Exonic deletions of FXN and early-onset Friedreich ataxia.

BACKGROUND: Friedreich ataxia (FA) is the most frequent type of autosomal recessive cerebellar ataxia, occurring at a mean age of 16 years. Nearly 98% of patients with FA present with homozygous GAA expansions in the FXN gene. The remaining patients are compound heterozygous for an expansion and a point mutation. Patients who are compound heterozygous for an exonic deletion and an expansion are exquisitely rare. OBJECTIVES: To describe 6 patients affected with FA due to an exonic deletion mutation (FAexdel) and to compare these 6 patients with FAexdel with 46 patients consecutively diagnosed with typical FA due to homozygous GAA expansion and whose small expansions were within the same range as that of the expansions of the patients with FAexdel. DESIGN: Description of a series. SETTING: Academic research. PATIENTS: Six patients with FAexdel and 46 patients with typical FA. INTERVENTION: FXN gene analysis, including assessments of GAA expansion and exon sequencing and determination of exonic copy numbers using multiplex ligation-dependent probe amplification. RESULTS: We identified 6 patients with FA who presented with the combination of 1 GAA expansion and 1 FXN exonic deletion. The mean (SD) age at onset of the disease was earlier for patients with FAexdel (7 [4] years [range, 3-12 years]) than for patients with typical FA (15 [5] years [range, 6-30 years]) (P = .001), and the median time to confinement to wheelchair was shorter for patients with FAexdel (20 years) than for patients with typical FA (28 years) (P = .002). There was no difference between the mean (SD) size of the expansion for the patients with FAexdel (780 [256] GAA triplet repeat sequences [range, 340-1070 GAA triplet repeat sequences]) and the mean (SD) size of the short expansion for the patients with typical FA (634 [163] GAA triplet repeat sequences [range, 367-1000 GAA triplet repeat sequences]) (P = .10). The mean disease duration before becoming wheelchair bound was shorter for patients with FAexdel (9 years) than for patients with typical FA (13 years), and the incidence of cardiomyopathy was higher for patients with FAexdel (84%) than for patients with typical FA (68%). However, these differences were not significant, probably owing to the small size of the FAexdel group. The other extraneurological signs, such as scoliosis or diabetes mellitus, were particularly frequently observed in the FAexdel group. One patient presented at 9 years of age with severe angina and marked cardiomyopathy that confined her to a wheelchair. Three patients had disabling autonomic disturbances. It appears that exonic deletion significantly contributes to the clinical picture of patients with FA. CONCLUSIONS: Friedreich ataxia due to an exonic deletion mutation corresponds to an early onset and severe variant of FA. FXN should be investigated for exonic deletion in patients with early-onset FA in which only 1 GAA expansion without a point mutation is found. Patients with FAexdel have to be carefully observed using cardiological, orthopaedic, endocrinological, gastroenterological, and ophthalmological data. Friedreich ataxia due to an exonic deletion mutation should be suspected in young patients presenting with severe scoliosis.

Clinical and molecular findings of ataxia with oculomotor apraxia type 2 in 4 families.

BACKGROUND: Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease caused by SETX mutations in 9q34 resulting in cerebellar ataxia in association with peripheral neuropathy, cerebellar atrophy on imaging, an elevated alpha-fetoprotein (AFP) serum level, and occasional oculomotor apraxia. OBJECTIVE: To describe the clinical and molecular findings of 7 patients with a clinical presentation of AOA2 and their relatives. DESIGN: Case report. SETTING: Projet Hospitalier de Recherche Clinique. PATIENTS: Seven patients with AOA2 and their family members. INTERVENTION: Linkage analysis and direct sequencing of all exons of SETX were performed in all patients. Magnetic resonance imaging and electroneuromyography were performed and the patients' AFP serum levels were tested. RESULTS: We identified 7 patients with AOA2 from 4 unrelated families. Three novel SETX mutations were found. The clinical picture of the patients reported is fairly homogeneous and in accordance with the classic AOA2 presentation: onset from 13 to 18 years of progressive cerebellar ataxia and areflexia. Oculomotor apraxia was detected in 1 patient. Predominant axonal neuropathy and a diffuse cerebellar atrophy were found in the 4 patients tested. All patients had elevated AFP serum levels and 5 of 8 nonsymptomatic heterozygous relatives had moderately increased AFP serum levels as well. CONCLUSIONS: Ataxia with oculomotor apraxia type 2 is a homogeneous form of cerebellar ataxia with occasional oculomotor apraxia. Most nonsymptomatic heterozygous carriers present with increased AFP serum levels.

Cardiomyopathy in Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS) is a rare but well-documented X-linked disorder characterized by small size, developmental delay/mental retardation, and characteristic facial and skeletal findings in affected males. The phenotype in affected females is far more variable and can include developmental differences, obesity, and characteristic facial and skeletal differences. Cardiac anomalies are reported in less than 20% of affected males, with cardiomyopathy being one of the rare but reported complications of this disorder. However, cardiomyopathy is not well characterized in CLS. Here, we report on a 14-year-old boy with physical and developmental findings consistent with CLS who presented with a relatively sudden onset of signs of congestive heart failure due to a restrictive cardiomyopathy; an endomyocardial biopsy demonstrated non-specific hypertrophic myocyte alterations consistent with cardiomyopathy. This is the first description of the histology and electron microscopy of cardiomyopathy in CLS.

Large deletion of the GJB6 gene in deaf patients heterozygous for the GJB2 gene mutation: genotypic and phenotypic analysis.

Recent investigations identified a large deletion of the GJB6 gene in trans to a mutation of GJB2 in deaf patients. We looked for GJB2 mutations and GJB6 deletions in 255 French patients presenting with a phenotype compatible with DFNB1. 32% of the patients had biallelic GJB2 mutations and 6% were a heterozygous for a GJB2 mutation and a GJB6 deletion. Biallelic GJB2 mutations and combined GJB2/GJB6 anomalies were more frequent in profoundly deaf children. Based on these results, we are now assessing GJB6 deletion status in cases of prelingual hearing loss.