Clinical and pathological studies of familial amyotrophic lateral sclerosis (FALS) with SOD1 H46R mutation in large Japanese families

Abstract

We clarified the clinical and pathological aspects of familial amyotrophic lateral sclerosis (FALS) with SOD1 H46R heterozygous mutation in the Miyakonojo Basin, a region in southern Japan where the prevalence of ALS is 11.4 per 10(5) of the population. We studied 17 patients, including one autopsy case, in three FALS families with the mutation. The average age at disease onset in the families was 44.3+/-8.7 years, and the mean disease duration was 12+/-7.6 years, with a range of 6 to 30 years. Ten of 17 patients were unable to walk by the mean age of 56.4+/-12.2 years. The initial symptom was muscle weakness in the distal leg muscle in all patients. The autopsy findings of one FALS patient showed atrophy of lateral and anterior funiculi, decreased numbers of anterior horn cells, preserved posterior funiculus and absence of neuronal inclusion bodies. Percentages of mutant SOD1 protein measured by mass spectrometry were 14% in erythrocytes, 43% in the spinal cord, 47% in the iliopsoas muscle and 60% in the diaphragm. In this study, we confirmed that FALS with SOD1 H46R mutation showed uniform initial symptoms and slow disease progression with intra-familial variation of disease severity and that inclusion body formation is not essential in FALS with this mutation.

Distinctive clinicopathological features of 2 large families with amyotrophic lateral sclerosis having L106V mutation in SOD1 gene

“…There have been no reports of accumulation of p-TDP43 in SOD1 mutations except for the C111Y mutation [34], and Bunina bodies have not been reported in SOD1 gene mutations. The severe motor neuron loss and slight degeneration of the corticospinal tracts observed in the present patients were common to other SOD1 mutations, such as A4V [14,15], A4T [16], H43R [17], H46R [35,36], H48Q [37], D101N [38], and L144FVX [39] (Table 4, Fig. 4B).…”

Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production

“…In effect, the H46RH48Q mice developed ALS despite remarkably little muscle mass loss. Incidentally, ALS patients with the H46R mutation have a very long survival (4). The different patterns of muscle atrophy in the G93A and H46RH48Q mutants provide insight into the role of denervation in the etiology of ALS.…”

Flexor-dominant myopathic phenotype in patients with His46Arg substitution in the Cu/Zn superoxide dismutase gene

“…Arisato et al [3] report that FALS patients with the SOD1 H46R mutation invariably exhibit uniform initial symptoms of muscle weakness in a unilateral distal leg. Our paper is the first to report that the initial symptoms at an early stage of the disease are restricted to the flexor muscle group in the unilateral distal leg.…”

“…Our patients originated from a region in southern Japan that is known to have a high prevalence of FALS. Arisato et al [3] clarified the clinical and pathological aspects of FALS associated with SOD1 H46R heterozygous mutation in this region. Ohi et al [16,17] also evaluated the clinical features of FALS families from this area with the H46R mutation in SOD1.…”

“…All 3 patients were originally from a region in southern Japan that is known to have a high prevalence of FALS associated with the H46R mutation of SOD1 [3]. In order to confirm whether this atypical form of flexor dominant muscle weakness and wasting in the lower limbs was attributed to a SOD1 mutation, genetic analysis was performed.…”