kidney failure by late childhood, if untreated.
Specific therapy with a drug that allows for removal of cystine from its lysosomal accumulation has been associated with marked improvement in the outlook for kidney function and quality of life in patients with nephropathic cystinosis.
Pathophysiology
Ingested protein enters the lysosome, where acid hydrolases degrade it to its component amino acids, including cysteine. Within the lysosome, cysteine is readily oxidized to cystine (a disulfide of the amino acid cysteine). In healthy individuals, both cystine and cysteine can normally enter the cytoplasm, where cystine is rapidly converted to cysteine by the reducing agent glutathione. Cytoplasmic cysteine is incorporated into protein or degraded to inorganic sulfate for excretion.
Cystinosis is caused by one of several mutations in the gene that encodes cystinosin, the cystine-lysomal exporter. Because of the defect in cystinosin, cystine cannot leave the lysosomes and is accumulated there as birefringent, hexagonal, or rectangular crystals within cells of various organ systems.
In the infantile nephropathic form of cystinosis, the kidney is affected early in life by cystine crystals deposited in proximal tubule cells. This leads eventually to a Fanconi syndrome, characterized by wasting of substances reabsorbed in this nephron segment, including sodium, potassium, phosphate, calcium, magnesium, bicarbonate, and others. Metabolic acidosis and electrolyte disturbances ensue and contribute to the stunting of growth in children with cystinosis. Cystinosis is the most common inherited cause of Fanconi syndrome.
Frequency
United States
In North America, the incidence of infantile nephropathic cystinosis is 1 case per 100,000-200,000 live births; an estimated 300-400 children in the United States have cystinosis.
International
The incidence of cystinosis is higher in certain subpopulations. France's Brittany province has an estimated incidence of 1 case per 26,000 population; the incidence in the rest of France is 1 case per 326,440 population. The incidence rate of infantile and adolescent cystinosis in the former Federal Republic of Germany was reported to be approximately 1 case per 179,000 live births.
Mortality/Morbidity
Medical perceptions regarding the complications and outcome of cystinosis have changed over the years. Prior to the availability of renal transplantation, infantile cystinosis was considered a fatal disease. By the early 1970s, the salutary effects of renal transplants had been recognized.
Cysteamine, introduced in the early 1980s, was shown to blunt the decline in renal function and improve linear growth in these children, despite the fact that it does not ameliorate the defect in renal tubule transport. However, the increased life expectancy afforded by the progress in medical and surgical treatment was accompanied by the development of serious complications due to the continuous accumulation of cystine in nonrenal organs, including the eye, thyroid, brain, liver, pancreas, and muscle. However, many patients survive into the third or fourth decade of life and are able to pursue fulfilling lifestyles.
Race
Cystinosis is often considered a disease of fair-skinned individuals of European descent; however, it is known to occur in blacks, Hispanics, and people of Middle Eastern descent. It has also been described in at least one Chinese patient and in several Japanese patients.
Sex
The male-to-female ratio among cystinotic children has been reported to be 1.4:1.
Age
Patients with infantile nephropathic cystinosis develop initial symptoms in infancy, frequently when younger than 1 year. In the adolescent form, symptoms are evident by age 8-12 years, and the progression is slow. The adult form of cystinosis does not include renal involvement and is limited to the eye (ocular cystinosis).
Clinical
History
Cystinosis is classified into 2 general phenotypes: nephropathic and nonnephropathic cystinosis (benign variant).
Nephropathic cystinosis is further subdivided into infantile and late-onset (intermediate cystinosis), based on the age at presentation.
Nephropathic infantile cystinosis is the most common and most severe variant.
Symptoms of multiorgan involvement may be mild to severe, depending on the patient's age at diagnosis, the age when treatment was instituted, and genetic factors.
Early in the natural history of infantile nephropathic cystinosis, clinical involvement follows a fairly predictable chronology. Patients usually present during the first year of life with polyuria, polydipsia, dehydration, metabolic acidosis (normal anion gap hyperchloremic acidosis), hypophosphatemic rickets, failure to thrive, and laboratory findings consistent with Fanconi syndrome. If untreated, renal failure develops by age 7-10 years.
Oral cysteamine therapy postpones the need for renal transplantation.
Renal transplantation has prolonged the lives of children with cystinosis. Renal transplantation is highly successful, disease does not recur in the graft, but cystine continues to accumulate in other tissues, resulting in such complications as eye disease (eg, severe photophobia, corneal ulcerations, retinal blindness), delayed puberty, hypothyroidism, pancreatic disease (eg, exocrine insufficiency, insulin-dependent diabetes mellitus), liver disease (eg, hepatosplenomegaly, nodular degenerative hyperplasia), distal vacuolar myopathy, swallowing difficulties, and CNS involvement (eg, calcifications, atrophy, pseudotumor cerebri).
Late-onset (intermediate) nephropathic cystinosis is a more indolent form of the disease. The first symptoms most commonly appear at age 8-12 years. The features of Fanconi syndrome are less severe, and end-stage renal disease occurs after age 15 years.
Nonnephropathic cystinosis is considered a benign variant and is usually diagnosed by an ophthalmologist treating patients for photophobia. Photophobia may not begin until middle age and is not usually as debilitating as in the nephropathic form of the disease. Slit-lamp examination reveals corneal crystal deposits. In addition to the eye, cystine crystals are present in the bone marrow and leukocytes but are absent in the kidney and the retina.
Physical
A typical cystinotic patient has pale blond hair and blue eyes, although the disease also occurs among dark-haired individuals.
Initial presentation of infantile nephropathic cystinosis
The initial symptoms include polydipsia, polyuria, vomiting, loss of appetite, constipation, and failure to thrive.
The first signs may go unrecognized for several months until the patient develops severe dehydration, electrolyte imbalance, and metabolic acidosis during a mild illness. Some children may have recurrent bouts of fever and manifestations of heat intolerance (becoming red like beets) caused by a defect in sweat production.
Patients typically have short stature and renal Fanconi syndrome.
They have poor appetite, crave salty and hot and spicy foods, and prefer specific food textures. Each patient has specific preferences that may already be evident by age 2 years.
Initial presentation of late-onset nephropathic (intermediate) cystinosis
Most cases are diagnosed by age 12 years.
Complete Fanconi syndrome often does not develop in late-onset cystinosis, but renal function deteriorates as in infantile nephropathic cystinosis, and patients often experience end-stage renal failure within a few years of diagnosis.
Nephropathic cystinosis (progressive disease)
Children younger than 1 year usually show growth retardation, rickets, metabolic acidosis, and other chemical evidence of renal tubular abnormalities, such as increased renal excretion of glucose, amino acids, phosphate, and potassium. They may require frequent hospital admissions because of dehydration.
As children age, failure to thrive is prominent. Without specific therapy, children remain below the third percentile in both height and weight throughout life.
Corneal crystals are apparent by age 1-2 years. The untreated cornea is packed with crystals by age 3-4 years, leading to photophobia in early childhood.
By age 7-10 years, previously noted symptoms become more severe, and patients develop renal failure, increased photophobia, and thyroid insufficiency.
Sexual maturation is almost always late.
Retinal damage does not occur until the second or third decade of life.
Cerebral calcifications and muscular and swallowing difficulties cluster around the third decade of life.
The major complication of cystinosis in patients older than 20 years is legal blindness, distal myopathy, cerebral calcifications or atrophy, swallowing dysfunction, diabetes mellitus, and liver disease (eg, hepatomegaly, nodular degenerative hyperplasia).
Causes
All forms of cystinosis have autosomal recessive patterns of inheritance. Cystinosis is caused by a defect in transport of cystine across the lysosomal membrane due to defective function of the lysosomal membrane protein cystinosin, resulting from mutations of the cystinosis gene (CTNS). CTNS has been mapped to chromosome arm 17p13. The CTNS gene has 12 exons, the last 10 of which code for cystinosin.
Cystinosin (an integral lysosomal membrane protein) has 367 amino acids and 7 transmembrane domains. In nephropathic cystinosis patients, CTNS mutations can cause either an absence of cystinosin or a disruption of transmembrane domains and loss of protein function, leading to inhibition of cystine transport through the lysosomal membrane (which is carrier-dependent). More than 80 different CTNS mutations (missense, nonsense, splice-site, deletion, and promoter mutations) are described in patients with nephropathic cystinosis; the most common are 57 kilobases (kb) (approximately 60% of the mutations in US patients).1
Patients with a mild form of cystinosis that is diagnosed when patients are younger than 7 years or patients with late-onset (intermediate) cystinosis have mutations of CTNS that affect functionally unimportant regions of cystinosin, accounting for a milder clinical course. The various CTNS mutations can explain why patients have a wide spectrum of clinical symptomatology.
The parents of patients with cystinosis are obligate heterozygotes for cystinosis; they each carry a single gene for the disease. Individuals heterozygous for cystinosis have never been reported to have cystine crystals in any tissue or cell. Despite the clinically normal appearance of individuals who are heterozygous for cystinosis, their polymorphonuclear cells contain an increased amount of cystine.
Late-onset (intermediate) cystinosis appears to be due to the inheritance of a mutation known to cause infantile disease in one allele and a relatively less clinically severe mutation in the other or due to the inheritance of a relatively less severe mutation in both alleles.
Background
Nephropathic cystinosis is an inherited (autosomal recessive) lysosomal storage disorder caused by defective transport of the amino acid cystine out of lysosomes. The stored cystine is poorly soluble and crystallizes within the lysosomes of many cell types, leading to widespread tissue and organ damage.
Three types of cystinosis have been described based on the age at diagnosis and magnitude of cellular cystine deposition: infantile onset, adolescent onset, and adult onset. Patients with the infantile nephropathic form of cystinosis (the most common and the most severe) develop symptoms early in life and develop end-stage kidney failure by late childhood, if untreated.
Specific therapy with a drug that allows for removal of cystine from its lysosomal accumulation has been associated with marked improvement in the outlook for kidney function and quality of life in patients with nephropathic cystinosis.
Pathophysiology
Ingested protein enters the lysosome, where acid hydrolases degrade it to its component amino acids, including cysteine. Within the lysosome, cysteine is readily oxidized to cystine (a disulfide of the amino acid cysteine). In healthy individuals, both cystine and cysteine can normally enter the cytoplasm, where cystine is rapidly converted to cysteine by the reducing agent glutathione. Cytoplasmic cysteine is incorporated into protein or degraded to inorganic sulfate for excretion.
Cystinosis is caused by one of several mutations in the gene that encodes cystinosin, the cystine-lysomal exporter. Because of the defect in cystinosin, cystine cannot leave the lysosomes and is accumulated there as birefringent, hexagonal, or rectangular crystals within cells of various organ systems.
