HUMAN BIOCHEMICAL GENETICS

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(1) We demonstrated defective lysosomal cystine transport in leucocytes and fibroblasts from patients with the intermediate (juvenile) and benign (adult) variants of cystinosis. In other studies, the cystine carrier was functional in rat thyroid-derived cells, and required protein synthesis but non N-linked glycosylation for its production. (2) Twenty-five children with cystinosis contributed data toward a national study demonstrating the efficacy of oral cysteamine therapy in enhancing growth and retarding renal failure. At the same time, late complications of cystinosis were described, including cerebral atrophy, impaired salivary function, diabetes mellitus, restrictive pulmonary function, corneal erosions, and reduced visual acuity. One patient received a corneal transplant, and a protocol for treating corneal erosions with cysteamine eyedrops was initiated. Oral cysteamine is being offered to post-renal transplant patients. Carnitine-deficient individuals with Fanconi syndrome are being treated with oral carnitine with some success in normalizing their muscle histology. (3) The second lysosomal storage disorder due to defective transport of a small molecule across the lysosomal membrane is Salla disease, a Finnish disease characterized by psychomotor retardation. Salla fibroblasts store free sialic acid within their lysosomes due to impaired egress of the charged sugar. Egress velocity of sialic acid out of normal lysosome-rich granular frctions increased with increasing loading and temperature (Q10=2.3). (4) Lowe (oculocerebrorenal) syndrome fibroblasts manifested normal rates of hyaluronic acid and proteoglycan synthesis and sulfation, with a large degree of variability among normals. (5) Using counter-transport, a lysosomal transport system for tyrosine and other neutral amino acids was characterized for rat thyroid cells in culture. The system, with a Q10 of 1.9 and apparent Km for tyrosine of 100 M, resembles the plasma membrane L system. (6) I-Cell (Mucolipidosis II) fibroblasts demonstrated impaired lysosomal clearance of cystine. Pyridoxine-nonresponsive homocystinuric patients are treated with betaine to study its effect on bone density.