Lysosomal Storage Disorder: cystinosis

Similar presentation in father [Ref Nelson pediatrics 18/e p 2184, 289, 2202, 261]

• Dent’s disease is an X-linked renal tubular disorder.
• X-linked disease cannot be transmitted from male to male i.e., from_.father to son.

Dent’s disease

• It occurs due to mutation in the ‘gene (CLCN5)”
• CLCN5 encodes a chloride channel which is situated in the proximal tubule of the kidney.
• The functional loss of the chloride channel due to mutation in the CLCN5 leads to generalized proximal tubular defect.
• This genetic abnormality results in four disorders of hereditary nephrolithasis.

– X-linked recessive nephrolithiasis (XRN)

– X-linked recessive hypophosphatemic rickets (XLRH)

– Japanese idiopathic low molecular weight proteinuria (JLLMWP)

– DENT’S disease

• “The common genetic aetiology and CLCN5 mutations and the phenotypic similarities between all these syndromes indicated that they were variant of one disorder and it has been proposed to refer them collectively as Dent’s disease”.
• All the hereditary nephrolithiasis share a common aetiology, having now been shown to be due to genetic mutation in renal chloride channel CLCN5.
• Loss of function of this channel causes a proximal tubular defect that leads to :-

– Low molecular weight protenuria

– Hypercalciuria

– Nephrocalcinosis

– Nephrolithiasis

– Renal_, failure

– Rickets

• In addition other renal proximal tubular defects occur which include.

– Aminoaciduria

– Phosphaturia

– Glycosuria

– Kalliuresis – Uricosuria and

– Acquired impairment of urinary acidification

Dent’s disease is believed to be a hypercalciuric variant of “Fanconi’s syndrome”, or a renal _.fanconi syndrome with nephrocalcinosis and kidney stones

Dent’s Disease

Cystinosis is an autosomal recessive disorder characterized by a defect in transport of cysteine across the lysosomal membrane.Kidneys are affected due to deposition of cystine crystals in proximal tubule cells causing features of fanconi syndrome.Renal calculi is not a feature of cystinosis.

Think Detail:

Cystinosis: is caused by a defect in transport of cystine across the lysosomal membrane due to defective function of the lysosomal carrier protein cystinosin, resulting from mutations of the cystinosis gene (CTNS). (CTNS has been mapped to chromosome arm 17pl3).

The stored cystine is poorly soluble and crystallizes within the lysosomes of many cell types, leading to widespread tissue and organ damage.

Types:

Three types of cystinosis have been described based on the age at diagnosis and magnitude of cellular cystine deposition:

• Infantile nephropathic form:the most common and the most severe,develop symptoms early in life and develop end-stage kidney failure by late childhood.

• Adolescent onset: is a more indolent form of the disease,features of disease are less severe, and end-stage renal disease occurs after age 15 years.

• Adult onset:does not include renal involvement and is limited to the eye (ocular cystinosis).

Fanconi syndrome:In the infantile nephropathic form of cystinosis, the kidney is affected early in life by cystine crystals deposited in proximal tubule cells. 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.

Clinical features:

A typical cystinotic patient has pale blond hair and blue eyes, and fair skin due to disturbances in pigment metabolism.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.

Diagnosis:confirmed by measuring cystine levels in polymorphonuclear leukocytes or cultured fibroblasts.Slit-lamp examination of the eyes reveals corneal and conjunctival cystine crystals (pathognomonic for cystinosis) as early as age 1 year, although photophobia does not usually become apparent until age 3-6 years.

Treatment:

• Oral cysteamine therapy:postpones the need for renal transplantation,should be initiated within days of diagnosis.

• Renal transplantation:has prolonged the lives of children with cystinosis. Renal transplantation is high successful, disease does not recur in the graft, but cystine continues to accumulate in other tissues, resulting in complications.

Reference:

Harrison’s Principle of internal medicine,17th Edition,Page 805

Ans:A.)Fragile X Syndrome.

Fragile X syndrome

• It is inherited in an X-linked dominant pattern.
• Symptoms often include mild to moderate intellectual disability.
• Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of people have features of autism such as problems with social interactions and delayed speech.
• Hyperactivity is common and seizures occur in about 10%.
• Males are usually more affected than females.
• Fragile X syndrome is typically due to an expansion of the CGG triplet repeat within the Fragile X mental retardation 1 (FMR1) gene on the X chromosome