Novel Compound Heterozygous Als2 Mutations Cause Juvenile Amyotrophic Lateral Sclerosis in Japan

Homozygous mutations in ALS2 on chromosome 2q33 are responsible for autosomal recessive, early-onset forms of upper motor neuron diseases such as infantile ascending hereditary spastic paraplegia (IAHSP) and juvenile primary lateral sclerosis (JPLS).1 These mutations are rarely associated with lower motor neuron involvement in juvenile amyotrophic lateral sclerosis (JALS).2 Seventeen mutations from 16 families have been reported, but the phenotype–genotype correlation remains unclear.3–5 We searched for ALS2 mutations in 2 Japanese siblings presenting with infantile-onset ascending spastic paraplegia, pseudobulbar palsy, and amyotrophy of the extremities. ### Case reports. The older sibling was a 32-year-old Japanese man who started walking on tiptoes at 13 months of age and had never run. He developed dysarthria at 11 years of age and lost the ability to speak at 14. He displayed spasticity predominantly in the lower limbs, bilateral extensor plantar responses, and complete paralysis of the tongue without atrophy or fasciculation at 32 years of age. He also had discrete signs of lower motor neuron involvement manifesting as muscular atrophy of the distal upper and lower limbs. However, he was ambulatory with support and there was no evidence of cognitive dysfunction. Brain and spinal MRI showed no abnormalities. The peripheral nerve conduction velocities and latencies were …