In the infantile nephropathic form of cystinosis, the kidney is affected early in life by cystine crystals deposited in proximal tubule cells. This leads eventually to a Fanconi syndrome, characterized by wasting of substances reabsorbed in this nephron segment, including sodium, potassium, phosphate, calcium, magnesium, bicarbonate, and others. Metabolic acidosis and electrolyte disturbances ensue and contribute to the stunting of growth in children with cystinosis. Cystinosis is the most common inherited cause of Fanconi syndrome.
Frequency
United States
In North America, the incidence of infantile nephropathic cystinosis is 1 case per 100,000-200,000 live births; an estimated 300-400 children in the United States have cystinosis.
International
The incidence of cystinosis is higher in certain subpopulations. France's Brittany province has an estimated incidence of 1 case per 26,000 population; the incidence in the rest of France is 1 case per 326,440 population. The incidence rate of infantile and adolescent cystinosis in the former Federal Republic of Germany was reported to be approximately 1 case per 179,000 live births.
Mortality/Morbidity
Medical perceptions regarding the complications and outcome of cystinosis have changed over the years. Prior to the availability of renal transplantation, infantile cystinosis was considered a fatal disease. By the early 1970s, the salutary effects of renal transplants had been recognized.
Cysteamine, introduced in the early 1980s, was shown to blunt the decline in renal function and improve linear growth in these children, despite the fact that it does not ameliorate the defect in renal tubule transport. However, the increased life expectancy afforded by the progress in medical and surgical treatment was accompanied by the development of serious complications due to the continuous accumulation of cystine in nonrenal organs, including the eye, thyroid, brain, liver, pancreas, and muscle. However, many patients survive into the third or fourth decade of life and are able to pursue fulfilling lifestyles.
Race
Cystinosis is often considered a disease of fair-skinned individuals of European descent; however, it is known to occur in blacks, Hispanics, and people of Middle Eastern descent. It has also been described in at least one Chinese patient and in several Japanese patients.
Sex
The male-to-female ratio among cystinotic children has been reported to be 1.4:1.
Age
Patients with infantile nephropathic cystinosis develop initial symptoms in infancy, frequently when younger than 1 year. In the adolescent form, symptoms are evident by age 8-12 years, and the progression is slow. The adult form of cystinosis does not include renal involvement and is limited to the eye (ocular cystinosis).
Clinical
History
Cystinosis is classified into 2 general phenotypes: nephropathic and nonnephropathic cystinosis (benign variant).
Nephropathic cystinosis is further subdivided into infantile and late-onset (intermediate cystinosis), based on the age at presentation.
Nephropathic infantile cystinosis is the most common and most severe variant.
Symptoms of multiorgan involvement may be mild to severe, depending on the patient's age at diagnosis, the age when treatment was instituted, and genetic factors.
Early in the natural history of infantile nephropathic cystinosis, clinical involvement follows a fairly predictable chronology. Patients usually present during the first year of life with polyuria, polydipsia, dehydration, metabolic acidosis (normal anion gap hyperchloremic acidosis), hypophosphatemic rickets, failure to thrive, and laboratory findings consistent with Fanconi syndrome. If untreated, renal failure develops by age 7-10 years.
Oral cysteamine therapy postpones the need for renal transplantation.
Renal transplantation has prolonged the lives of children with cystinosis. Renal transplantation is highly successful, disease does not recur in the graft, but cystine continues to accumulate in other tissues, resulting in such complications as eye disease (eg, severe photophobia, corneal ulcerations, retinal blindness), delayed puberty, hypothyroidism, pancreatic disease (eg, exocrine insufficiency, insulin-dependent diabetes mellitus), liver disease (eg, hepatosplenomegaly, nodular degenerative hyperplasia), distal vacuolar myopathy, swallowing difficulties, and CNS involvement (eg, calcifications, atrophy, pseudotumor cerebri).
Late-onset (intermediate) nephropathic cystinosis is a more indolent form of the disease. The first symptoms most commonly appear at age 8-12 years. The features of Fanconi syndrome are less severe, and end-stage renal disease occurs after age 15 years.
Nonnephropathic cystinosis is considered a benign variant and is usually diagnosed by an ophthalmologist treating patients for photophobia. Photophobia may not begin until middle age and is not usually as debilitating as in the nephropathic form of the disease. Slit-lamp examination reveals corneal crystal deposits. In addition to the eye, cystine crystals are present in the bone marrow and leukocytes but are absent in the kidney and the retina.
Physical
A typical cystinotic patient has pale blond hair and blue eyes, although the disease also occurs among dark-haired individuals.
Initial presentation of infantile nephropathic cystinosis
The initial symptoms include polydipsia, polyuria, vomiting, loss of appetite, constipation, and failure to thrive.
The first signs may go unrecognized for several months until the patient develops severe dehydration, electrolyte imbalance, and metabolic acidosis during a mild illness. Some children may have recurrent bouts of fever and manifestations of heat intolerance (becoming red like beets) caused by a defect in sweat production.
Patients typically have short stature and renal Fanconi syndrome.
They have poor appetite, crave salty and hot and spicy foods, and prefer specific food textures. Each patient has specific preferences that may already be evident by age 2 years.
Initial presentation of late-onset nephropathic (intermediate) cystinosis
Most cases are diagnosed by age 12 years.
Complete Fanconi syndrome often does not develop in late-onset cystinosis, but renal function deteriorates as in infantile nephropathic cystinosis, and patients often experience end-stage renal failure within a few years of diagnosis.
Nephropathic cystinosis (progressive disease)
Children younger than 1 year usually show growth retardation, rickets, metabolic acidosis, and other chemical evidence of renal tubular abnormalities, such as increased renal excretion of glucose, amino acids, phosphate, and potassium. They may require frequent hospital admissions because of dehydration.
As children age, failure to thrive is prominent. Without specific therapy, children remain below the third percentile in both height and weight throughout life.
Corneal crystals are apparent by age 1-2 years. The untreated cornea is packed with crystals by age 3-4 years, leading to photophobia in early childhood.
By age 7-10 years, previously noted symptoms become more severe, and patients develop renal failure, increased photophobia, and thyroid insufficiency.
Sexual maturation is almost always late.
Retinal damage does not occur until the second or third decade of life.
Cerebral calcifications and muscular and swallowing difficulties cluster around the third decade of life.
The major complication of cystinosis in patients older than 20 years is legal blindness, distal myopathy, cerebral calcifications or atrophy, swallowing dysfunction, diabetes mellitus, and liver disease (eg, hepatomegaly, nodular degenerative hyperplasia).
Causes
All forms of cystinosis have autosomal recessive patterns of inheritance. Cystinosis is caused by a defect in transport of cystine across the lysosomal membrane due to defective function of the lysosomal membrane protein cystinosin, resulting from mutations of the cystinosis gene (CTNS). CTNS has been mapped to chromosome arm 17p13. The CTNS gene has 12 exons, the last 10 of which code for cystinosin.
Cystinosin (an integral lysosomal membrane protein) has 367 amino acids and 7 transmembrane domains. In nephropathic cystinosis patients, CTNS mutations can cause either an absence of cystinosin or a disruption of transmembrane domains and loss of protein function, leading to inhibition of cystine transport through the lysosomal membrane (which is carrier-dependent). More than 80 different CTNS mutations (missense, nonsense, splice-site, deletion, and promoter mutations) are described in patients with nephropathic cystinosis; the most common are 57 kilobases (kb) (approximately 60% of the mutations in US patients).1
Patients with a mild form of cystinosis that is diagnosed when patients are younger than 7 years or patients with late-onset (intermediate) cystinosis have mutations of CTNS that affect functionally unimportant regions of cystinosin, accounting for a milder clinical course. The various CTNS mutations can explain why patients have a wide spectrum of clinical symptomatology.
The parents of patients with cystinosis are obligate heterozygotes for cystinosis; they each carry a single gene for the disease. Individuals heterozygous for cystinosis have never been reported to have cystine crystals in any tissue or cell. Despite the clinically normal appearance of individuals who are heterozygous for cystinosis, their polymorphonuclear cells contain an increased amount of cystine.
Late-onset (intermediate) cystinosis appears to be due to the inheritance of a mutation known to cause infantile disease in one allele and a relatively less clinically severe mutation in the other or due to the inheritance of a relatively less severe mutation in both alleles.
Cystinosis
Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of the amino acid cystine. It is a genetic disorder that typically follows an autosomal recessive inheritance pattern. Cystinosis is the most common cause of Fanconi syndrome in the pediatric age group. Fanconi syndrome occurs when the function of cells in renal tubules are impaired, leading to abnormal amounts of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium and phosphates.
Contents [hide]
1 Diagnosis
1.1 Symptoms
2 Genetics
3 Treatment
4 Types
5 See also
6 References
7 External links
[edit] Diagnosis
Cystinosis is a rare genetic disorder[1] that causes an accumulation of the amino acid cystine within cells, forming crystals that can build up and damage the cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes.
The accumulation is caused by abnormal transport of cystine from lysosomes, resulting in a massive intra-lysosomal cystine accumulation in tissues. Via an as yet unknown mechanism, lysosomal cystine appears to amplify and alter apoptosis in such a way that cells die inappropriately, leading to loss of renal epithelial cells. This results in renal Fanconi syndrome, and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease.
[edit] Symptoms
There are three distinct types of cystinosis each with slightly different symptoms: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. Infants affected by nephropathic cystinosis initially exhibit poor growth and particular kidney problems (sometimes called renal Fanconi syndrome). The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis).
By about age two, cystine crystals may also be present in the cornea. The buildup of these crystals in the eye causes an increased sensitivity to light (photophobia). Without treatment, children with cystinosis are likely to experience complete kidney failure by about age ten. Other signs and symptoms that may occur in untreated patients include muscle deterioration, blindness, inability to swallow, diabetes, and thyroid and nervous system problems.
The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals around age twelve to fifteen. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.
People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.
It is currently being researched at UC San Diego, Tulane University School of Medicine, and at the National Institutes of Health in Bethesda, Maryland as well as at Robert Gordon University in Aberdeen and in Sunderland, UK.
[edit] Genetics
Cystinosis has an autosomal recessive pattern of inheritance.Cystinosis occurs due to a mutation in the gene CTNS, located on chromosome 17, which codes for cystinosin, the lysosomal cystine transporter. Symptoms are first seen at about 3 to 18 months of age with profound polyuria (excessive urination), followed by poor growth, photophobia, and ultimately kidney failure by age 6 years in the nephropathic form.
