Heterozygous S44L missense change of the spastin gene in amyotrophic lateral sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a clinically and genetically heterogeneous group of disorders affecting the upper and lower motor neurons. Mutations in the spastin gene represent the most common cause of dominantly inherited hereditary spastic paraplegia (HSP). The majority of patients with spastin mutations develop uncomplicated HSP, but additional features are common. Here we report a patient with rapidly progressing adult-onset ALS. Molecular genetic analysis revealed a heterozygous missense change (S44L) of the spastin gene.

Methods: The patient was a 50 year old woman, who developed a rapidly progressing paresis of the lower limbs at age 48. Two years after the onset, the revised ALS Severity Scale score is 18 of 48. Genomic DNA from the patient was isolated from peripheral blood leukocytes. All 17 exons and flanking intronic sequences of the spastin gene were amplified by PCR and followed by single strand conformation analysis (SSCP) and direct DNA sequencing.

Results: Mutation analysis of the spastin gene identified a previously described heterozygous missense change (c.131C>L) located in exon 1 (RefSeq NM_014946). The sequence variant is predicted to replace serine by leucine in position 44 (S44L) of the putative spastin protein.

Conclusion: The single case of ALS with a spastin mutation presented here does not allow any conclusion about causality, but there is also no evidence against a monogenic cause of ALS by a spastin mutation. Alternatively, the spastin S44L change may serve as a previously unknown genetic risk factor for ALS. The present study suggests that spastin sequence changes may contribute to a wider range of phenotypes, including ALS. Given the common and perhaps universal finding of axonal dysfunction in both ALS and HSP, variants of the spastin gene may contribute to a common pathway in the complex pathogenesis of motor neuron disorders.