Elsevier

Neuromuscular Disorders

Volume 8, Issue 7, October 1998, Pages 474-479
Neuromuscular Disorders

Autosomal recessive spastic ataxia of Charlevoix–Saguenay

https://doi.org/10.1016/S0960-8966(98)00055-8Get rights and content

Abstract

A form of autosomal recessive spastic ataxia unique to the Charlevoix–Saguenay area was clinically identified 20 years ago in patients from that region. This region of Québec, Canada, was once considered a genetic isolate. First noted at gait initiation, signs of ataxia slowly progress along with spasticity of the four limbs, slurred speech, and followed by distal amyotrophy. Early diagnosis relies on the presence of prominent myelinated fibers embedding retinal blood vessels at funduscopy and marked saccadic alteration of ocular smooth pursuit. Imaging of the posterior fossa shows cerebellar vermis atrophy and nerve conduction studies reveal loss of sensory and reduced motor conduction velocities. The clinical features are consistent with a developmental defect in myelination of both retinal and peripheral nerve fibers. The cause of this defect and the progressive axonal degeneration in the corticospinal and spinocerebellar tracts, as well as in the peripheral nerves is still unknown. Results of recent molecular genetic linkage analysis have located the gene locus to chromosome 13q12. Further research is needed to define where this hereditary spastic ataxia stands in the classification of the early onset spinocerebellar degenerations.

Introduction

Hereditary spastic ataxia is a familial neurological disorder showing both pyramidal tract and cerebellar progressive involvement [1]. In the past, it was referred to as a `forme de passage' between the classical form of Friedreich's ataxia (FA), the spinocerebellar degenerations (SCDs) included in the former olivopontocerebellar atrophies (OPCA), now renamed spinocerebellar ataxias (SCA), and the familial spastic paraplegia (FSP). In 1939, Bell and Carmichael [2]summarized the previously published cases of spastic ataxia and provided evidence for two major forms: an early onset autosomal recessive one and a second with late onset and dominant inheritance. Before the recent advent of molecular genetics, the spastic ataxia syndromes were simply included under `complicated forms of spastic paraplegia', as in the comprehensive classification of the hereditary ataxias and paraplegias published by Harding in 1984 [3]. Dominant spastic ataxia was reviewed by M.J. Eadie [1]in 1991. He emphasized that different pathological entities appear to have fallen within the clinical syndrome of hereditary spastic ataxia. He also indicated the association of spastic ataxia with optic atrophy or other eye involvement. Finally, he concluded that it might be more realistic to use the term `hereditary spastic ataxia' for what is openly acknowledged as a clinical syndrome with more than one pattern of inheritance and more than one pathological basis.

Reports of recessive spastic ataxia with various accompanying neurological and ocular signs have only been sporadic 4, 5, 6. The reports described a limited number of patients from communities considered as genetic isolates. Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) (McKusick 270550) was first described in 1978 [7]. With more than 300 affected individuals known to live in Québec, ARSACS is the most common of all inherited spastic ataxias. In northeastern Québec, most of the patients' families originate from a region where the 300 000-plus inhabitants share a limited number of common ancestors. The estimated carrier frequency of ARSACS gene is 1/22 in the Saguenay-Lac-Saint-Jean population for the 1941–1985 period [8]. All ascertained cases show autosomal recessive transmission pattern. There has been no report of vertical transmission as none of the patients had an affected parent or offspring in the last four generations. The male to female patient ratio is even.

Section snippets

Clinical features and evolution

Over a 20-year period, 320 ARSACS patients were identified and followed in the neuromuscular clinics located in Québec City (J.-P.B.) and Chicoutimi (J.M.). Basic investigation included ophtalmoscopic evaluation, electrophysiologic studies, and CT scan imaging of the head. Most of the patients have been followed on a yearly basis. A group consisting of the same eight patients has participated in detailed investigations in 1977, 1982 and 1992, including neuropsycological, EEG and evoked

Electrophysiological studies

In most cases, electromyography shows signs of severe denervation in distal muscles by the end of the twenties [12]. Nerve conduction studies (NCS) demonstrate signs of both early dysmyelination and progressive axonal neuropathy 9, 10, the latter confirmed by nerve biopsy [13]. Motor nerve conduction velocities (Fig. 2) are moderately reduced (median nerve 29–44 m/s, peroneal nerve 17–35 m/s) but do not worsen with time on repeated examinations (Table 2). Usually by the end of the third decade

Imaging and pathological findings

Atrophy of the superior cerebellar vermis (Fig. 3) is always present on CT or MRI 9, 16, even in younger patients and progresses. The inferior vermis remains thicker throughout the disease but there is a progressive cerebellar cortical atrophy. Furthermore, there is a conspicuous cerebral atrophy in late life. The cervical spinal cord is flattened and markedly reduced. There is no scoliosis.

The pathological findings in a postmortem examination of a 21-year-old man were described in 1991 [9]. A

Genetics

The ARSACS gene was initially excluded from linkage to the Friedreich's ataxia gene region on chromosome 9q13-21.1 18, 19and from close linkage to other regions of chromosome 9 [20]. We then undertook a large scale mapping study. We investigated eight families (31 patients, 108 individuals) with 121 polymorphic microsatellite markers at approximately every 25–30 cM on the Généthon map [21]. The method for rapid genotyping of DNA samples with microsatellite makers was used [22]. LOD-scores were

Discussion

The syndrome identified 20 years ago as a recessive form of spastic ataxia encountered in the Charlevoix–Saguenay area of Québec, has shown consistency and homogeneity on clinical, electrophysiological and morphological grounds. These characteristics have made possible the localization of the ARSACS gene on chromosome 13q12. On a practical aspect, the imaging features, the early NCS findings, and the ocular signs are all together diagnostic of ARSACS and help to distinguish it from cerebral

Acknowledgements

We would like to thank Dr. J. Rioux, J. Mercier, J. Poirier, D. Julien, C. Vestegaard, F. Gosselin and C. Prévost for their contribution to the work. Drs. D. Chaigne and C. Lamy provided us with DNA samples from French and Moroccan spastic ataxia families, respectively. This research was supported by grants from the Association Canadienne de l'Ataxie de Friedreich (J.-P.B. and A.R.); the Muscular Dystrophy Association of Canada (A.R.); the Réseau de Génétique médicale appliquée-FRSQ (S.B.M.);

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