All forms of cystinosis (nephropathic, juvenile and ocular) are autosomal recessive, which means that the trait is located on an autosomal gene, and an individual who inherits two copies of the gene - one from both parents - will have the disorder. There is a 25% risk of having a child with the disorder, when both parents are carriers of an autosomal recessive trait.
Cystinosis "breeds true", indicating that parents of a child with the juvenile variety of cystinosis will not have another child with the nephropathic form, etc. Cystinosis affects approximately 1 in 100,000 to 200,000 newborns.[citation needed] and there are only around 2,000 known individuals with cystinosis in the world. The incidence is higher in the province of Brittany, France, where the disorder affects 1 in 26,000 individuals.[citation needed]
[edit] Treatment
Cystinosis is normally treated with a drug called cysteamine (brand name Cystagon), which fools the cells into thinking that cystine is lysine, thus evacuating the aminoacid normally. When administered regularly, cysteamine decreases the amount of cystine stored in lysosomes and correlates with conservation of renal function and improved growth. Cysteamine eyedrops remove the cystine crystals in the cornea that can cause photophobia if left unchecked. Patients with cystinosis are also often given sodium citrate to treat the blood acidosis, as well as potassium and phosphorus supplements.
Contents [hide]
1 Diagnosis
1.1 Symptoms
2 Genetics
3 Treatment
4 Types
5 See also
6 References
7 External links
[edit] Diagnosis
Cystinosis is a rare genetic disorder[1] that causes an accumulation of the amino acid cystine within cells, forming crystals that can build up and damage the cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes.
The accumulation is caused by abnormal transport of cystine from lysosomes, resulting in a massive intra-lysosomal cystine accumulation in tissues. Via an as yet unknown mechanism, lysosomal cystine appears to amplify and alter apoptosis in such a way that cells die inappropriately, leading to loss of renal epithelial cells. This results in renal Fanconi syndrome, and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease.
[edit] Symptoms
There are three distinct types of cystinosis each with slightly different symptoms: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. Infants affected by nephropathic cystinosis initially exhibit poor growth and particular kidney problems (sometimes called renal Fanconi syndrome). The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis).
By about age two, cystine crystals may also be present in the cornea. The buildup of these crystals in the eye causes an increased sensitivity to light (photophobia). Without treatment, children with cystinosis are likely to experience complete kidney failure by about age ten. Other signs and symptoms that may occur in untreated patients include muscle deterioration, blindness, inability to swallow, diabetes, and thyroid and nervous system problems.
The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals around age twelve to fifteen. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.
People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.
It is currently being researched at UC San Diego, Tulane University School of Medicine, and at the National Institutes of Health in Bethesda, Maryland as well as at Robert Gordon University in Aberdeen and in Sunderland, UK.
[edit] Genetics
Cystinosis has an autosomal recessive pattern of inheritance.Cystinosis occurs due to a mutation in the gene CTNS, located on chromosome 17, which codes for cystinosin, the lysosomal cystine transporter. Symptoms are first seen at about 3 to 18 months of age with profound polyuria (excessive urination), followed by poor growth, photophobia, and ultimately kidney failure by age 6 years in the nephropathic form.
All forms of cystinosis (nephropathic, juvenile and ocular) are autosomal recessive, which means that the trait is located on an autosomal gene, and an individual who inherits two copies of the gene - one from both parents - will have the disorder. There is a 25% risk of having a child with the disorder, when both parents are carriers of an autosomal recessive trait.
Cystinosis "breeds true", indicating that parents of a child with the juvenile variety of cystinosis will not have another child with the nephropathic form, etc. Cystinosis affects approximately 1 in 100,000 to 200,000 newborns.[citation needed] and there are only around 2,000 known individuals with cystinosis in the world. The incidence is higher in the province of Brittany, France, where the disorder affects 1 in 26,000 individuals.[citation needed]
[edit] Treatment
Cystinosis is normally treated with a drug called cysteamine (brand name Cystagon), which fools the cells into thinking that cystine is lysine, thus evacuating the aminoacid normally. When administered regularly, cysteamine decreases the amount of cystine stored in lysosomes and correlates with conservation of renal function and improved growth. Cysteamine eyedrops remove the cystine crystals in the cornea that can cause photophobia if left unchecked. Patients with cystinosis are also often given sodium citrate to treat the blood acidosis, as well as potassium and phosphorus supplements.
Homocysteine disease(2)
Etiology:
Homocysteine as a disease lysosomal storage disease, because of section 17 of the short arm of chromosome 13 position (17p13) of the CTNS gene defects, leading to cysteine (cystine) to carry out the lysosomal enzyme transport (transporter ) dysfunction, making the accumulation of homocysteine in cell lysosomal up, resulting in organizations and organs of the lesion.
According to time of onset and disease severity can be divided into three types: First, nephropathy type / child type (Nephropathic cystinosis); II, intermediate / juvenile (Intermediate cystinosis); three, non-nephropathogenic type / Adult (Non -nephropathic cystinosis). One of nephropathy in type / child-type the most common symptoms are the most serious.
Incidence:
The incidence of this disease is estimated at 1/200000. In the Brittany area of France (Brittany), found in the area of disease incidence of 1 / 26000.
At present, this disease has been classified as rare diseases Notice our country, it was estimated the incidence of the Taiwan area should be one ten thousandth of the following.
Genetic model:
For autosomal recessive genetic diseases, said parents with a mutation for the gene, the next generation of each child regardless of gender will have 1 / 4 chance of suffering from this disease.
Characterization of clinical on:
Typing clinical
Nephropathy type / child care-type patients in the newborn during the first few months are usually asymptomatic, but 6-9 when the month that is gradually emerging in anorexia, vomiting, polyuria, growth retardation of the situation, and a lesion of the kidney and other organs. Kidneys are the main clinical manifestations of Fanconi's syndrome.
Fanconi's syndrome (Renal tubular Fanconi syndrome):
Often in large happened in June, can not be due to renal tubular water, electrolytes, bicarbonate, phosphate, calcium, carnitine, glucose and amino acid molecules, such as re-absorption, and the emergence of polyuria, polydipsia, dehydration and even symptoms of acidosis.
Electrolyte and amino acid molecules, such as the loss will be patients with a variety of diseases; include: (1) low phosphate rickets; often cause pain when walking patients. (2) low blood calcium; convulsion caused by hands and feet, severe low will hinder the normal cardiac conduction. (3) occasional hyponatremia and hypomagnesemia situation happened. (4) bone age than actual age backward.
Due to progressive glomerular damage, while the growth of serious adverse renal glomerular filtration rate decreased about 10-year-old kidney failure that may occur.
Corneal cystine crystals (Corneal cystine crystals):
Patients often at 2-3 years of age when the symptoms of photophobia, after corneal examination, can be found in the eye corneal cystine crystals of (corneal crystals), can happen before the age of one. Untreated patients with nephropathy at 16 months after the big one can often find this characterization.
In addition, there are retinopathy (Peripheral retinopathy), repeated injury to the cornea (Recurrent corneal erosions), visual acuity and low variability characterization. Happen that some young patients with eye diseases and may even lead to blindness.
Growth retardation:
Usually found at six months
Endocrine disorders:
Low thyroid may occur, the pituitary gonadal function and insulin secretion disorders.
Others: normal intelligence, but may occur late in the disease brain atrophy and neurological lesions.
Between type / juvenile renal disease of relatively minor symptoms, the occurrence of late time, usually 6-8 at the age of onset.
Non-nephrotic variant / adult-type symptoms for this type of eye and bone marrow have on homocysteine crystals, usually occurs only photophobia symptoms.
Diagnosis:
Be able to use cysteine protein technology (cystine binding protein assay), detection of homocysteine in blood leukocytes (cystine) concentration; nephropathogenic type / child type of numerical often 50-100 times normal. This detection technology can also be used for detection of fibrous tissue, such as conjunctiva and muscle intracellular homocysteine concentration. Also available from the first three months of pregnancy from skin, amniotic fluid or chorionic cells by fibrous tissue cultured cells for prenatal diagnosis.
Treatment:
Drug therapy
Study found that cysteine (cysteamine bitartrate, drugs called Cystagon) of drug therapy for homocysteine treatment of choice for patients, this one free of the mercaptan-type material, the structure can be self-cysteine dissolved in a 90% homocysteine of more than cells, will be able to effectively control the type of patients with nephropathy disease progression.
Positive long-term treatment, can avoid or delay kidney failure and the incidence of thyroid Lower and dissolution of muscle tissue accumulation of homocysteine in order to alleviate the symptoms, to promote growth and development of the case patients.
After diagnosis, provide treatment as soon as possible; if at birth or within one month after the start, and often get the best treatment results, and contribute to the growth of the kidney to avoid the deterioration of renal function. Long-term treatment found that although there is no cure the disease, but can be avoided in patients with significant late complications.
At the side effects on nausea and vomiting may occur, but may be due to displeasure with the smell of drugs with the result of Taste; Recent studies have suggested with the use of gastrointestinal medication ─ omeprazole, to improve gastrointestinal discomfort up.
But must be noted that the cysteine of oral medication, there is no benefit from the improvement of corneal cystine crystals, it is proposed can be used in patients with CYSTEAMINE hydrogen bromide (Cysteamine hydrochloride) eye drops, in a couple of months can reduce the corneal cystine crystals, a few weeks to alleviate photophobia eyes; and wearing dark-colored or sunglasses, but also reduce sunlight circumstances brought about by photophobia.
The main goals of treatment, in order to complement because of kidney disease caused by electrolytes, amino acids, such as the loss of material, including water, sodium, potassium, phosphorus, calcium, magnesium, vitamin D ... and so on, the volume of its intake is required by patients condition and advised to regularly monitor the physical requirements to achieve.
Low happen if the thyroid, pituitary gonadal function, such as the issue of endocrine disorders may be related to endocrine accept medication.
Prognosis:
When the progressive deterioration of renal function to kidney failure, the patients are usually required to undergo blood or peritoneal dialysis and other treatment, and may need to consider the kidney transplant. After kidney transplant, even if the cystine crystals are deposited in the kidneys after transplantation on, but still will not have Fanconi's syndrome, may occur more frequently after transplantation of exclusion cases, patients need regular follow-up appointment to return to readily available treatment.
Homocysteine as a disease lysosomal storage disease, because of section 17 of the short arm of chromosome 13 position (17p13) of the CTNS gene defects, leading to cysteine (cystine) to carry out the lysosomal enzyme transport (transporter ) dysfunction, making the accumulation of homocysteine in cell lysosomal up, resulting in organizations and organs of the lesion.
