Juvenile amyotrophic lateral sclerosis type 4: case report and review

Juvenile amyotrophic lateral sclerosis (ALS) presents a group of few rare monogenic disorders with onset from early childhood up to 25 years and much more benign course than “classic” ALS. Autosomal dominant ALS type 4 (ALS4) related to SETX gene is one of them. In spite of characteristic combined involvement of central and peripheral motor neurons, ALS4 clinical diagnostics may be difficult, particularly in atypical and/or non‑familial cases and electroneuromyography underestimation. Massive parallel sequencing permits diagnosing majority of cases and performing genetic counselling in families.
Aim of this work: to describe non‑familial ALS4 case detected by whole‑exome sequencing and present a review on poorly known disorder.
A 21‑year‑old female patient in a consanguineous family was examined; methods: clinical, genealogical, electroneuromyography, peripheral nerves ultrasound; molecular: panel and whole‑exome sequencing, bioinformatical analysis.
The girl is an only child and an only patient in a family of Mountain Jews – first cousins. She had spastic paraparesis since age of independent walking (1.5 y.o.) and early feet deformation, her first diagnosis was cerebral palsy. In 12 years spasticity progressed, walking was lost. After orthopedic surgery in 15 years supported walking restored, at that age leg distal amyotrophy developed with no further progressing. Due to electroneuromyography results polyneuropathy was misdiagnosed. In 21 years repeated electroneuromyography excluded polyneuropathy and detected generalized motor neuron impairment and juvenile ALS was suggested. On neurological examination pronounced spastic paraparesis together with peripheral leg paraparesis without sensory impairment were detected; her supported gait was of mixed spastic and paretic types; there were no fasciculations or fibrillations.
Whole‑exome sequencing detected a novel heterozygous missense mutation c.4442A>G (p.Lys1481Arg) in SETX exon 10. Sanger familial sequencing was not possible, but DNA finding matching the phenotype supported ALS4 diagnosis. Juvenile ALS4 (SETX gene) is a relatively benign autosomal dominant disease, imitating in different stages other nervous disorders of early and young age; genealogy is not always informative. Along with typical cases (like our patient) clinical variability exists. Electroneuromyography is the main instrumental tool. Methods of massive parallel sequencing are optimal in DNA testing of juvenile ALS.