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.