According to time of onset and disease severity can be divided into three types: First, nephropathy type / child type (Nephropathic cystinosis); II, intermediate / juvenile (Intermediate cystinosis); three, non-nephropathogenic type / Adult (Non -nephropathic cystinosis). One of nephropathy in type / child-type the most common symptoms are the most serious.
Incidence:
The incidence of this disease is estimated at 1/200000. In the Brittany area of France (Brittany), found in the area of disease incidence of 1 / 26000.
At present, this disease has been classified as rare diseases Notice our country, it was estimated the incidence of the Taiwan area should be one ten thousandth of the following.
Genetic model:
For autosomal recessive genetic diseases, said parents with a mutation for the gene, the next generation of each child regardless of gender will have 1 / 4 chance of suffering from this disease.
Characterization of clinical on:
Typing clinical
Nephropathy type / child care-type patients in the newborn during the first few months are usually asymptomatic, but 6-9 when the month that is gradually emerging in anorexia, vomiting, polyuria, growth retardation of the situation, and a lesion of the kidney and other organs. Kidneys are the main clinical manifestations of Fanconi's syndrome.
Fanconi's syndrome (Renal tubular Fanconi syndrome):
Often in large happened in June, can not be due to renal tubular water, electrolytes, bicarbonate, phosphate, calcium, carnitine, glucose and amino acid molecules, such as re-absorption, and the emergence of polyuria, polydipsia, dehydration and even symptoms of acidosis.
Electrolyte and amino acid molecules, such as the loss will be patients with a variety of diseases; include: (1) low phosphate rickets; often cause pain when walking patients. (2) low blood calcium; convulsion caused by hands and feet, severe low will hinder the normal cardiac conduction. (3) occasional hyponatremia and hypomagnesemia situation happened. (4) bone age than actual age backward.
Due to progressive glomerular damage, while the growth of serious adverse renal glomerular filtration rate decreased about 10-year-old kidney failure that may occur.
Corneal cystine crystals (Corneal cystine crystals):
Patients often at 2-3 years of age when the symptoms of photophobia, after corneal examination, can be found in the eye corneal cystine crystals of (corneal crystals), can happen before the age of one. Untreated patients with nephropathy at 16 months after the big one can often find this characterization.
In addition, there are retinopathy (Peripheral retinopathy), repeated injury to the cornea (Recurrent corneal erosions), visual acuity and low variability characterization. Happen that some young patients with eye diseases and may even lead to blindness.
Growth retardation:
Usually found at six months
Endocrine disorders:
Low thyroid may occur, the pituitary gonadal function and insulin secretion disorders.
Others: normal intelligence, but may occur late in the disease brain atrophy and neurological lesions.
Between type / juvenile renal disease of relatively minor symptoms, the occurrence of late time, usually 6-8 at the age of onset.
Non-nephrotic variant / adult-type symptoms for this type of eye and bone marrow have on homocysteine crystals, usually occurs only photophobia symptoms.
Diagnosis:
Be able to use cysteine protein technology (cystine binding protein assay), detection of homocysteine in blood leukocytes (cystine) concentration; nephropathogenic type / child type of numerical often 50-100 times normal. This detection technology can also be used for detection of fibrous tissue, such as conjunctiva and muscle intracellular homocysteine concentration. Also available from the first three months of pregnancy from skin, amniotic fluid or chorionic cells by fibrous tissue cultured cells for prenatal diagnosis.
Treatment:
Drug therapy
Study found that cysteine (cysteamine bitartrate, drugs called Cystagon) of drug therapy for homocysteine treatment of choice for patients, this one free of the mercaptan-type material, the structure can be self-cysteine dissolved in a 90% homocysteine of more than cells, will be able to effectively control the type of patients with nephropathy disease progression.
Positive long-term treatment, can avoid or delay kidney failure and the incidence of thyroid Lower and dissolution of muscle tissue accumulation of homocysteine in order to alleviate the symptoms, to promote growth and development of the case patients.
After diagnosis, provide treatment as soon as possible; if at birth or within one month after the start, and often get the best treatment results, and contribute to the growth of the kidney to avoid the deterioration of renal function. Long-term treatment found that although there is no cure the disease, but can be avoided in patients with significant late complications.
At the side effects on nausea and vomiting may occur, but may be due to displeasure with the smell of drugs with the result of Taste; Recent studies have suggested with the use of gastrointestinal medication ─ omeprazole, to improve gastrointestinal discomfort up.
But must be noted that the cysteine of oral medication, there is no benefit from the improvement of corneal cystine crystals, it is proposed can be used in patients with CYSTEAMINE hydrogen bromide (Cysteamine hydrochloride) eye drops, in a couple of months can reduce the corneal cystine crystals, a few weeks to alleviate photophobia eyes; and wearing dark-colored or sunglasses, but also reduce sunlight circumstances brought about by photophobia.
The main goals of treatment, in order to complement because of kidney disease caused by electrolytes, amino acids, such as the loss of material, including water, sodium, potassium, phosphorus, calcium, magnesium, vitamin D ... and so on, the volume of its intake is required by patients condition and advised to regularly monitor the physical requirements to achieve.
Low happen if the thyroid, pituitary gonadal function, such as the issue of endocrine disorders may be related to endocrine accept medication.
Prognosis:
When the progressive deterioration of renal function to kidney failure, the patients are usually required to undergo blood or peritoneal dialysis and other treatment, and may need to consider the kidney transplant. After kidney transplant, even if the cystine crystals are deposited in the kidneys after transplantation on, but still will not have Fanconi's syndrome, may occur more frequently after transplantation of exclusion cases, patients need regular follow-up appointment to return to readily available treatment.
Homocystinuria
1960, Carson and Neill et al in 1962 in Northern Ireland issued the first report on the disease in patients, this case was originally described as an unusual one Marfan syndrome and Marfan syndrome at the age of seven when the kidney accompanied by abnormal situation, in happened when the six-year-old with acute non-inflammatory kidney lesions silk (glomerulonephritis) after recovery and found that there is high blood pressure phenomenon, in this case on the development of mental retardation and is relatively thin, light-colored hair, pale skin, cheeks change red, slender means (arachnodactyly), air-concave foot (pes cavus) and on both sides of the lens dislocation and other symptoms.
Homocystinuria (Homocystinuria) are congenital diseases of amino acid metabolic abnormalities, patients discharged from the urine of a large number of high homocysteine, high blood homocysteine values and methionine values are high. Patients are usually 48-96 hours of birth, you can check out in the urine Homocystinuria existence.
Clinical features
Smart enough ectopic eye lens, heart and vascular disease, blood clots, osteoporosis, thin bones (malformation) clinical symptoms such as ...
The incidence of
Europe and the United States about 1/200000, and Taiwan the incidence of very low, estimated at around 1/500000 or less.
Genetic model
Homocystinuria is an autosomal recessive genetic disorders of amino acid metabolism, both parents are carriers of the recessive (carrier: the Parent with a defective gene, but no clinical symptoms), Patients must be at the same time with two defective genes (from the Parent's to a) be the incidence; parents for the carrier, while at the next pair give birth to the next child for Homocystinuria patients high probability of Tatsu quarter. Probability of disease-free sex.
Treatment
The most common reason is that "CBS enzyme (cystathionine-β-synthase, CBS) cystathionine synthesis of functional lack." While the "CBS lack of enzyme function" can be divided into
1. Of vitamin B6 treatment responders: of "vitamin B6 treatment" of patients, may, by supplementary vitamin B6 so that CBS enzyme function in order to reduce the blood and urine methionine high homocysteine concentration . For newborns and small children, in addition to the "low-methionine diet restrictions" should be given to 25 ~ 100 mg / day of vitamin B6, four weeks; called big babies and adults were given 1 g / day. Such as methionine in the blood for high homocysteine concentrations reduced, would reduce the dose of vitamin B6, because of long-term use will result in peripheral nerve problem. Oral vitamin B12 and vitamin B6 combined betaine (Betaine) supplement, can reduce high homocysteine concentration in blood after a meal, such as methylation process due to consumption of folic acid too much folic acid should also be added.
2. Of vitamin B6 treatment of those who failed to respond: If patients with doses of vitamin B6 is added when no response 1000mg/day should start with low methionine diet for diet control treatment, in order to maintain blood methionine suitable concentration; consumption of low-methionine special formula to supplement the amino acids the body must be in order to maintain normal growth and physiological functions. Also need to add cysteine (L-cysteine) and betaine (Betaine).
Prognosis
Although this disease, we have yet to have special treatment, about 50% of patients treated by vitamin B6 has been improved.
Homocystinuria (Homocystinuria) are congenital diseases of amino acid metabolic abnormalities, patients discharged from the urine of a large number of high homocysteine, high blood homocysteine values and methionine values are high. Patients are usually 48-96 hours of birth, you can check out in the urine Homocystinuria existence.
Clinical features
Smart enough ectopic eye lens, heart and vascular disease, blood clots, osteoporosis, thin bones (malformation) clinical symptoms such as ...
The incidence of
Europe and the United States about 1/200000, and Taiwan the incidence of very low, estimated at around 1/500000 or less.
Genetic model
Homocystinuria is an autosomal recessive genetic disorders of amino acid metabolism, both parents are carriers of the recessive (carrier: the Parent with a defective gene, but no clinical symptoms), Patients must be at the same time with two defective genes (from the Parent's to a) be the incidence; parents for the carrier, while at the next pair give birth to the next child for Homocystinuria patients high probability of Tatsu quarter. Probability of disease-free sex.
Treatment
The most common reason is that "CBS enzyme (cystathionine-β-synthase, CBS) cystathionine synthesis of functional lack." While the "CBS lack of enzyme function" can be divided into
1. Of vitamin B6 treatment responders: of "vitamin B6 treatment" of patients, may, by supplementary vitamin B6 so that CBS enzyme function in order to reduce the blood and urine methionine high homocysteine concentration . For newborns and small children, in addition to the "low-methionine diet restrictions" should be given to 25 ~ 100 mg / day of vitamin B6, four weeks; called big babies and adults were given 1 g / day. Such as methionine in the blood for high homocysteine concentrations reduced, would reduce the dose of vitamin B6, because of long-term use will result in peripheral nerve problem. Oral vitamin B12 and vitamin B6 combined betaine (Betaine) supplement, can reduce high homocysteine concentration in blood after a meal, such as methylation process due to consumption of folic acid too much folic acid should also be added.
