A fragile X case with an amplification/deletion mosaic pattern.

Fragile X syndrome is the most common cause of hereditary mental retardation. The FMR1 gene, which is involved in fragile X syndrome, contains a polymorphic CGG repeat, which expands in affected patients. Expanding triplet repeats have been shown to be a new type of mutation, termed "dynamic mutation", responsible for more than 12 genetic diseases. These mutations occur as multiple steps rather than as a single event. The first step leads to an unstable allele that then becomes increasingly unstable generally achieving further increases in copy or occasionally contraction. In this report, we describe a fragile X boy with both a hypermethylated full mutation and a deletion of 905 bp encompassing the CGG repeat. The upstream breakpoint is 438 bp 5' to the CGG repeat and the downstream breakpoint is 420 bp 3' of the triplet repeats. The deletion includes the ATG starting codon for translation of the FMR1 gene. This was confirmed by using FMRP immunocytochemistry both on blood smears and hair roots. The deleted region is flanked by a ccgg direct repeat next to the breakpoints; this may have had a critical role in the formation of a secondary DNA structure leading to the deletion.

alpha-N-acetylgalactosaminidase deficiency with mild clinical manifestations and difficult biochemical diagnosis.

Two additional patients with alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency are described. An 11-month-old girl with nonconsanguineous parents had generalized seizures and no angiokeratoma. Biochemical investigation showed persistent slight oligosacchariduria; enzymatic analysis of plasma, leukocytes, and fibroblasts revealed profound alpha-NAGA deficiency. Heterozygote enzyme levels were found in both parents. The mother has epilepsy, and epilepsy is present in the father's family. A younger, clinically healthy brother also had the enzyme deficiency. Electron microscopy of lymphocytes from the index patient showed no vacuolization. Incubation of cultured fibroblasts with Helix pomatia lectin showed the presence of intracellular N-acetylgalactosamine-containing storage material, not present in a series of 12 normal fibroblast lines. Our cases cannot be classified definitely as infantile cases. Biochemically the diagnosis could easily have been missed. Urinary oligosaccharide pattern after resorcinol staining was identical to those previously described, but excretion was significantly lower than in the reported infantile cases and the bands disappeared after the urine was desalted. The enzyme defect in leukocytes would have been missed with one of the commercial substrates used. For this mild variant of alpha-NAGA deficiency, the clinical pattern is not yet clear; a longer follow-up period is needed.