HUMAN BIOCHEMICAL GENETICS

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(1) Cystine movement out of lysosomes is enhanced by permeant potassium ions. Cysteamine depletes cystinotic lysosomes of cystine by forming cysteine-cysteamine mixed disulfide, which leaves the lysosome by a process not requiring the cystine carrier, which is defective in cystinosis. (2) Children with nephropathic cystinosis manifest improved growth and slowed renal deterioration if treated with cysteamine before 3 years of age. Children with renal Fanconi syndrome exhibited a marked deficiency of plasma and muscle free carnitine due to failure of the kidney to reabsorb carnitine. Carnitine supplementation restored plasma free carnitine levels to normal. Cystinotic children receiving cysteamine chronically displayed a blunted prolactin response to TRH. Heterozygote testing verified that the occurrence of Fabry disease and cystinosis in 2 siblings represented a rare manifestation of the two classical mutations in a single family. Late complications of cystinosis were shown to include involvement of the CNS, eyes, pancrease, lungs, and salivary glands. (3) Mucolipidosis II, or I-cell, fibroblasts were shown to store cystine due to impaired egress of cystine out of isolated granular fractions. The half-times for such egress were over 100 min for I-cell lysosomes and 40 min for normals. (4) Free sialic acid storage disease fibroblasts store free sialic acid in their lysosomes. Sialic acid egress from these lysosomes was negligible compared with normals, suggesting that the disorder represents a defect in lysosomal transport of free sialic acid. (5) A normal 31-year-old man with methionine adenosyltransferase deficiency offers 25 years of additional natural history to the disorder, previously described only in 5 children age 6 or below. (6) Six patients with homocystinuria are receiving betaine therapy in a double-blind, placebo-controlled study to determine if the drug improves vertebral body bone density, measured by CT scan. (7) Cysteamine charge-shifted apolipoprotein E molecules in vitro and in vivo, making feasible the treatment by oral cysteamine of diseases with cysteine-for-arginine substitutions which result in nonfunctional proteins.