2. Of vitamin B6 treatment of those who failed to respond: If patients with doses of vitamin B6 is added when no response 1000mg/day should start with low methionine diet for diet control treatment, in order to maintain blood methionine suitable concentration; consumption of low-methionine special formula to supplement the amino acids the body must be in order to maintain normal growth and physiological functions. Also need to add cysteine (L-cysteine) and betaine (Betaine).
Prognosis
Although this disease, we have yet to have special treatment, about 50% of patients treated by vitamin B6 has been improved.
Homocysteine disease (1)
Homocysteine disease (Cystinosis)
First, biochemical principle
Homocysteine disease is a lysosomal storage disease, due to cystathionine amine can not be carried through the lysosomal membrane, so the accumulation of homocysteine in the lysosomal caused a lot of organ dysfunction of cells, the kidneys are the most serious damage. Can be divided into three types: 1. Nephropathogenic type (or child-type); 2. Between type (or juvenile onset); 3. Benign type (or adult). One of nephropathy in type (child type) are the most common type.
Metabolic disorders --
Caused by the cysteine lysosomal storage in the kidneys, bone marrow, conjunctiva, thyroid, muscle, choroid plexus, brain mass, and lymph nodes of the main causes are still unknown, most of the enzymes break down homocysteine defect or not the conclusions of the study. However, and normal lysosomal cysteine of comparison can still be seen in the lysosomal cystine out of the ability of lysosomal markedly reduced. This anomaly may be responsible for carrying conveyor homocysteine through the lysosomal membrane protein atoms on the defect. Why is homocysteine storage will lead to loss of function of cells is still no reason to answer, but recent in vitro (in vitro) experiments pointed out that the proximal renal tubular cell storage will cause homocysteine three phosphoric acid adenosine (ATP) of缺乏.
Second, genetic mechanisms and genetic model
Degenerative kidney disease for homocysteine autosomal recessive genetic disease, juvenile and adult-type is the same genetic model.
Third, diagnostic methods
Homocysteine diagnosis can check the white blood cells to establish the concentration of free cysteine, the merger of homocysteine neuropathy patients white blood cells of normal homocysteine concentration is about 50 ~ 100 times. Combination of technical inspection of the use of protein polymorphonuclear white blood cells cystine concentrations are very sensitive, or even can detect homozygous gene varies from those with (heterozygous carriers). Such inspection techniques can also be used for fibrous tissue, conjunctiva organizations, and muscle and other cells, so in the first three months of pregnancy from skin, amniotic fluid cells or chorionic cultivated fibrous disease of the middle class to provide homocysteine pre-genetic diagnosis.
Four, clinical characterization of
Child care type cysteine deficiency
The first phase
After birth, usually at 3 to 6 months are asymptomatic, while in one-year-old will appear before the clinical symptoms. These symptoms include: anorexia, vomiting, polyuria, and not dependent. If you do not timely diagnosed, there is no vitamin D, at 18 months will be presented rickets. At the same time, if the urinary glucose and protein, that is, whether the patient is suspected to be suffering from disease homocysteine. When symptoms arise, usually in the first visit will be entirely performance Fanconi's syndrome (Franconi's syndrome) symptoms. Symptoms of this syndrome include: urine sugar normal blood sugar values (normoglycemic glycosuria), amino acids in urine (generalized aminoaciduria), there is β2-microglobulin protein and lysosome substantial tubular secretion of urine protein (tubular proteinuria), combined with low phosphate salt of phosphoric acid in urine hyperlipidemia (phosphaturia with hypophosphatemia), and due to substantial loss of potassium and sodium carbonate caused severe hypokalemia, hyponatremia, and acidosis. Often merging many high calcium in urine and blood urea is too small. Botulinum salty (Carnitine) loss resulting from renal tubular botulinum salty (Carnitine) insufficient, and at the same time can be seriously complicated by abnormal urine concentrated urine caused by many, every day from about 2 to 5 liters of urine. Homocysteine patients the typical profile of urine: white, turbidity of Special Taste, Taste This may be due to amino acids from urine.
Biological symptoms and proximal tubular reabsorption defect-related functions, which led to serious water and electrolyte imbalance, or even life-threatening. Fever often happened, the reason might be from dehydration. Will happen cases were smaller stones, stones and urine mainly to exclude excessive urate, calcium, and organic acids relevant. Suffering from disease homocysteine white children will show golden hair and tan skin is more difficult.
Cysteine deficiency violations of the most important parts are the eyes, photophobia are just beginning, usually 2 ~ 3 years old at the time there will be more or less the symptoms of photophobia, ophthalmology sub-beam and optical microscopy can be seen cystine crystals storage, while the merger retinopathy fundus abnormalities.
Stage renal failure (ESRF)
Symptoms of end stage renal failure are serious adverse renal growth Glomerular filtration rate decreased, while the kidney in 6 ~ 12 years old when renal failure. With cysteamine (cystiamine) treatment can delay the occurrence of renal failure, if that is born within one month after the beginning the effect of better treatment, but also help to improve growth rate. This kind of therapy in glomerular filtration rate of renal failure to reduce the process, may also increase the excretion of urine increased and Fanconi's syndrome improvement. Renal failure at the end of the period will be the development of serious renal hypertension, the patient may also be in hemodialysis, the phenomenon of recurring nosebleeds. After kidney transplant, even if the cystine crystals are deposited on the graft-on, you would not have Fanconi's syndrome, post-transplant patients are many symptoms of renal tubular function from exclusion.
Late symptoms
With renal replacement therapy and transplantation of organs other than the kidney was found to continue for storage homocysteine, so apart from violations of kidney cysteine know but also violations of the eyes, thyroid, liver, spleen, pancreas, muscles and central nervous system.
Advanced eye complications
The severity of eye complications varies from person to person, the cornea gradually sediment storage in all the patient's corneal stroma and iris stroma and the former crystal surface, in addition there is also some people retinal sediment storage. Photophobia, tears, and the eyelids may lead to varus visual impairment, these symptoms may be due to corneal erosion of the epidermal cells and eventually lead to keratopathy. Kidney transplant can be improved photophobia. Vision will gradually subside, some young eyes that happened symptoms sick even blindness.
Endocrine disorders
Low endocrine disorders including thyroid, pituitary gonadal function and insulin secretion disorders.
1. Low Thyroid Function: Thyroid function abnormalities are usually at the age of 8 ~ 12 happened, but some people even after the age of 20 will not be Low thyroid function, clinical presentation was not obvious at this time, so in a systematic examination of thyroid function, Low thyroid function may also be caused partly due to growth retardation.
2. Pituitary gonadal function: a cysteine in the male patients are often low plasma testosterone and high follicle-stimulating Fibroin / luteinising hormone (FSH / LH), they may be the development of secondary sexual characteristics have been hampered . Gonadal function of women appears to be normal.
3. Endocrine pancreas: Some cysteine deficiency in kidney transplant patients after the merger of high blood sugar after surgery and permanent insulin-dependent diabetes mellitus.
First, biochemical principle
Homocysteine disease is a lysosomal storage disease, due to cystathionine amine can not be carried through the lysosomal membrane, so the accumulation of homocysteine in the lysosomal caused a lot of organ dysfunction of cells, the kidneys are the most serious damage. Can be divided into three types: 1. Nephropathogenic type (or child-type); 2. Between type (or juvenile onset); 3. Benign type (or adult). One of nephropathy in type (child type) are the most common type.
Metabolic disorders --
Caused by the cysteine lysosomal storage in the kidneys, bone marrow, conjunctiva, thyroid, muscle, choroid plexus, brain mass, and lymph nodes of the main causes are still unknown, most of the enzymes break down homocysteine defect or not the conclusions of the study. However, and normal lysosomal cysteine of comparison can still be seen in the lysosomal cystine out of the ability of lysosomal markedly reduced. This anomaly may be responsible for carrying conveyor homocysteine through the lysosomal membrane protein atoms on the defect. Why is homocysteine storage will lead to loss of function of cells is still no reason to answer, but recent in vitro (in vitro) experiments pointed out that the proximal renal tubular cell storage will cause homocysteine three phosphoric acid adenosine (ATP) of缺乏.
Second, genetic mechanisms and genetic model
Degenerative kidney disease for homocysteine autosomal recessive genetic disease, juvenile and adult-type is the same genetic model.
Third, diagnostic methods
Homocysteine diagnosis can check the white blood cells to establish the concentration of free cysteine, the merger of homocysteine neuropathy patients white blood cells of normal homocysteine concentration is about 50 ~ 100 times. Combination of technical inspection of the use of protein polymorphonuclear white blood cells cystine concentrations are very sensitive, or even can detect homozygous gene varies from those with (heterozygous carriers). Such inspection techniques can also be used for fibrous tissue, conjunctiva organizations, and muscle and other cells, so in the first three months of pregnancy from skin, amniotic fluid cells or chorionic cultivated fibrous disease of the middle class to provide homocysteine pre-genetic diagnosis.
Four, clinical characterization of
Child care type cysteine deficiency
The first phase
After birth, usually at 3 to 6 months are asymptomatic, while in one-year-old will appear before the clinical symptoms. These symptoms include: anorexia, vomiting, polyuria, and not dependent. If you do not timely diagnosed, there is no vitamin D, at 18 months will be presented rickets. At the same time, if the urinary glucose and protein, that is, whether the patient is suspected to be suffering from disease homocysteine. When symptoms arise, usually in the first visit will be entirely performance Fanconi's syndrome (Franconi's syndrome) symptoms. Symptoms of this syndrome include: urine sugar normal blood sugar values (normoglycemic glycosuria), amino acids in urine (generalized aminoaciduria), there is β2-microglobulin protein and lysosome substantial tubular secretion of urine protein (tubular proteinuria), combined with low phosphate salt of phosphoric acid in urine hyperlipidemia (phosphaturia with hypophosphatemia), and due to substantial loss of potassium and sodium carbonate caused severe hypokalemia, hyponatremia, and acidosis. Often merging many high calcium in urine and blood urea is too small. Botulinum salty (Carnitine) loss resulting from renal tubular botulinum salty (Carnitine) insufficient, and at the same time can be seriously complicated by abnormal urine concentrated urine caused by many, every day from about 2 to 5 liters of urine. Homocysteine patients the typical profile of urine: white, turbidity of Special Taste, Taste This may be due to amino acids from urine.
Biological symptoms and proximal tubular reabsorption defect-related functions, which led to serious water and electrolyte imbalance, or even life-threatening. Fever often happened, the reason might be from dehydration. Will happen cases were smaller stones, stones and urine mainly to exclude excessive urate, calcium, and organic acids relevant. Suffering from disease homocysteine white children will show golden hair and tan skin is more difficult.
