Cystinosis

Cystine disease is a lysosomal storage disease , resulting from cysteine ​​amino group can not be carried through the lysosomal membrane , so cystine accumulation in the lysosomes of cells caused by dysfunction of many organs , the most serious kidney damaged . Can be divided into three types: 1. Nephropathy type ( or infantile ) ; 2 . Intermediate ( or juvenile -onset ) ; 3 . Benign type ( or adult ) . Among nephropathy type ( infantile ) is the most common type .

Metabolic disorders , resulting in lysosomal cystine piling up in the kidney , bone marrow, conjunctiva , thyroid , muscle, choroid plexus , brain matter , and the main cause is still unknown lymph nodes , the majority on the decomposition of the enzyme defect in homocysteine ​​research or no conclusion . However, and normal comparison can still be seen lysosomal cysteine ​​sexual lysosomal cystine out of the lysosomes was markedly reduced. Such abnormalities may be responsible for carrying through the lysosomal cystine transport membrane protein atomic defects related . Why cystine piling cause cells lose functional reasons there is still no answer , but recently in vitro (in vitro) experiments pointed out that the proximal tubular cell cystine piling will cause three phosphorous acid adenosine (ATP) of lacking.

Biochemical principles
Hypothyroidism : Thyroid dysfunction usually occurs in 8 to 12 years old , but some people even after the age of 20 will not be hypothyroidism , clinical presentation is not obvious at this time , so have a systematic examination of thyroid function , hypothyroidism may also be partly caused by growth retardation .

Pituitary gonadal function : cystine disease in male patients often have low testosterone and high serum follicle stimulating hormone / luteinizing hormone (FSH / LH), they may therefore leaving thwarted the development of secondary sexual characteristics . Female gonadal function seems to be normal .

Endocrine pancreas : Some cystine disease in kidney transplant patients after combined surgery and permanent hyperglycemia with insulin-dependent diabetes mellitus.

Genetic model :
Degeneration of cystine kidney disease is an autosomal recessive genetic disease , juvenile and adult type is the same genetic pattern .

Diagnosis:
The diagnosis cystine inside white blood cells can be checked to establish the concentration of free cysteine ​​, cystine merger neuropathy symptoms of the patient's white blood homocysteine ​​concentration of about 50 to 100 times normal . Protein binding techniques using polymorphonuclear leukocytes check in the concentration of cystine is very sensitive to even heterozygous genes can be detected by a band because (heterozygous carriers). This test technique can also be used fibrous tissue , conjunctival tissue , and muscle and other cells, so in the first three months of pregnancy from the skin, amniotic fluid cells or chorionic the cultured cells with fibrous tissue disease homocysteine ​​production before genetic diagnosis.

Clinical characterization :

* Damage to the liver and spleen
One-third to half of patients 15 years of age will hepatosplenomegaly , liver enlargement because of cystine crystals into Kupffer cells (Kupffer's cells), so that this cell -like cells forming foam (foam cells) . This swelling can cause portal hypertension may cause the esophagus , gastric variceal bleeding . Splenomegaly and splenic red pulp also foam cells generate information can be obtained from spleen hyperparathyroidism diagnosed hematological symptoms .

* Muscle
Some patients have reported that some of the limbs, muscle atrophy comprehensive phenomenon, especially the interosseous muscles (interossei muscles) and thenar muscles (muscles of the thenar eminence) atrophy of the most serious .

* The central nervous system
Patients with various neurological disorders cystine complications have been reported before, cramps may occur at any age , but it is difficult to discern because homocysteine ​​disease or uremia , electrolyte imbalance , or drug toxicity caused by nerve complications . Recently has been reported that there are cases visually impaired and visually impaired memory and due to a lower cognitive abilities. More severe symptoms of central nervous system damage , these symptoms include muscle low tension , difficulty swallowing and speaking difficulties , both sides of the pyramidal symptoms , difficulty walking, brain symptoms, and progressive mental deterioration . Some patients will be complicated by acute ischemia paralyzed or aphasia . Such cystine encephalopathy incidence is only 19 years old but still can not understand its incidence . Semi acid (cysteamine) whether treatment is effective in preventing violations of the central nervous also unknown, but does have some cases to improve the result of taking half- lysine central nervous symptoms. Cystine disease cases CT scan of the brain will show a variety of different degree of abnormality , usually in the 15 to 20 years of age through nuclear magnetic resonance examination revealed cerebral atrophy, calcification, white matter abnormalities and so on.

