F. Cavalcanti

Late onset Friedreich's disease: clinical features and mapping of mutation to the FRDA locus.

Twenty two patients from 17 families with Friedreichs disease phenotype but with onset ranging from the ages of 21 to 36 are described. Comparison with typical Friedreichs disease with onset before 20 years of age showed only a lower occurrence of skeletal deformities. The peripheral and central neurophysiological findings, sural nerve biopsy, and the neuroradiological picture did not allow the differentiation between late onset and typical Friedreichs disease. Duration of disease from onset to becoming confined to a wheelchair was five years longer in late onset patients. Sixteen patients and 25 healthy members from eight families were typed with the chromosome 9 markers MLS1, MS, and GS4 tightly linked to the FRDA locus. All families showed positive lod scores with a combined value of 5.17 at a recombination fraction of theta = 0.00. It is concluded that late onset Friedreichs disease is milder than the typical form and that it maps to the same locus on chromosome 9.

Relation between trinucleotide GAA repeat length and sensory neuropathy in Friedreich’s ataxia

OBJECTIVE To verify if GAA expansion size in Friedreich’s ataxia could account for the severity of sensory neuropathy. METHODS Retrospective study of 56 patients with Friedreich’s ataxia selected according to homozygosity for GAA expansion and availability of electrophysiological findings. Orthodromic sensory conduction velocity in the median nerve was available in all patients and that of the tibial nerve in 46 of them. Data of sural nerve biopsy and of a morphometric analysis were available in 12 of the selected patients. The sensory action potential amplitude at the wrist (wSAP) and at the medial malleolus (m mal SAP) and the percentage of myelinated fibres with diameter larger than 7, 9, and 11 μm in the sural nerve were correlated with disease duration and GAA expansion size on the shorter (GAA1) and larger (GAA2) expanded allele in each pair. Pearson’s correlation test and stepwise multiple regression were used for statistical analysis. RESULTS A significant inverse correlation between GAA1 size and wSAP, m mal SAP, and percentage of myelinated fibres was found. Stepwise multiple regression showed that GAA1 size significantly affects electrophysiological and morphometric data, whereas duration of disease has no effect. Conclusion—The data suggest that the severity of the sensory neuropathy is probably genetically determined and that it is not progressive

Has spinocerebellar ataxia type 2 a distinct phenotype? Genetic and clinical study of an Italian family

Article abstract-The gene for spinocerebellar ataxia type 2 (SCA2) is mapped to chromosome 12q23-24.1. Using D12S79 and D12S105, we performed linkage analysis in nine individuals including six affected members of a four-generation family in which we excluded SCA1 by direct mutation analysis. We obtained a lod score = 2.37 at theta = 0.00 for the compound haplotype. The clinical picture appeared homogeneous, showing the absence of corticospinal signs and the presence of peripheral neuropathy. The present study suggests that this SCA2 family is clinically different from most SCA1 families. NEUROLOGY 1995;45: 793-796

Broadened Friedreich's ataxia phenotype after gene cloning Minimal GAA expansion causes late-onset spastic ataxia

We describe three siblings from an Italian family affected by an autosomal recessive spinocerebellar degeneration. Gait ataxia, presenting between 38 and 45 years, was the first symptom in all three patients. Dysarthria, dysmetria, brisk tendon reflexes, extensor plantar response, and scoliosis were constant features. Disease progression was slow. Electrophysiologic studies demonstrated a slight reduction in sural nerve sensory action potential in only one patient. Analysis of GAA expansion within the X25 gene showed that patients were homozygous for the expansion, with the shorter expanded allele ranging from 120 to 156 triplets. The size of the GAA expansion may be smaller than we previously described. Such minimal expansions may result in atypical forms of Friedreichs ataxia.

Accuracy of clinical diagnostic criteria for Friedreich's ataxia.

The accuracy of the diagnostic criteria for Friedreichs ataxia proposed by Harding and by the Quebec Cooperative Study on Friedreichs Ataxia was studied in 142 patients with progressive unremitting ataxia of autosomal recessive inheritance or sporadic occurrence. Eighty‐eight patients received the molecular diagnosis of Friedreichs ataxia. Traditional diagnostic criteria are characterized by high specificity, but they yield a high number of false‐negative diagnoses. We suggest three levels of diagnostic certainty: (1) possible Friedreichs ataxia, defined as sporadic or recessive progressive ataxia with (a) lower limb areflexia and dysarthria, Babinski sign, or electrocardiographic repolarization abnormalities, or (b) with lower limb retained reflexes and electrocardiographic repolarization abnormalities (95% sensitivity and 88% positive predictive value); (2) probable Friedreichs ataxia as defined by Hardings criteria (63% sensitivity and 96% positive predictive value) or by Quebec Cooperative Study on Friedreichs Ataxia criteria (63% sensitivity and 98% positive predictive value); (3) definite diagnosis, molecularly confirmed.

Clinical and genetic heterogeneity in early onset cerebellar ataxia with retained tendon reflexes.

A clinical and genetic study was performed on 20 patients affected by early onset cerebellar ataxia with retained tendon reflexes (EOCA). Mean age at onset was 8.8 (SD 6.0) years. The frequency distribution of age of onset significantly differed from the normal distribution. Consanguinity rate was 16.7% and segregation ratio 0.164. As well as ataxia, which was a constant feature, there were signs of involvement of the cortico-spinal tracts and/or peripheral nerves in most patients. Results of neurophysiological studies were not homogeneous, nor were morphological findings of the sural nerve biopsy. The data suggest that EOCA may be genetically and clinically heterogeneous.

Atypical Friedreich ataxia phenotype associated with a novel missense mutation in the X25 gene

Article abstract We describe two sisters with early onset gait ataxia, rapid disease progression, absent or very mild dysarthria and upper limb dysmetria, retained knee jerks in one, slight to moderate peripheral nerve involvement, and diabetes. Molecular analysis showed that they are compound heterozygotes for GAA expansion and a novel exon 5a missense mutation (R165P). This mutation appears to be associated with an atypical but not milder Friedreich ataxia phenotype.

Intrafamilial phenotype variation in Friedreich's disease: possible exceptions to diagnostic criteria

SummaryThree families are described which include members with “typical” Friedreichs disease (FD) and others who are ataxic but do not satisfy all the diagnostic criteria for that disease. In family A two patients have an early-onset, rapidly progressive FD, while two others have a late-onset, more benign form. In families B and C one member has “typical” FD, and another has a similar ataxic syndrome, except for preservation of knee jerks. Laboratory evaluation is consistent with the diagnosis of FD in all cases. FD diagnosis appears justified in secondary cases with late onset or preserved tendon reflexes, provided that the index case fulfils all diagnostic criteria. Whether the diagnosis of FD is tenable in sporadic “atypical” cases remains to be seen. Echocardiographic and neurophysiological examination may be valuable in classifying such cases.

Linkage disequilibrium between FD1-D9S202 haplotypes and the Friedreich's ataxia locus in a central-southern Italian population.

We used two recently described genetic markers in the region of the Friedreichs ataxia locus to study 33 affected pedigrees from central-southern regions of Italy. These markers are predicted, by physical mapping, to be localised more closely to the Friedreichs ataxia locus than other previously described markers. No recombination was found between these markers and the disease locus. Strong linkage disequilibrium is present between the compound haplotype and the disease locus. Since this population was also previously studied by using three other more distal genetic markers, a total of five markers has been used to identify the extended haplotype. Homozygosity in consanguineous pedigrees was also studied. Extended haplotype analysis and homozygosity studies suggest the presence of few common disease causing mutations in our population.