Cysteine deficiency violations of the most important parts are the eyes, photophobia are just beginning, usually 2 ~ 3 years old at the time there will be more or less the symptoms of photophobia, ophthalmology sub-beam and optical microscopy can be seen cystine crystals storage, while the merger retinopathy fundus abnormalities.
Stage renal failure (ESRF)
Symptoms of end stage renal failure are serious adverse renal growth Glomerular filtration rate decreased, while the kidney in 6 ~ 12 years old when renal failure. With cysteamine (cystiamine) treatment can delay the occurrence of renal failure, if that is born within one month after the beginning the effect of better treatment, but also help to improve growth rate. This kind of therapy in glomerular filtration rate of renal failure to reduce the process, may also increase the excretion of urine increased and Fanconi's syndrome improvement. Renal failure at the end of the period will be the development of serious renal hypertension, the patient may also be in hemodialysis, the phenomenon of recurring nosebleeds. After kidney transplant, even if the cystine crystals are deposited on the graft-on, you would not have Fanconi's syndrome, post-transplant patients are many symptoms of renal tubular function from exclusion.
Late symptoms
With renal replacement therapy and transplantation of organs other than the kidney was found to continue for storage homocysteine, so apart from violations of kidney cysteine know but also violations of the eyes, thyroid, liver, spleen, pancreas, muscles and central nervous system.
Advanced eye complications
The severity of eye complications varies from person to person, the cornea gradually sediment storage in all the patient's corneal stroma and iris stroma and the former crystal surface, in addition there is also some people retinal sediment storage. Photophobia, tears, and the eyelids may lead to varus visual impairment, these symptoms may be due to corneal erosion of the epidermal cells and eventually lead to keratopathy. Kidney transplant can be improved photophobia. Vision will gradually subside, some young eyes that happened symptoms sick even blindness.
Endocrine disorders
Low endocrine disorders including thyroid, pituitary gonadal function and insulin secretion disorders.
1. Low Thyroid Function: Thyroid function abnormalities are usually at the age of 8 ~ 12 happened, but some people even after the age of 20 will not be Low thyroid function, clinical presentation was not obvious at this time, so in a systematic examination of thyroid function, Low thyroid function may also be caused partly due to growth retardation.
2. Pituitary gonadal function: a cysteine in the male patients are often low plasma testosterone and high follicle-stimulating Fibroin / luteinising hormone (FSH / LH), they may be the development of secondary sexual characteristics have been hampered . Gonadal function of women appears to be normal.
3. Endocrine pancreas: Some cysteine deficiency in kidney transplant patients after the merger of high blood sugar after surgery and permanent insulin-dependent diabetes mellitus.
Cystinosis
Homocysteine disease is a lysosomal storage disease, due to cystathionine amine can not be carried through the lysosomal membrane, so the accumulation of homocysteine in the lysosomal caused a lot of organ dysfunction of cells, the kidneys are the most serious damage. Can be divided into three types: 1. Nephropathogenic type (or child-type); 2. Between type (or juvenile onset); 3. Benign type (or adult). One of nephropathy in type (child type) are the most common type.
Metabolic disorders, resulting in the lysosomal cystine storage in the kidneys, bone marrow, conjunctiva, thyroid, muscle, choroid plexus, brain mass, and lymph nodes of the main causes are still unknown, most of the enzymes break down homocysteine Study defect or there is no conclusion. However, and normal lysosomal cysteine of comparison can still be seen in the lysosomal cystine out of the ability of lysosomal markedly reduced. This anomaly may be responsible for carrying conveyor homocysteine through the lysosomal membrane protein atoms on the defect. Why is homocysteine storage will lead to loss of function of cells is still no reason to answer, but recent in vitro (in vitro) experiments pointed out that the proximal renal tubular cell storage will cause homocysteine three phosphoric acid adenosine (ATP) of lack.
Biochemical principles of
Low Thyroid Function: Thyroid function abnormalities are usually at the age of 8 ~ 12 happened, but some people even after the age of 20 will not be Low thyroid function, clinical presentation was not obvious at this time, so in a systematic examination of thyroid function, thyroid function Low may also be caused partly due to growth retardation.
Pituitary gonadal function: a cysteine in the male patients are often low plasma testosterone and high follicle-stimulating Fibroin / luteinising hormone (FSH / LH), they may be the development of secondary sexual characteristics of being obstructed. Gonadal function of women appears to be normal.
Endocrine pancreas: Some cysteine deficiency in kidney transplant patients after the merger of high blood sugar after surgery and permanent insulin-dependent diabetes mellitus.
Genetic model:
Degenerative kidney disease for homocysteine autosomal recessive genetic disease, juvenile and adult-type is the same genetic model.
Diagnostic methods:
Homocysteine diagnosis can check the white blood cells to establish the concentration of free cysteine, the merger of homocysteine neuropathy patients white blood cells of normal homocysteine concentration is about 50 ~ 100 times. Combination of technical inspection of the use of protein polymorphonuclear white blood cells cystine concentrations are very sensitive, or even can detect homozygous gene varies from those with (heterozygous carriers). Such inspection techniques can also be used for fibrous tissue, conjunctiva organizations, and muscle and other cells, so in the first three months of pregnancy from skin, amniotic fluid cells or chorionic cultivated fibrous disease of the middle class to provide homocysteine pre-genetic diagnosis.
Clinical presentation:
* Damage to the liver and spleen
There is one-third to one-half of patients at 15-year-old will hepatosplenomegaly, liver enlargement because cystine crystals are to enter the library's cell (Kupffer's cells), making this cell, a bubble-like cells (foam cells) . This swelling may cause portal hypertension, due to the esophagus, gastric variceal bleeding. Splenomegaly and spleen red pulp is also the generation of foam cells, and from the spleen of hematology hyperthyroidism symptoms diagnosed.
* Muscle
Has been reported that certain patients comprehensiveness limbs have the phenomenon of muscle atrophy, especially in inter-muscular bones (interossei muscles) and muscles (muscles of the thenar eminence) of the shrinkage of the most serious.
* Central nervous system
Homocysteine patients a variety of neurological complications have been reported, cramps may occur at any age, but it is difficult to differentiate because homocysteine are disease or uremia, electrolyte imbalance, or drug toxicity caused by nerve complications. Have recently reported that there is case there will be a result of visual impairment and visual memory deficits and to lower cognitive ability. More serious symptoms of central nervous system injury, these symptoms include low muscle tension, difficulty swallowing and speaking difficult, both sides of the pyramidal symptoms, difficulty in walking, brain symptoms, and progressive intellectual decline. Some patients will be complicated by acute ischemic period hemiplegia or aphasia. Brain lesions such homocysteine only in incidence over the age of 19 and still can not know the incidence of it. Semi-acid (cysteamine) treatment can be effective in preventing violations of the central nervous system is also unknown, but indeed in some cases a result of taking semi-acid to improve the central nervous system symptoms. Homocysteine cases of brain CT scan will show a variety of unusual extent, usually at 15 ~ 20-year-old could be a total shock through magnetic resonance imaging examination revealed brain atrophy, calcification, white matter abnormalities and so on.
Child care type cysteine deficiency
* The first phase
After birth, usually at 3 to 6 months are asymptomatic, while in one-year-old will appear before the clinical symptoms. These symptoms include: anorexia, vomiting, polyuria, and not dependent. If you do not timely diagnosed, there is no vitamin D, at 18 months will be presented rickets. At the same time, if the urinary glucose and protein, that is, whether the patient is suspected to be suffering from disease homocysteine. When symptoms arise, usually in the first visit will be entirely performance Fanconi's syndrome (Franconi's syndrome) symptoms. Symptoms of this syndrome include: urine sugar normal blood sugar values (normoglycemic glycosuria), amino acids in urine (generalized aminoaciduria), there is β2-microglobulin protein and soluble? Substantial body of tubular secretion of urine protein (tubular proteinuria), combined with low phosphate salt of phosphoric acid in urine hyperlipidemia (phosphaturia with hypophosphatemia), and due to substantial loss of potassium and sodium carbonate caused severe hypokalemia, hyponatremia, and acidosis. Often merging many high calcium in urine and blood urea is too small. Botulinum salty (Carnitine) loss resulting from renal tubular botulinum salty (Carnitine) insufficient, and at the same time can be seriously complicated by abnormal urine concentrated urine caused by many, every day from about 2 to 5 liters of urine. Homocysteine patients the typical profile of urine: white, turbidity of Special Taste, Taste This may be due to amino acids from urine.
Biological symptoms and proximal tubular reabsorption defect-related functions, which led to serious water and electrolyte imbalance, or even life-threatening. Fever often happened, the reason might be from dehydration. Will happen cases were smaller stones, stones and urine mainly to exclude excessive urate, calcium, and organic acids relevant. Suffering from disease homocysteine white children will show golden hair and tan skin is more difficult.
Cysteine deficiency violations of the most important parts are the eyes, photophobia are just beginning, usually 2 ~ 3 years old at the time there will be more or less the symptoms of photophobia, ophthalmology sub-beam and optical microscopy can be seen cystine crystals storage, while the merger retinopathy fundus abnormalities.
* Stage renal failure (ESRF)
Symptoms of end stage renal failure are serious adverse renal growth Glomerular filtration rate decreased, while the kidney in 6 ~ 12 years old when renal failure. With cysteamine (cystiamine) treatment can delay the occurrence of renal failure, if that is born within one month after the beginning the effect of better treatment, but also help to improve growth rate. This kind of therapy in glomerular filtration rate of renal failure to reduce the process, may also increase the excretion of urine increased and Fanconi's syndrome improvement. Renal failure at the end of the period will be the development of serious renal hypertension, the patient may also be in hemodialysis, the phenomenon of recurring nosebleeds. After kidney transplant, even if the cystine crystals are deposited on the graft-on, you would not have Fanconi's syndrome, post-transplant patients are many symptoms of renal tubular function from exclusion.
* Late symptoms
With renal replacement therapy and transplantation of organs other than the kidney was found to continue for storage homocysteine, so apart from violations of kidney cysteine know but also violations of the eyes, thyroid, liver, spleen, pancreas, muscles and central nervous system.
* Advanced eye complications
The severity of eye complications varies from person to person, the cornea gradually sediment storage in all the patient's corneal stroma and iris stroma and the former crystal surface, in addition there is also some people retinal sediment storage. Photophobia, tears, and the eyelids may lead to varus visual impairment, these symptoms may be due to corneal erosion of the epidermal cells and eventually lead to keratopathy. Kidney transplant can be improved photophobia. Vision will gradually subside, some young eyes that happened symptoms sick even blindness.
