• amylotrophic lateral sclerosis
• superoxide dismutase

A myotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the degeneration of motor neurons in the spinal cord, brain stem, and motor cortex, resulting in paralysis of limb, bulbar, and respiratory muscles. About 10% of ALS show a familial trait, and up to 20% of familial ALS is caused by missense mutations of Cu/Zn superoxide dismutase (SOD1). More than 70 mutations have been reported, including a mutation hotspot at codon 93.¹ Mice expressing human mutant SOD1 develop age dependent ALS-like neurological symptoms and pathological features of motor neuron degeneration and cytoplasmic inclusions consisting of mutant SOD1. Patients with SOD1 mutations represent divergent phenotypes, including age of onset, duration of disease, and clinical symptoms, mostly depending on the nature of SOD1 mutation. Acceleration of the age of onset in successive generations called anticipation has been reported in the missense mutations at codon 84 (L84F and L84V) in the SOD1 mutations in Japan, the United States, and Italy.² We experienced anticipation of age at onset in Japanese families with SOD1-G93S mutation. In the families with the G93S mutation, age of onset became younger in the patients of successive generations, exhibiting anticipation (fig 1). We estimated the degree of anticipation of onset age in nine parent-offspring pairs from four Japanese families with G93S mutation of SOD1 (fig 1). The mean age of onset was 64.4 (SD 6.30) years in the parents, against 44.8 (SD 12.1) years in the offspring in the patients. The mean difference in age of onset in the parent-offspring pairs was 19.6 (SD 10.4) years in the G93S families, showing a statistical significance (p=0.0005 by paired t test and p=0.0077 by Wilcoxon test; fig 1). Thus, the age of onset accelerated in successive generations in the patients with G93S mutation. In addition, the duration of diseases with G93S mutation was slightly longer in the children than in the parents, although the difference was not significant (fig 1). Six amino acid substitutions (Ser [S], Val [V], Asp [D], Ala [A], Cys [C], and Arg [R]) have been known at glycine 93 of SOD1. Position 93 is located at the apex of a β hairpin joining two β strands of the SOD1 monomer, and it is critical for the stability of the backbone conformation of SOD1. These substitutions are all of the possible single base changes in codon 93, as the changes in the third position of the codon conserve its coding for glycine. However, the age of onset of patients with other mutations at codon 93 such as G93A mutation remained uniform.^1,3 The patients with G93S mutation present a relatively late onset with a long clinical course, compared with those with G93A mutation:G93S v G93A; 51.9 (SD 14.9) and 43.1 (SD 16.6) years in onset age; and 7.1 (SD 3.1) and 2.4 (SD 1.4) years in disease duration.³ The present results imply that different amino acid substitution at codon 93 resulted in different phenotypes, but anticipation could be a unique feature in familial ALS with G93S mutation. It is still possible that anticipation is due to observer bias in that one does not know whether other offspring are going to get the disease later but are not affected at this stage. Although the mutation testing in all unaffected members is necessary to completely solve this issue, this is somewhat difficult because of ethical problems. At least the eldest sisters in families 1 and 3 (fig 1), who are alive without any symptoms over the age of onset of their parents, are shown to have no mutation of SOD1, further supporting the present view and alleviating the observer bias. Although anticipation has been reported in several neurodegenerative diseases, including most of the polyglutamine diseases, familial amyloidotic polyneuropathy (FAP) with V30M mutation of transthyretin and Creutzfelt-Jakob disease (CJD) with E200K mutation of prion, the molecular basis for anticipation is understood only in the polyglutamine diseases with instability of CAG repeat expansion.^4,5 It is unknown whether the mechanism for anticipation is the result of an additional genetic effect or of a related environmental factor. Anticipation was documented in the particular codons of the target proteins in FAP⁴ and CJD⁵, as well as in familial ALS, suggesting the presence of genetic background, which interacts with particular codon mutations. The G93S mutation was reported almost exclusively in Japan, whereas other glycine 93 mutations were demonstrated elsewhere. It would be of interest to compare our results with the G93S mutation in other countries. Factors that generate anticipation of the G93S mutation might be related to the ethnic genetic determinants in addition to the difference of amino acid substitution at position 93, exacerbating the conformational abnormality of mutant SOD1 between successive generations.

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Figure 1

Pedigrees and anticipation of familial ALS with SOD1-G93S mutation. The nine parent-offspring pairs in four families (A, B, C, and D) were subjected to statistical analysis. The left and right sided numbers indicate age at onset and years of disease duration. The probands are indicated by arrows. Age differences at disease onset and duration between the parent and offspring generation (E) are calculated for the four families including the family (D) data⁶ (reprinted from J Neurol Sci with permission from Elsevier Science), and expressed as mean (SD, SEM). *Paired t test; †Wilcoxon test.