Chapter 39 - Hereditary Cystinosis

Abstract

This chapter reviews the most recent advances in the molecular biology of cystinosis, focuses on the causative CTNSmutations identified to date, and explains a correlation between genotype and the differing clinical phenotypes. Cystinosis is a rare autosomal recessive monogenic disorder with an incidence of ~1/200,000 live births, characterized by an intralysosomal accumulation of cystine. It constitutes the most common familial form of the renal Fanconi syndrome. The underlying metabolic defect of cystinosis is an accumulation of cystine in the lysosomes. Cystine, the disulfide of the amino acid cysteine, is a by-product of lysosomal protein hydrolysis, and is reduced to cysteine in the cytoplasm. Lysosome hydrolases, responsible for the digestion of macromolecules, have optimal activity at acid pH and the acidification of the lysosomal lumen is accomplished by the presence of an ATPase H+-pump in its membrane. In the case of cystinosis, the lysosomal cystine transporter is defective leading to an abnormal storage of cystine. It is due to its poor solubility that cystine forms crystals as its concentration increases. A measure of leukocyte cystine levels using a cystine binding protein assay is generally used to confirm a suspicion of cystinosis. Oral cysteamine therapy, if administered early in the course of the disease and in high doses, delays the progression of renal insufficiency. In addition, it prevents the appearance of hypothyroidism, and decreases the severity of oral motor and swallowing dysfunction, which is correlated with generalized muscle atrophy. Approximately 90 different CTNSmutations have been detected in all forms of cystinosis up to now. Many of the point mutations associated with the infantile form are deletions, insertions, and splice site mutations that cause premature termination of cystinosin.