* Endocrine disorders
Low endocrine disorders including thyroid, pituitary gonadal function and insulin secretion disorders.
Cysteine-type disease of young people
Cysteine-type disease of young people are relatively minor symptoms of one type, in the clinical symptoms and end stage renal failure (ESRF) have happened later, usually at 6-8 years of age when first symptoms appear. Protein in urine are sometimes mistaken for the normal range of renal function, and Fanconi's syndrome will be relatively minor symptoms and loss of tubular material will be more infantile disorder of homocysteine minor, other symptoms are also relatively minor. Most of this type of sick at the age of 15 only after the development of terminal renal failure (ESRF). Youth-based diagnosis method of homocysteine may be to check white blood cell concentration of homocysteine to establish.
Adult homocysteine benign disease
Adult homocysteine or benign disease first reported in 1957 are made by Cogan, this autosomal recessive genetic disease characterized by eye and bone marrow have homocysteine on the crystal, the crystals on the cornea is usually Random been checked that the homocysteine concentration of white blood cells are between homozygous (homozygotes) degenerative kidney disease and different homozygous homocysteine (heterozygotes) nephropathy between homocysteine disease.
Treatment and prognosis:
Neuropathy of homocysteine on the treatment of disease should include the symptoms and special treatment, symptoms of the main objectives of treatment are added Fanconi's syndrome of renal tubular loss of material, including the following treatment:
* Water: eating part must be based on the amount of urine, weight change and changes in plasma protein concentration to do adjust, if a fever will increase the liquid supplement and mineral supplement.
* Medium and pH: heavy weight potassium carbonate or sodium carbonate and citric acid must be given in order to make plasma bicarbonate concentrations maintained at 21-24 mmol / l, but in general in order to maintain such a concentration very difficult.
* Sodium: sometimes even reach base and still can not make up for the loss of sodium, hyponatremia may also cause long-term growth in patients with adverse phenomenon.
* Potassium: hypokalemia potassium supplement doses were necessary so that the concentration of serum potassium to maintain greater than 3 mmol / l. per kilogram of body weight can be added 4-10 mmol achieve this, some cases take 2-5 mg per day of stay sodium potassium row of diuretics (amiloride) and effective.
* P: blood phosphate is too small to be every day 0.5-2 grams of sodium or potassium phosphate to complement the objective can be added to the plasma phosphorus concentration can be greater than 1.0-1.2mmol / l, such a supplement may be necessary continuous months or years in order to stop.
* Calcium and magnesium: added the loss of these two substances to avoid when taking phosphate, calcium gluconate (calcium glucanate) and heavy calcium carbonate (calcium carbonate) are two commonly used drugs to supplement calcium, and magnesium supplement drug compared with magnesium salts (magnesium chloride).
* Vitamin D supplement :25-OHD3 drain water from urine can be 10-25μg every day to make up for that with the disease symptoms, added every day 0.10-0.50μg of 1α-OHD or 1α25-OHD can make up for every day of the loss, especially to improve the symptoms of rickets very effective. Added when these drugs need to make regular checks of serum calcium concentration.
* Carnitine supplement every day, supplementary carnitine per kg body weight the amount of 100 mg taken four times, has reportedly confirmed that the improvement of the lack of effective muscle carnitine.
Because of the loss of material is a long-term problem so add these substances must be regularly using it, there is a good method is to have to add more than the material apart from other than calcium, on a bottle of water, put it as an open water to drink. Calcium and magnesium, and meals are taken together. Every day to take indomethacin per kg body weight using 1.5-3mg, the second sub-served, but also can effectively improve the water, the loss of potassium and sodium. When the progressive deterioration of kidney and renal glomerular filtration rate decreased, the tubular will also reduce wastage, when all of the supplementary material also have to gradually reduce, we will not be added cause excessive, especially sodium and potassium overdose . At hemodialysis period, minerals do not have to add.
* The treatment of kidney transplant
Homocysteine disorder children do not have to kidney transplants, dialysis or peritoneal dialysis (CAPD / CCPD) are very effective method, but if the child has reached the kidney failure (ESRF) have to view only kidney transplant. At the European Association of dialysis and kidney transplantation in children log data showed that homocysteine disorders of children who have received kidney transplants after more than children of primary kidney disease kidney transplant after getting even better.
* Outside the complications of renal symptoms treatment
Low thyroid function can be used to treat L-thyroxine, even asymptomatic thyroid Low functional and effective. Kidney degeneration growth retardation are the most serious disease homocysteine complications, has reported that the use of per kilogram of body weight every day 1U (1U/kg) of growth hormone can improve symptoms. Portal hypertension will lead to ascites and esophageal variceal bleeding control, have to rely on the portal vein bypass surgery to improve. Expansion of the combined long-term spleen leukopenia or thrombocytopenia when necessary to the purposes of splenectomy. Ophthalmic treatment with artificial tears, partial lubricants, as well as ultra-thin soft contact lenses can improve the local eye symptoms, the report has pointed out that the use of 0.5% cysteine (cysteamine) in the cornea of the eye drops can prevent and reduce sediment pre-existing sediments, and the effectiveness of corneal transplantation is not the same.
* Special treatment
There is a lot of special for inhibiting lysosomal storage cystathionine amidocyanogen treatment was tried, sulfur amino acid diet restrictions are invalid, ascorbic acid (ascorbic acid) in vitro tests can be reduced homocysteine storage plot, but are not up in the clinical effect, they can lead to more serious kidney damage, Dithiotreital also invalid, only one type of drug known as cysteine (cysteamine) in a number of studies showing a good improvement. However, cysteine also has some problems, because homocysteine bad smell and taste, may also result in the patient has bad breath odor, generally phosphorus homocysteine smell better (and its cysteine the effect is the same).
Homocysteine is an orphan drug, the general hospital's Pharmacy Department is also very difficult to supply such drugs, drug ingredients for chloride cysteine (cysteamine chlorhydrate), capsules and there is water-soluble powder formulations of two, dose per kilogram of body weight from the every day gradually increased to 10mg per kilogram of body weight 50mg. Homocysteine can be quickly absorbed, taking 1-2 hours after the white blood cells could be detected within the amino acid cysteine concentrations to assess its biggest effect, the general efficacy of sustainable 5-8 hours, so need to take 3 -4 times in order to achieve effective prevention of storage homocysteine.
Careful monitoring of polymorphonuclear leukocytes in the homocysteine concentration is necessary because patients on the reaction of homocysteine are different. Determination of homocysteine concentration of white blood cells in the best time at the next to take the drug before the cysteine, homocysteine concentrations would like to maintain at each mg of protein containing 1.5-2μmol (1.5-2μmol/mg protein) under. 1 However, the diagnosis was identified, treatment should begin as soon as possible. Because of homocysteine in the prevention of kidney disease has good results, but it also applies to patients have complications happen.
Metabolic disorders, resulting in the lysosomal cystine storage in the kidneys, bone marrow, conjunctiva, thyroid, muscle, choroid plexus, brain mass, and lymph nodes of the main causes are still unknown, most of the enzymes break down homocysteine Study defect or there is no conclusion. However, and normal lysosomal cysteine of comparison can still be seen in the lysosomal cystine out of the ability of lysosomal markedly reduced. This anomaly may be responsible for carrying conveyor homocysteine through the lysosomal membrane protein atoms on the defect. Why is homocysteine storage will lead to loss of function of cells is still no reason to answer, but recent in vitro (in vitro) experiments pointed out that the proximal renal tubular cell storage will cause homocysteine three phosphoric acid adenosine (ATP) of lack.
Biochemical principles of
Low Thyroid Function: Thyroid function abnormalities are usually at the age of 8 ~ 12 happened, but some people even after the age of 20 will not be Low thyroid function, clinical presentation was not obvious at this time, so in a systematic examination of thyroid function, thyroid function Low may also be caused partly due to growth retardation.
Pituitary gonadal function: a cysteine in the male patients are often low plasma testosterone and high follicle-stimulating Fibroin / luteinising hormone (FSH / LH), they may be the development of secondary sexual characteristics of being obstructed. Gonadal function of women appears to be normal.
Endocrine pancreas: Some cysteine deficiency in kidney transplant patients after the merger of high blood sugar after surgery and permanent insulin-dependent diabetes mellitus.
Genetic model:
Degenerative kidney disease for homocysteine autosomal recessive genetic disease, juvenile and adult-type is the same genetic model.
Diagnostic methods:
Homocysteine diagnosis can check the white blood cells to establish the concentration of free cysteine, the merger of homocysteine neuropathy patients white blood cells of normal homocysteine concentration is about 50 ~ 100 times. Combination of technical inspection of the use of protein polymorphonuclear white blood cells cystine concentrations are very sensitive, or even can detect homozygous gene varies from those with (heterozygous carriers). Such inspection techniques can also be used for fibrous tissue, conjunctiva organizations, and muscle and other cells, so in the first three months of pregnancy from skin, amniotic fluid cells or chorionic cultivated fibrous disease of the middle class to provide homocysteine pre-genetic diagnosis.
Clinical presentation:
* Damage to the liver and spleen
There is one-third to one-half of patients at 15-year-old will hepatosplenomegaly, liver enlargement because cystine crystals are to enter the library's cell (Kupffer's cells), making this cell, a bubble-like cells (foam cells) . This swelling may cause portal hypertension, due to the esophagus, gastric variceal bleeding. Splenomegaly and spleen red pulp is also the generation of foam cells, and from the spleen of hematology hyperthyroidism symptoms diagnosed.
* Muscle
Has been reported that certain patients comprehensiveness limbs have the phenomenon of muscle atrophy, especially in inter-muscular bones (interossei muscles) and muscles (muscles of the thenar eminence) of the shrinkage of the most serious.
* Central nervous system
Homocysteine patients a variety of neurological complications have been reported, cramps may occur at any age, but it is difficult to differentiate because homocysteine are disease or uremia, electrolyte imbalance, or drug toxicity caused by nerve complications. Have recently reported that there is case there will be a result of visual impairment and visual memory deficits and to lower cognitive ability. More serious symptoms of central nervous system injury, these symptoms include low muscle tension, difficulty swallowing and speaking difficult, both sides of the pyramidal symptoms, difficulty in walking, brain symptoms, and progressive intellectual decline. Some patients will be complicated by acute ischemic period hemiplegia or aphasia. Brain lesions such homocysteine only in incidence over the age of 19 and still can not know the incidence of it. Semi-acid (cysteamine) treatment can be effective in preventing violations of the central nervous system is also unknown, but indeed in some cases a result of taking semi-acid to improve the central nervous system symptoms. Homocysteine cases of brain CT scan will show a variety of unusual extent, usually at 15 ~ 20-year-old could be a total shock through magnetic resonance imaging examination revealed brain atrophy, calcification, white matter abnormalities and so on.
