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Keywords:

  • A4D;
  • ALS mutation database;
  • amyotrophic lateral sclerosis;
  • SOD1 mutation

Abstract

  1. Top of page
  2. Abstract
  3. Acknowledgements
  4. References
  5. Supporting Information

Our objective was to obtain clinical presentations of familial amyotrophic lateral sclerosis (FALS) with a novel Ala4Asp (A4D) SOD1 mutation in a Japanese family and to determine the epidemiological features of the SOD1 mutation on the basis of the ALS mutation database. The clinical histories and neurological findings of three affected individuals in a Japanese FALS pedigree are described. DNA analysis of SOD1 was conducted by a direct nucleotide sequence analysis. We identified a novel heterozygous A4D mutation in exon 1 in SOD1. The clinical presentations of the family were characterized by late age at onset and rapid progression. Comprehensive analysis of genotype-phenotype correlations using the ALS mutation database revealed that all the patients with SOD1 amino acid 4 mutations tended to have a rapid progressive course of the disease with a duration of 1.27 years. The age at onset varied among SOD1 amino acid 4 mutations, but all three patients with A4D mutation had a very late age at onset of over 70 years. In conclusion, FALS patients with a novel A4D mutation in SOD1 showed a late age at onset with a rapid disease course. This study supports the previous observations that SOD1 amino acid 4 mutations contribute to the acceleration of disease progression and emphasizes the usefulness of the ALS mutation database.

Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons. Most cases are sporadic (SALS), whereas about 5–10% are familial (FALS). Mutations in the superoxide dismutase-1 gene (SOD1) have been shown to be frequent (20%).[1, 2] The substitution of valine for alanine at amino acid 4 (A4V) is responsible for about 50% of SOD1 mutations in North America and causes a rapidly progressive phenotype.[3] FALS patients with substitutions of threonine (A4T), serine (A4S) or phenylalanine (A4F) for alanine 4 have also been reported.[4-6] We herein report the clinical presentations of a Japanese FALS family with a novel Ala4Asp (A4D) mutation of SOD1, referring to the ALS mutation database that we have recently constructed.[2]

The pedigree chart is shown in Fig 1a. All three patients displayed a rapidly progressive disease course and a late disease onset. Their clinical features are briefly described as follows. (Their detailed clinical features and laboratory data are presented in Supplementary Table 1.)

image

Figure 1. (a) Pedigree charts of family with Ala4Asp (A4D) mutation in the superoxide dismutase-1 gene (SOD1). Amyotrophic lateral sclerosis (ALS)-affected individuals are indicated by filled symbols. Unaffected individuals are indicated by open symbols. Slashed symbols indicate the deceased subjects. Squares denote the male family members and circles denote the female family members. Their father (II-4) died of cerebrovascular disease at the age of 70. Their mother (II-6) died of respiratory failure at the age of 81. She had suffered from gait disorder before her death, but detailed information about her symptoms was not available. Their elder brother (III-1) died of cerebrovascular disease at the age of 48. Their younger brother (III-7) died of pneumonia in his first year of life. No other familial history of a similar disease or premature death was noted. There was no consanguineous marriage. (b) Electropherogram of heterozygous SOD1 c.14A>C (Ala4Asp (p.Ala5Asp)) point mutation (arrow) in Case 1 (III-5). Since the first methionine (Met) is excised in mature SOD1, the second encoded amino acid (alanine (Ala)) has been conventionally assigned as residue 1 to describe mutations. The Human Genome Variation Society (HGVS, www.hgvs.org) recommends assigning the first Met as residue 1. Since genotype–phenotype correlations of previously reported SOD1 mutations are described for comparing the clinical presentations in this manuscript, the conventional nomenclature is used. Nomenclature based on the recommendation of HGVS is shown in parenthesis. (c). Mutational analysis of the patients with A4D mutation and previously reported SOD1 mutations utilizing the ALS mutation database.[2] The relationship between the average age of onset and disease duration for each mutation is shown in small diamonds. The data of all patients with A4V and A4T in the ALS mutation database and three familial ALS (FALS) patients in the pedigree with A4D in the present study are also plotted respectively using triangles, squares and circles. The age at onset is the time of the appearance of the first sign of muscle weakness, atrophy or clinical symptoms involving upper or lower motor neurons. The disease duration is the number of years until initiation of mechanical ventilation or death.

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Case 1 (III-5)

A 76-year-old man presented with progressive upper limb weakness and dysarthria. Upper limb weakness, dysarthria and respiratory impairment gradually worsened. He died of respiratory failure 13 months after onset.

Case 2 (III-4)

A 79-year-old woman noted right arm weakness. Muscle weakness gradually worsened and she died of respiratory failure 15 months after onset.

Case 3 (III-9)

A 71-year-old woman noted twitching of facial muscles and dysarthria, and she was diagnosed as having bulbar-type ALS. Dysarthria, dysphagia and muscle weakness worsened rapidly and she died of respiratory failure 13 months after onset.

Mutational analysis of the two affected siblings, III-5 and III-4, revealed a novel heterozygous A4D mutation of SOD1 (Fig. 1b), confirming the cosegregation of the mutation. The mutation was absent in 520 chromosomes from healthy controls.

We compared the clinical presentations of the patients carrying the novel A4D mutation with those of patients with previously reported SOD1 mutations utilizing the ALS mutation database.[2] All the patients with mutations involving alanine 4 tended to have a rapidly progressive disease course; the mean period from the onset to initiation of mechanical ventilation or death is 1.27 years (Fig. 1c). Although the age at onset varied, all the patients with the A4D mutation had a strikingly late onset at over 70 years of age. In addition to the markedly late onset, the uniformity of the disease onset and severity among family members is considered to be characteristic of the A4D mutation.

The factors leading to the modification of disease-initiating events or disease progression need to be elucidated.[5] This study supports the previous observations that SOD1 amino acid 4 mutations contribute to the acceleration of disease progression and emphasizes the usefulness of the ALS mutation database.[2]

Acknowledgements

  1. Top of page
  2. Abstract
  3. Acknowledgements
  4. References
  5. Supporting Information

This work was supported in part by KAKENHI (Grant-in-Aid for Scientific Research on Innovative Areas (22129001 and 22129002), and the Global COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a Grant-in-Aid (H21-Kokoro-Ippan-016) from the Ministry of Health, Welfare and Labour, Japan.

References

  1. Top of page
  2. Abstract
  3. Acknowledgements
  4. References
  5. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Acknowledgements
  4. References
  5. Supporting Information
FilenameFormatSizeDescription
ncn38-sup-0001-TableS1.pdfapplication/PDF44KTable S1. Summary of clinical features of affected members

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