A cryptic full mutation in a male with a classical fragile X phenotype.

Fragile X syndrome (FRX) is the most common inherited cause of mental retardation affecting approximately 1/4000 males and half as many females. Mosaicism has been reported in 12-41% of male cases. We present a 47-year-old male with the typical FRX phenotype referred for an evaluation of mental retardation and a psychiatric disorder. Analysis of the FMR-1 CGG repeat size was performed on peripheral blood by PCR and Southern blot analysis. The proband was shown to carry a premutation allele of 58 CGG repeats. Because of the compelling clinical phenotype, further testing was performed on DNA extracted from skin fibroblasts, which yielded a 500 CGG repeat allele. Mosaic cases of FRX have been reported but rarely without detectable mosaicism in peripheral blood. Therefore, this case is atypical because of the striking differences in the results obtained for the two different cell types. We concur with others that testing of ectodermally derived tissues may provide improved diagnosis and perhaps better insight into the overall prognosis of the affected individual. This case demonstrates the need to consider further study on other tissues when there is a strong clinical suspicion of FRX.

The E326K mutation and Gaucher disease: mutation or polymorphism?

Gaucher disease is caused by mutations in the gene for human glucocerebrosidase, a lysosomal enzyme involved in the intracellular hydrolysis of glucosylceramide. While over 150 different glucocerebrosidase mutations have been identified in patients with Gaucher disease, not all reported mutations have been fully characterized as being causative. One such mutation is the E326K mutation, which results from a G to A nucleotide substitution at genomic position 6195 and has been identified in patients with type 1, type 2 and type 3 Gaucher disease. However, in each instance, the E326K mutation was found on the same allele with another glucocerebrosidase mutation. Utilizing polymerase chain reaction (PCR) screening and restriction digestions of both patients with Gaucher disease and normal controls, we identified the E326K allele in both groups. Of the 310 alleles screened from patients with Gaucher disease, the E326K mutation was detected in four alleles (1.3%). In addition, screening for the E326K mutation among normal controls from a random population revealed that three alleles among 316 screened (0.9%) also carried the E326K mutation. In the normal controls with the E326K allele, the glucocerebrosidase gene was completely sequenced, but no additional mutations were found. Because the E326K mutation may be a polymorphism, we caution that a careful examination of any allele with this mutation should be performed to check for the presence of other glucocerebrosidase mutations.

Cryptic duplication of 21q in an individual with a clinical diagnosis of Down syndrome.

We describe an adult male who was diagnosed with Down syndrome (DS) at 9 months of age, but had repeatedly normal karyotypes until recent mid-resolution chromosome studies showed a possible duplication of 21q22.13 to 21q22.3. The abnormality was investigated using fluorescent in situ hybridization (FISH) studies. These showed hybridization of a whole chromosome paint probe (wcp21, Oncor Coatasome 21) to the entire length of both chromosome 21 homologues and one very large hybridization signal of a cosmid contig probe localized within bands 21q22.13-21q22.2(LSI-21, Vysis) on the ?dup(21q) homologue. CGH analysis identified a ratio of 1.5 for the segment of chromosome 21 involving band 21q22, indicating a gain of part, or all, of the terminal band of chromosome 21. The karyotype was thus defined as 46,XY,?dup(21) (q22.13q22.2).ish dup(21)(LSI-21++,wcp21+). Common DS characteristics in our case and 12 previously reported cases with duplications involving chromosome 21 included mental retardation, fifth finger clinodactyly, open mouth and oblique eye fissures. Transverse palmar creases and congenital heart defects, seen in DS less than 40% of the time, were infrequent. Presence of these features did not appear to depend on the specific portion of chromosome 21 that was duplicated. A review of 18 additional clinical features showed no consistent phenotype-genotype correlations.

Enzyme replacement therapy for Gaucher's disease: the early Canadian experience.

BACKGROUND: The management of severe Gaucher's disease was dramatically improved by the development of enzyme replacement therapy. However, this treatment is very costly (currently about $21,000 per infusion for adults at the starting dose recommended by the manufacturer). The goal of this study was to determine how enzyme replacement therapy was being prescribed and financially supported in various parts of Canada. In addition, demographic and outcome information was elicited. METHODS: Prescribing physicians were identified through professional associations and with the help of the manufacturer of the enzyme preparations used for the treatment of Gaucher's disease. The physicians were surveyed by questionnaire in July 1995. The study included all patients in Canada who had received enzyme replacement therapy for Gaucher's disease before July 1, 1995. RESULTS: A total of 25 patients (15 children and 10 adults) with type 1 Gaucher's disease, the common nonneuronopathic variant of the disease, were receiving enzyme replacement therapy by the end of 1995. The indications for treatment included massive splenomegaly, growth failure, and severe bony, hematologic and pulmonary complications of the disease; no patients with mild disease were receiving treatment. Treatment regimens varied markedly (from 12 to 160 units of enzyme/kg per month). All the patients were reported to have responded well to therapy, based on serial measurements of hematologic indices, liver and spleen volumes, and numbers of bony crises as well as patients' subjective impressions. Financial support for therapy varied markedly from one province to another. None of the reporting physicians was aware of any patients with severe Gaucher's disease who were denied therapy as a result of inability to pay for the medication. Various agencies provided financial support for therapy, including both federal and provincial governments, private insurance carriers and the commercial supplier of the enzyme. In Ontario provincial health care officials accepted the development, by a multidisciplinary panel of medical experts, of formal guidelines for determining eligibility, on the basis of objective medical criteria, for reimbursement for enzyme replacement treatment. INTERPRETATION: Although some differences were found across the country with respect to the details of treatment, the indications for enzyme replacement therapy and the selection of severely affected patients were similar in the various provinces. However, financial support was inconsistent and varied among provinces and patients. This will prove to be a challenge in future, not only with respect to this disease but also for other diseases for which effective, expensive therapy has been developed.

X linked spondyloepiphyseal dysplasia: a clinical, radiological, and molecular study of a large kindred.

X linked spondyloepiphyseal dysplasia (SEDT) is a rare disorder characterised by disproportionate short stature and degenerative changes in the spine and hips. We report a large kindred with 11 affected males and 17 obligate carrier females. We examined clinically and radiographically the seven living affected males and obtained detailed historical information on the four dead. The natural history was characterised by normal growth until late childhood. Decreased growth velocity was the earliest detectable abnormality. In adulthood, four subjects required hip replacements but disability was minimal. Clinical examinations showed a characteristic habitus with short stature (> 2 SD below the mean) and a decreased upper segment to lower segment ratio (> 1 SD below the mean) in all affected subjects. Also noted were scoliosis (6/7), and decreased range of hip rotation (6/7), and decreased range of movement of the lumbar spine (4/7). Radiographic evaluations were available on nine subjects. Radiographic changes were evident in two patients in childhood; findings in adulthood included narrow disc spaces (8/9), platyspondyly (7/9), the characteristic central and posterior hump of the vertebral bodies (6/9), bony spurs (7/ 8), and pelvic abnormalities (7/9). We also systematically evaluated eight obligate carrier females. They could not be distinguished from the general population on clinical and radiographic findings. Linkage analysis showed significant linkage with markers on Xp22, as previously reported. A recombinant event between DXS43 and DXS207 places the locus distal to DXS43.