Child care type cysteine deficiency
* The first phase
After birth, usually at 3 to 6 months are asymptomatic, while in one-year-old will appear before the clinical symptoms. These symptoms include: anorexia, vomiting, polyuria, and not dependent. If you do not timely diagnosed, there is no vitamin D, at 18 months will be presented rickets. At the same time, if the urinary glucose and protein, that is, whether the patient is suspected to be suffering from disease homocysteine. When symptoms arise, usually in the first visit will be entirely performance Fanconi's syndrome (Franconi's syndrome) symptoms. Symptoms of this syndrome include: urine sugar normal blood sugar values (normoglycemic glycosuria), amino acids in urine (generalized aminoaciduria), there is β2-microglobulin protein and soluble? Substantial body of tubular secretion of urine protein (tubular proteinuria), combined with low phosphate salt of phosphoric acid in urine hyperlipidemia (phosphaturia with hypophosphatemia), and due to substantial loss of potassium and sodium carbonate caused severe hypokalemia, hyponatremia, and acidosis. Often merging many high calcium in urine and blood urea is too small. Botulinum salty (Carnitine) loss resulting from renal tubular botulinum salty (Carnitine) insufficient, and at the same time can be seriously complicated by abnormal urine concentrated urine caused by many, every day from about 2 to 5 liters of urine. Homocysteine patients the typical profile of urine: white, turbidity of Special Taste, Taste This may be due to amino acids from urine.
Biological symptoms and proximal tubular reabsorption defect-related functions, which led to serious water and electrolyte imbalance, or even life-threatening. Fever often happened, the reason might be from dehydration. Will happen cases were smaller stones, stones and urine mainly to exclude excessive urate, calcium, and organic acids relevant. Suffering from disease homocysteine white children will show golden hair and tan skin is more difficult.
Cysteine deficiency violations of the most important parts are the eyes, photophobia are just beginning, usually 2 ~ 3 years old at the time there will be more or less the symptoms of photophobia, ophthalmology sub-beam and optical microscopy can be seen cystine crystals storage, while the merger retinopathy fundus abnormalities.
* Stage renal failure (ESRF)
Symptoms of end stage renal failure are serious adverse renal growth Glomerular filtration rate decreased, while the kidney in 6 ~ 12 years old when renal failure. With cysteamine (cystiamine) treatment can delay the occurrence of renal failure, if that is born within one month after the beginning the effect of better treatment, but also help to improve growth rate. This kind of therapy in glomerular filtration rate of renal failure to reduce the process, may also increase the excretion of urine increased and Fanconi's syndrome improvement. Renal failure at the end of the period will be the development of serious renal hypertension, the patient may also be in hemodialysis, the phenomenon of recurring nosebleeds. After kidney transplant, even if the cystine crystals are deposited on the graft-on, you would not have Fanconi's syndrome, post-transplant patients are many symptoms of renal tubular function from exclusion.
* Late symptoms
With renal replacement therapy and transplantation of organs other than the kidney was found to continue for storage homocysteine, so apart from violations of kidney cysteine know but also violations of the eyes, thyroid, liver, spleen, pancreas, muscles and central nervous system.
* Advanced eye complications
The severity of eye complications varies from person to person, the cornea gradually sediment storage in all the patient's corneal stroma and iris stroma and the former crystal surface, in addition there is also some people retinal sediment storage. Photophobia, tears, and the eyelids may lead to varus visual impairment, these symptoms may be due to corneal erosion of the epidermal cells and eventually lead to keratopathy. Kidney transplant can be improved photophobia. Vision will gradually subside, some young eyes that happened symptoms sick even blindness.
* Endocrine disorders
Low endocrine disorders including thyroid, pituitary gonadal function and insulin secretion disorders.
Cysteine-type disease of young people
Cysteine-type disease of young people are relatively minor symptoms of one type, in the clinical symptoms and end stage renal failure (ESRF) have happened later, usually at 6-8 years of age when first symptoms appear. Protein in urine are sometimes mistaken for the normal range of renal function, and Fanconi's syndrome will be relatively minor symptoms and loss of tubular material will be more infantile disorder of homocysteine minor, other symptoms are also relatively minor. Most of this type of sick at the age of 15 only after the development of terminal renal failure (ESRF). Youth-based diagnosis method of homocysteine may be to check white blood cell concentration of homocysteine to establish.
Adult homocysteine benign disease
Adult homocysteine or benign disease first reported in 1957 are made by Cogan, this autosomal recessive genetic disease characterized by eye and bone marrow have homocysteine on the crystal, the crystals on the cornea is usually Random been checked that the homocysteine concentration of white blood cells are between homozygous (homozygotes) degenerative kidney disease and different homozygous homocysteine (heterozygotes) nephropathy between homocysteine disease.
Treatment and prognosis:
Neuropathy of homocysteine on the treatment of disease should include the symptoms and special treatment, symptoms of the main objectives of treatment are added Fanconi's syndrome of renal tubular loss of material, including the following treatment:
* Water: eating part must be based on the amount of urine, weight change and changes in plasma protein concentration to do adjust, if a fever will increase the liquid supplement and mineral supplement.
* Medium and pH: heavy weight potassium carbonate or sodium carbonate and citric acid must be given in order to make plasma bicarbonate concentrations maintained at 21-24 mmol / l, but in general in order to maintain such a concentration very difficult.
* Sodium: sometimes even reach base and still can not make up for the loss of sodium, hyponatremia may also cause long-term growth in patients with adverse phenomenon.
* Potassium: hypokalemia potassium supplement doses were necessary so that the concentration of serum potassium to maintain greater than 3 mmol / l. per kilogram of body weight can be added 4-10 mmol achieve this, some cases take 2-5 mg per day of stay sodium potassium row of diuretics (amiloride) and effective.
* P: blood phosphate is too small to be every day 0.5-2 grams of sodium or potassium phosphate to complement the objective can be added to the plasma phosphorus concentration can be greater than 1.0-1.2mmol / l, such a supplement may be necessary continuous months or years in order to stop.
* Calcium and magnesium: added the loss of these two substances to avoid when taking phosphate, calcium gluconate (calcium glucanate) and heavy calcium carbonate (calcium carbonate) are two commonly used drugs to supplement calcium, and magnesium supplement drug compared with magnesium salts (magnesium chloride).
* Vitamin D supplement :25-OHD3 drain water from urine can be 10-25μg every day to make up for that with the disease symptoms, added every day 0.10-0.50μg of 1α-OHD or 1α25-OHD can make up for every day of the loss, especially to improve the symptoms of rickets very effective. Added when these drugs need to make regular checks of serum calcium concentration.
* Carnitine supplement every day, supplementary carnitine per kg body weight the amount of 100 mg taken four times, has reportedly confirmed that the improvement of the lack of effective muscle carnitine.
Because of the loss of material is a long-term problem so add these substances must be regularly using it, there is a good method is to have to add more than the material apart from other than calcium, on a bottle of water, put it as an open water to drink. Calcium and magnesium, and meals are taken together. Every day to take indomethacin per kg body weight using 1.5-3mg, the second sub-served, but also can effectively improve the water, the loss of potassium and sodium. When the progressive deterioration of kidney and renal glomerular filtration rate decreased, the tubular will also reduce wastage, when all of the supplementary material also have to gradually reduce, we will not be added cause excessive, especially sodium and potassium overdose . At hemodialysis period, minerals do not have to add.
* The treatment of kidney transplant
Homocysteine disorder children do not have to kidney transplants, dialysis or peritoneal dialysis (CAPD / CCPD) are very effective method, but if the child has reached the kidney failure (ESRF) have to view only kidney transplant. At the European Association of dialysis and kidney transplantation in children log data showed that homocysteine disorders of children who have received kidney transplants after more than children of primary kidney disease kidney transplant after getting even better.
* Outside the complications of renal symptoms treatment
Low thyroid function can be used to treat L-thyroxine, even asymptomatic thyroid Low functional and effective. Kidney degeneration growth retardation are the most serious disease homocysteine complications, has reported that the use of per kilogram of body weight every day 1U (1U/kg) of growth hormone can improve symptoms. Portal hypertension will lead to ascites and esophageal variceal bleeding control, have to rely on the portal vein bypass surgery to improve. Expansion of the combined long-term spleen leukopenia or thrombocytopenia when necessary to the purposes of splenectomy. Ophthalmic treatment with artificial tears, partial lubricants, as well as ultra-thin soft contact lenses can improve the local eye symptoms, the report has pointed out that the use of 0.5% cysteine (cysteamine) in the cornea of the eye drops can prevent and reduce sediment pre-existing sediments, and the effectiveness of corneal transplantation is not the same.
* Special treatment
There is a lot of special for inhibiting lysosomal storage cystathionine amidocyanogen treatment was tried, sulfur amino acid diet restrictions are invalid, ascorbic acid (ascorbic acid) in vitro tests can be reduced homocysteine storage plot, but are not up in the clinical effect, they can lead to more serious kidney damage, Dithiotreital also invalid, only one type of drug known as cysteine (cysteamine) in a number of studies showing a good improvement. However, cysteine also has some problems, because homocysteine bad smell and taste, may also result in the patient has bad breath odor, generally phosphorus homocysteine smell better (and its cysteine the effect is the same).
Homocysteine is an orphan drug, the general hospital's Pharmacy Department is also very difficult to supply such drugs, drug ingredients for chloride cysteine (cysteamine chlorhydrate), capsules and there is water-soluble powder formulations of two, dose per kilogram of body weight from the every day gradually increased to 10mg per kilogram of body weight 50mg. Homocysteine can be quickly absorbed, taking 1-2 hours after the white blood cells could be detected within the amino acid cysteine concentrations to assess its biggest effect, the general efficacy of sustainable 5-8 hours, so need to take 3 -4 times in order to achieve effective prevention of storage homocysteine.
Careful monitoring of polymorphonuclear leukocytes in the homocysteine concentration is necessary because patients on the reaction of homocysteine are different. Determination of homocysteine concentration of white blood cells in the best time at the next to take the drug before the cysteine, homocysteine concentrations would like to maintain at each mg of protein containing 1.5-2μmol (1.5-2μmol/mg protein) under. 1 However, the diagnosis was identified, treatment should begin as soon as possible. Because of homocysteine in the prevention of kidney disease has good results, but it also applies to patients have complications happen.
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