M. Ragno

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

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.

Autosomal dominant cerebellar ataxia type I: multimodal electrophysiological study and comparison between SCA1 and SCA2 patients

A multimodal electrophysiological study was performed on 41 patients from 24 families with autosomal dominant cerebellar ataxia type I (ADCA I). Upper- and lower-limb motor evoked potentials (MEPs) to transcranial magnetic stimulation, median and tibial nerve somatosensory evoked potentials (Mn and Tn-SSEPs), orthodromic sensory (SCV) and motor conduction (MCV) velocity along median and tibial nerve, brainstem auditory evoked potentials (BAEPs), and visual evoked potentials (VEPs) were examined. Molecular analysis showed 2 SCA1 families and 2 families linked to the SCA2 locus. A sural nerve biopsy was performed in 5 patients. Brainstem damage of the auditory pathway was observed in 79% of patients examined. VEP abnormalities possibly of central origin were found in 52% of patients. MEP and SSEP abnormalities were differently distributed along the pathways examined: the longer the pathway, the higher the occurrence and severity of impairment. Peripheral dying-back neuropathy (confirmed by nerve bioptic data) was a frequent finding (56%). A progressive degenerative process involving first the longest tracts of the central motor and central and peripheral branches of somatosensory pathways is hypothesized in ADCA I. MEP abnormalities were more frequent in SCA1, and the sensory-motor neuropathy was more severe in SCA2.

Friedreich's ataxia: electrophysiological and histological findings

ABSTRACT‐ Electromyography was performed, and motor and sensory nerve conduction velocities were measured in 19 patients definitely affected by Friedreichs ataxia. Biopsy of the sural nerve was also performed in 9 patients.

Wide expressivity variation and high but no gender-related penetrance in two dopa-responsive dystonia families with a novel GCH-I mutation.

We describe the clinical and molecular correlates in two Italian families with dopa‐responsive dystonia (DRD) and the same novel mutation of GTP‐cyclohydrolase I (GCH‐I) gene. Thirty‐five subjects were examined and the genotype correlated to phenotype. Childhood onset foot dystonia is present in 7 subjects currently under the age of 40. In 1 patient bilateral foot dystonia was evident at birth suggesting that dystonia may be active as early as in utero. In another patient, dystonia spontaneously remitted in adolescence, to relapse 8 years later, as writers cramp. Dystonia and parkinsonian signs are present in 5 other patients. In 2 subjects an isolated parkinsonism started over the age of 45. A 5‐base pair insertion at codon 242 within exon 6 of GTP‐cyclohydrolase I (GCH‐I) gene that shifts the reading frame and results in a premature stop at codon 247 with truncation of the polypeptide has been detected in 21 subjects. Considering dystonia and parkinsonism the overall penetrance is 0.71 and not significantly different in men (0.69) and women (0.75). Genealogical studies seem to exclude that these families are related but haplotype analysis suggests a single founder. Our findings in subjects with the same mutation indicate a wide intrafamilial variation in expressivity and high penetrance in DRD but do not confirm the reported influence of gender on GCH‐I gene mutation penetrance.

A family with tomaculous neuropathy mimicking Charcot-Marie-Tooth disease

The appearance of Guillain-Barré syndrome in a 9-year-old girl led to the detection of a hereditary neuropathy in her family. This neuropathy showed clinical and electrophysiological characteristics of Charcot-Marie-Tooth disease. Only nerve biopsy performed in a sister of the proband allowed diagnosis of tomaculous neuropathy which presented unusual clinical, electrophysiological and bioptic aspects.

Correlations between clinical, electrophysiological and histological findings in patients with different diseases of the peripheral nervous system

Dear Sir, Between February 1978 and December 1982 49 subjects, 24 males and 25 females, 6-59 years of age, suffering from fair to severe clinical signs of peripheral neuropathy, were examined in our Department of Clinical Neurophysiology. Based on family history and clinical findings, diagnosis was established in all but 7 (14 per cent) patients. 16 patients were grouped as peroneal muscular atrophy; 7 subjects were generically classified as motor neuron disease; 2 had RoussyLevy syndrome; 2 had alcoholic neuropathy; 1 patient had a leather-cementing neuropathy, while another case had Refsum disease; finally, 14 were classified as Friedreich ataxia. All subjects underwent conventional electromyography in the brachial biceps, anterior tibial and abductor digiti minimi muscles, and in addition motor and sensory conduction studies along the median, tibial and sural nerves were performed according to Buchthals criteria [1, 4, 5]. Electrophysiological studies assisted in differentiating the 16 cases of peroneal muscular atrophy into hypertrophic type (13 patients) and neuronal type (3 patients) but did not help to define a specific etiology in clinically undefined cases. In the remaining 27 subjects, both conduction studies and conventional electromyography supported the clirfical hypothesis. Sural nerve biopsy was done in all patients. Sampies of in toto excised nerve were examined both by fight and electron microscopy; morphometric measurements and teased nerve fibre studies were performed according to Behse et al. [2, 3]. Quantitative histological findings were in agreement with clinical data and electrophysiological abnormalities in all cases but one. In this case, clinically and electrophysiologically classified as Friedreich ataxia, a severe loss of both large and small fibres was evident. Nerve biopsy was non contributory in clinically undiagnosed neuropathies. According to this experience, the nature and type of a neuropathy can be defined in most patients from clinical examination alone. Nerve conduction studies, conventional electromyography and nerve biopsy can confirm a clinical diagnosis; nerve biopsy can also provide information on the severity of the pathology. But neither electrophysiological studies nor histological findings can establish a diagnosis in the absence of a clinical diagnosis.