Infantile disorder cystine

* Phase
After birth usually 3 to 6 months are asymptomatic , but in an age before clinical symptoms appear . These symptoms include: anorexia , vomiting , polyuria, and raising small. If not promptly diagnosed , there is no vitamin D, at 18 months old will show rickets . If urine glucose and protein also found that the need to wonder whether the patient is suffering from cystine disease. When the symptoms of the disease appear, usually in the first visit will be completely performance Fanconi syndrome (Franconi's syndrome) symptoms. Symptoms of this syndrome include : normal blood glucose urine (normoglycemic glycosuria), amino acids in urine (generalized aminoaciduria), with β2 microglobulin and solvent ? Tubular secretion in the body in urine protein (tubular proteinuria), combined with low phosphate urinary phosphate hyperlipidemia (phosphaturia with hypophosphatemia), and due to a huge loss of potassium and sodium bicarbonate caused hypokalemia , hyponatremia and acidosis . Also often associated with a lot of calcium in urine and blood urea too little . Botulinum salty (Carnitine) loss from the tubules caused botulinum salty (Carnitine) deficiency , and also may be complicated by serious concentrated urine caused by abnormal urination, can be discharged each day is about 2 to 5 liters of urine. Patient with urinary cystine typical characteristics are: white , cloudy with a special taste , the smell of urine amino acids may be due to come .

Biological symptoms and proximal tubular reabsorption defect , whereas the ground water and electrolyte imbalance can cause serious , even life-threatening . Fever also occurs , which may be due to dehydration from. Cases will occur is less stones , stones and urine mainly exclude excessive urate , calcium, and organic acids related . Cystine disease suffering hair will show white kids golden yellow and tan skin is more difficult .

Violations of homocysteine ​​disorders main part of it is the eyes , the beginning is photophobia , usually in 2 to 3 years of age there will be more or less the symptoms of photophobia , eye and splitting light microscopic examination can be seen cystine crystals piling up , and diabetic retinopathy fundus abnormalities.

* End stage renal failure (ESRF)
Stage renal failure symptoms are severe poor growth and renal glomerular filtration rate decreased, while the kidney at the age of 6 to 12 will be kidney failure. With cysteamine (cystiamine) therapy can delay the occurrence of renal failure , and if within one month after birth that its better to start treatment , but also help to increase growth rate . This treatment in the glomerular filtration rate reduction of renal failure process, but also increase the excretion of urine and Fanconi syndrome improved. During the end stage renal failure , may develop severe renal hypertension, dialysis patients may also be conducting when the phenomenon of recurring nosebleeds . After kidney transplantation , even cystine crystals deposited on the graft , and still not produce Fanconi syndrome, renal transplant patient symptoms are mostly derived from the repulsion .

* Late symptoms
With renal replacement therapy and transplantation organs other than kidneys will continue piling up cystine , cysteine ​​in addition to violations of the kidneys so understanding , we will also violated the eyes , thyroid, liver, spleen , pancreas, muscles and the central nervous system.

* Late eye complications
The severity of complications varies eye , corneal precipitate gradually piling corneal stroma in all patients and iris stroma and the front lens surface , in addition to some of the human retina also piling precipitate. Photophobia , lacrimation , and Entropion may cause visual disturbances , these symptoms may be due to erosion of the cornea tissue cells of the epidermis and ultimately lead to corneal lesions. Kidney transplantation can improve photophobia . Vision will gradually decline, which happened some younger patients with symptoms of eye or even blindness.

* Endocrine disorders
Endocrine disorders , including hypothyroidism , pituitary gonadal function and insulin secretion disorders .

The homocysteine ​​juvenile disease
The homocysteine ​​juvenile disease is a type of relatively minor symptoms , clinical symptoms and end stage renal failure (ESRF) have occurred later , usually at 6-8 years of age before the first symptoms . Sometimes mistaken for urinary protein is a normal range of renal function , and Fanconi symptom clusters of symptoms will be milder and the loss of tubular material will be relatively mild infantile disorder of cystine , other symptoms are also relatively minor . Most of these types of patients 15 years of age will develop end-stage renal failure (ESRF). The homocysteine ​​juvenile disease diagnosis by checking the white blood homocysteine ​​levels to establish .

Adult benign disease homocysteine
Homocysteine ​​adult or benign disease was first reported in 1957 by the Cogan proposed that this autosomal recessive genetic disease characterized by eye and bone marrow on the cystine crystals, the crystals on the cornea is usually randomly check into , the white blood cells is between homocysteine ​​levels homozygotes (homozygotes) cystine kidney disease and degeneration heterozygous (heterozygotes) nephrotic syndrome between homocysteine ​​.

