Cystinosis as a lysosomal storage disease with multiple mutant alleles: Phenotypic-genotypic correlations

Cystinosis is an autosomal recessive lysosomal storage dis-ease with an unclear enzymatic defect causing lysosomal cystine accumulation with no corresponding elevation of plasma cystine levels leading to multisystemic dysfunc-tion. The systemic manifestations include a proximal re-nal tubular defect （Fanconi-like）, endocrinal disturbances, eye involvements, with corneal, conjunctival and retinal depositions, and neurological manifestations in the form of brain and muscle dysfunction. Most of the long-term ill effects of cystinosis are observed particularly in pa-tients with long survival as a result of a renal transplant. Its responsible CTNS gene that encodes the lysosomal cystine carrier protein （cystinosin） has been mapped on the short arm of chromosome 17 （Ch17 p13）. There are three clinical forms based on the onset of main symp-toms： nephropathic infantile form, nephropathic juvenile form and non-nephropathic adult form with predominant ocular manifestations. Avoidance of eye damage from sun exposure, use of cystine chelators （cysteamine） and fnally renal transplantation are the main treatment lines. Pre-implantation genetic diagnosis for carrier parents is pivotal in the prevention of recurrence.

Fanconi-Bickel syndrome as an example of marked allelic heterogeneity

Renal tubular acidosis （RTA） encompasses many re-nal tubular disorders characterized by hyperchloremic metabolic acidosis with a normal anion gap. Untreated patients usually complain of growth failure, osteoporo-sis, rickets, nephrolithiasis and eventually renal insuff-ciency. Fanconi-Bickel syndrome （FBS） is an example of proximal RTA due to a single gene disorder; it is caused by defects in the facilitative glucose transporter 2 gene that codes for the glucose transporter protein 2 ex-pressed in hepatocytes, pancreatic β-cells, enterocytes and renal tubular cells. It is a rare inherited disorder of carbohydrate metabolism manifested by huge hepa-tomegaly [hence it is classified as glycogen storage disease （GSD） type XI; GSD XI], severe hypophospha-temic rickets and failure to thrive due to proximal renal tubular dysfunction leading to glucosuria, phosphaturia, generalized aminoaciduria, bicarbonate wasting and hy-pophosphatemia. The disorder has been reported from all parts of Europe, Turkey, Israel, Arabian countries, Ja-pan and North America. Many mutant alleles have been described, its exact frequency is unknown and there is no single mutation found more frequently than the oth-ers. The presence of consanguinity in affected families suggests an autosomal recessive pattern of inheritance. New cases of FBS have been recently reported in the Middle and Far East in collaboration with specialized centers. Two novel mutations have been discovered in two unrelated Egyptian families. The first was two bases deletion, guanine and adenine, （c.253_254delGA） causing a frameshift mutation （p. Glu85fs） and the sec-ond is mutation in exon6 in splicing acceptor site with intron5 （c.776-1G〉C or IVS5-1G〉A）. Moreover, a new different mutation was described in a 3 year old Indian boy.