The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group.

The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.

FMR1 gene deletion/reversion: a pitfall of fragile X carrier testing.

The Fragile X syndrome is, in the majority of cases, caused by CGG trinucleotide amplification within the FMR1 gene. The syndrome is rarely caused by point mutations or deletions. Here we describe a family with 2 sons and 1 daughter affected by Fragile X syndrome and 2 unaffected daughters whose carrier status was unknown prior to this study. Analysis of DNA from each of the 2 daughters revealed two alleles in the normal size range. However, 1 daughter carried one allele of 10 CGG repeats that was not present in either the mother or the father. No evidence for mosaicism could be detected. Haplotype analysis of flanking polymorphic markers revealed that the 10 CGG allele was derived from the mutated allele inherited from the mother. Thus, this case most likely represents an additional case of a reverse mutation from a premutation allele in a female to a normal-sized allele in the offspring. It remains unclear how frequently such reversion events occur. The observation has important consequences for genetic testing, because many laboratories prescreen for the Fragile X syndrome by determining the length of the CGG repeat using PCR. If this shows alleles in the normal size range, a diagnosis of Fragile X syndrome is considered to be excluded. Because the routine PCR and/or Southern blot analyses alone may yield false-negative results in cases of a regression of the number of CGG repeats, we strongly recommend the inclusion of fragment length or haplotype analysis when determining the carrier status within Fragile X syndrome families.

Nonsyndromic X-linked mental retardation: mapping of MRX58 to the pericentromeric region.

An Austrian family with nonsyndromic X-linked mental retardation (MRX) is reported in which the obligatory carrier females are normal, and 5 affected males have mild to moderate mental retardation. Linkage analysis indicated an X pericentromeric localization, with flanking markers DXS989 and DXS1111 and a maximum multipoint LOD score of 2.09 (straight theta = 0) for the 7 cosegregating markers DXS1243, CybB, MAOB, DXS988, ALAS2, DXS991, and AR. MRX58 thus mapped within a 50-cM interval between Xp11.3 and Xq13.1 and overlapped with 23 other MRX families already described. This pericentromeric clustering of MRX families suggests allelism, with a minimum of 2 X-linked mental retardation (XLMR) genes in this region.