Treatment and Prognosis:
Homocysteine ​​neuropathy symptoms on the symptoms and treatment should include special therapies to treat the symptoms of the main objectives is to supplement the Fanconi syndrome in renal loss of substances, including the following treatment :
* Water: eating part must be based on the amount of urine , weight changes and changes in plasma protein concentration to make adjustments , if the fever will have to increase the liquid supplement , and minerals are added .
* PH Neutralization: weight potassium carbonate or sodium bicarbonate and citric acid must be given so that the plasma bicarbonate concentration was maintained at 21-24 mmol / l, but in general to maintain this concentration is very difficult.
* Sodium: sometimes even to acid-base and still can not make up for the loss of sodium , long-term patients with hyponatremia also cause poor growth phenomenon.
* Potassium: hypokalemia need potassium supplementation agent to maintain the serum potassium concentration greater than 3 mmol / l. 4-10 mmol per kilogram of body weight can be added to achieve the above objectives, some cases daily doses of 2-5 mg of potassium- row of sodium diuretics (amiloride) is also effective .
* Phosphorus: hypophosphatemia must 0.5-2 g daily sodium phosphate or potassium phosphate to make up , the goal is to supplement the phosphorus concentration in plasma can be greater than 1.0-1.2mmol / l, with such additions may need to last for months or years to stop .
* Calcium and magnesium : Supplementary loss of these two substances should avoid while taking phosphate , calcium gluconate (calcium glucanate) and heavy calcium carbonate (calcium carbonate) are two drugs commonly used to supplement calcium and magnesium supplement drug is of magnesium chloride salt (magnesium chloride).
* Vitamin D supplementation :25-OHD3 water loss from the urine , 10-25μg a day to make up , with the symptoms of the disease , a daily supplement of 0.10-0.50μg of 1α-OHD or 1α25-OHD can compensate for the loss of a day , especially is to improve the symptoms of rickets is very effective . Supplement these drugs must be checked regularly when the calcium concentration in the serum .
* Daily supplement carnitine , carnitine supplement per kilogram of body weight of 100 mg taken four times the amount , has proven to improve muscle carnitine at the lack of effective .

The substance is a long-term problem of the loss of these substances therefore must be regularly taking a supplement , there is a good way to supplement the above subject matter exception of calcium on a bottle of water and drink it as open . Calcium and magnesium , and meals are taken together . Every day taking indomethacin per kg of body weight taking 1.5-3mg, finished second service , but also can effectively improve the water , potassium and sodium are lost. When the kidneys gradually deteriorating renal glomerular filtration rate was gradually reduced, tubular loss will be reduced, then all of the supplementary material should also be gradually reducing the amount , it will not cause excessive supplement , especially sodium and potassium overdose . In hemodialysis period , minerals do not have to add it.

* Treatment of kidney transplant
Cystine syndrome children do not need a kidney transplant , dialysis or peritoneal dialysis (CAPD / CCPD) is a very effective method , but if the child's kidneys to renal failure (ESRF) period when required a kidney transplant. In the European Dialysis and Kidney Transplant Association of Children's login data showed that homocysteine ​​disorders in children have received a kidney transplant prognosis of primary renal disease than children receiving a kidney transplant prognosis even better .

* Outside the kidney to treat the symptoms of complications
Hypothyroidism low availability L-thyroxine to treat the symptoms of hypothyroidism even lower are also effective. Growth failure is the most serious disease cystine kidney degeneration of complications has been reported that daily use per kilogram of body weight 1U (1U/kg) growth hormone can improve symptoms . Portal hypertension can cause ascites and esophageal varices bleed tube , to rely on the portal vein bypass surgery to improve . Spleen enlarged combined long-term leukopenia or thrombocytopenia is essential purposes of splenectomy . Eye treatment , use artificial tears , topical lubricants, as well as ultra-thin soft contact lenses may improve local symptoms eye , there are reports that containing 0.5% cysteine ​​(cysteamine) eye drops can prevent and minimize corneal precipitates existing sediment, and the effectiveness of corneal transplantation is not the same.

* Special treatment
Many special for inhibiting lysosomal cysteine ​​amino piling of therapy has been tried, sulfur amino acids in the diet restriction is invalid , ascorbic acid (ascorbic acid) in vitro can be reduced homocysteine ​​piling up , but is not effective in clinical kidney damage and even cause more severe , Dithiotreital also does not work, a drug called cysteine ​​(cysteamine) in some studies show a good improvement effect . But there are some problems cysteine ​​, because cysteine ​​taste and bad taste , can also cause the patient breath smells , generally phosphorus cysteine ​​smell better ( and its cysteine the effects are the same ) .

Homocysteine ​​is an orphan drug , general hospital pharmacy department also difficult to supply these drugs , drug ingredients chloride homocysteine ​​(cysteamine chlorhydrate), there are water soluble capsules and powder two formulations , dose from 10mg per day per kilogram of body weight per kg body weight gradually increased to 50mg. Cysteine ​​can be quickly absorbed , taking 1-2 hours after the white blood cells can be detected in the concentration of amino acids cystine , assess its maximum efficacy, general medical sustainable 5-8 hours , it must take 3 -4 times can be effective in preventing cystine are piling up .

Careful monitoring of polymorphonuclear leukocytes in homocysteine ​​levels is necessary because the patient 's response to the cysteine ​​is different. Leukocytes homocysteine ​​concentrations were measured at the next best time to take medication before homocysteine ​​, hoping to maintain concentrations of homocysteine ​​per mg of protein containing 1.5-2μmol (1.5-2μmol/mg protein) below . Once the diagnosis is determined, treatment should begin as soon as possible . Since cysteine ​​in preventing kidney disease have a good effect, but it also applies to patients who have complications occur .