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Case study- Cystinosis
A 2 –year-old child was brought to pediatrics department for consultation. Mother of child reported that the child was born normally; there was no complication during delivery, and her other two children were also normal. The child was not taking feeds properly and was also not growing well.
There was history of increased frequency of urination from the previous few months for which the mother was very much apprehensive. The child avoided going to sun and there was apparent visual impairment.
On general physical examination, the child was found pale, thin and small for his age. There was slight hepatomegaly and he looked slightly dehydrated.
A urine sample was sent for complete analysis. The urine examination revealed presence of excessive amount of phosphates and amino acids. A thorough examination of eye was also done to know the cause of visual impairment. On slit lamp microscopic examination,characteristic crystals were found deposited in the cornea.
What is the possible defect?
What is the biochemical basis for phosphate and aminoacids in urine?
The child is suffering from Cystinosis. Cystinosis is a Lysosomal storage disease characterized by the abnormal accumulation of the amino acid Cystine. Excess cystine forms crystals that can build up and damage cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes. Excessive urination, phosphaturia and aminoaciduria in the given patient are due to renal tubular damage while the visual impairment is due to deposition of cystine crystals in cornea.
Inheritance- Cystinosis is an autosomal recessive genetic disease.
Endogenous 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 aminoacid 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 under the activity of oxidoreductase enzyme.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-lysosomal 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.
Clinical Manifestations- There are three distinct types of cystinosis. In order of decreasing severity, they are –
· Nephropathic Cystinosis (Infantile)
· Intermediate Cystinosis (Juvenile)
· Non-Nephropathicor ocular Cystinosis (Adult)
1) Nephropathic Cystinosis-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.
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’s syndrome. If untreated, renal failure develops by age 7-10 years.
Cystine continues to accumulate in other tissues,resulting in such complications as eye disease (eg, severe photophobia, corneal ulcerations, and retinal blindness), delayed puberty, hypothyroidism,pancreatic disease (eg, exocrine insufficiency, insulin-dependent diabetes mellitus), liver disease, swallowing difficulties, and CNS involvement
2)Intermediate Cystinosis-The signs and symptoms of intermediate cystinosis are the same as Nephropathic Cystinosis, but they occur at a later age.Intermediate cystinosis typically becomes apparent in affected individuals in adolescence. 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.
3) 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.
1) Serum electrolytes measurements are used to detect the presence of acidosis (hyperchloremic, normal anion gap) and severity of hypokalemia,hyponatremia, hypophosphatemia, and low bicarbonate concentration in patients with cystinosis.
2) Blood gases may be used to detect metabolic acidosis and the degree of respiratory compensation.
3) Urine testing reveals low osmolality, glucosuria, and tubular proteinuria(including generalized amino aciduria).
4) Measurements of urine electrolytes serve to detect the loss of bicarbonate and phosphaturia.
Definitive diagnosis and treatment monitoring are most often performed through measurement of white blood cell cystine level.
- Renal ultrasonography, Radiography for kidneys, ureters, and bladder (KUB) may be needed to evaluate possible urinary tract calcifications.
- CT scanning and MRI are used to evaluate adult patients with infantile nephropathic cystinosis who have CNS symptoms.
- Slit-lamp examination of the eyes reveals corneal and conjunctival cystine crystals (pathognomonic for cystinos is) as early as age 1 year, although photophobia does not usually become apparent until age 3-6 years.
- Examination of the eye fundi may reveal the presence of peripheral retinopathy. In some patients, retinopathy may lead to blindness.
Treatment- Cystinosis is a common cause of the Fanconi Syndrome, a renal tubular disease. By about one year of age,patients eliminate large volumes of urine and lose large amounts of salt and other minerals in their urine.
Replacement of urinary losses: The child must be well-hydrated and administered supplements of potassium and bicarbonate, as needed. Rickets should be treated with vitamin D and phosphate supplementation.Without specific treatment, these children progress to end-stage renal failure by an average age of nine years. These patients can receive renal dialysis or transplantation, but even with successful transplantations, they develop abnormalities in other organs.The drug cysteamine slows the progression of cystinos is by removing the cystine from cells, but for the drug treatment to be effective, it must be taken every six hours. When administered regularly, cysteamine decreases the amount of cystine stored in lysosomes and correlates with conservation of renal function and improved growth. Cysteamine eye drops remove the cystine crystals in the cornea that can cause photophobia if left unchecked.