Prominent sensory and autonomic disturbances in familial amyotrophic lateral sclerosis with a Gly93Ser mutation in the SOD1 gene

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Abstract

A missense mutation (Gly93→Ser) was identified in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene of a 48-year-old Japanese man with familial amyotrophic lateral sclerosis (FALS). The SOD1 activities in the fibroblasts and in a lysate of erythrocytes of the patient did not differ from those of healthy controls. The clinical characteristics of the patient were fairly slow progression of the illness, prominent sensory impairment, urinary disturbance and blood pressure fluctuation due to sympathetic hyperactivity. The severe sensory and autonomic disturbances, association of which with FALS has not been previously reported, may represent specific clinical features associated with the Gly93Ser mutation or may indicate the variability of clinical findings even in patients with the same mutation.

Introduction

About 5–10% of cases of amyotrophic lateral sclerosis (ALS) are familial (FALS) with autosomal dominant inheritance (Mulder et al., 1986). Recently, mutations in the Cu/Zn superoxide dismutase (SOD1) gene were identified in 15–20% of patients with FALS (Rosen et al., 1993, Deng et al., 1993, Gurney et al., 1994). To date, 49 mutations in the SOD1 gene have been reported in cases of FALS (Siddique and Deng, 1996). Although some genotypes are associated with a consistent phenotype, considerable phenotypic heterogeneity, especially in terms of the age at onset and the duration of the disease, exists among family members carrying the same mutation (de Belleroche et al., 1996). We report here on a FALS patient with a Gly93Ser missense mutation in exon 4 of the SOD1 gene, with special reference to unusually severe sensory and autonomic disturbances.

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Case report

The patient's father died of ALS at age 73, about 7 years after the onset of the illness (Fig. 1, II-5). The father's first symptom of ALS was weakness of the leg muscles. Weakness of the hand muscles and dysarthria were noted 6 and 7 years after the onset of the disease, respectively. No other family members showed similar neurological symptoms.

The proband (Fig. 1, III-3) is a 48-year-old man who first noted weakness of the muscles in his left leg at age 33 (1981). Within 5 months, weakness

SOD1 gene mutation identification

Complete sequence analysis of the SOD1 cDNA for this patient revealed only a single base pair substitution in exon 4 at codon 93 (GGT→AGT) (Fig. 2). Subsequent sequence analysis of exon 4 of the SOD1 gene in a sample of the patient's genomic DNA confirmed the mutation. This change creates a glycine 93 to serine missense mutation. The mutation was also confirmed with ASO. The patient carried one wild-type and one mutant SOD1 gene allele (data not shown). ASO analysis of exon 4 of the SOD1 gene

Discussion

We diagnosed our patient as having FALS because of the progressive systemic motor neuron signs and the positive family history. A clinical characteristic of the patient was fairly slow progression of the illness. Another remarkable clinical features were prominent sensory and autonomic disturbances, but the possibility of polyneuropathy associated with vitamin deficiency was ruled out.

The durations from the onset of illness to the appearance of overt respiratory symptoms in the patient and his

Acknowledgements

We thank Drs T. Joichi, R. Okiyama, T. Shimizu, Y. Shiio, M. Suda and T. Kanda who provided the detailed clinical information on this patient and also thank Drs K. Houi and T. Kobayashi for the measurement of the levels of SOD1 activity in the fibroblasts. We also are grateful to Drs R. Takahashi and H. Misawa for advice and discussion and T. Tsuchikura for secretarial assistance.

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