Amyotrophic Lateral Sclerosis 2, Juvenile

A number sign (#) is used with this entry because juvenile amyotrophic lateral sclerosis-2 (ALS2) can be caused by homozygous mutation in the gene encoding alsin (ALS2; 606352) on chromosome 2q33.

Juvenile primary lateral sclerosis (PLSJ; 606353) and infantile-onset ascending spastic paralysis (IAHSP; 607225) are allelic disorders with overlapping phenotypes.

For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).

Clinical Features

In an Amish isolate, Gragg et al. (1971) observed 2 brothers with onset in the first decade of the ALS symptom complex: distal muscular atrophy, increased deep tendon reflexes, spasticity, and fasciculations. Refsum and Skillicon (1954) described the same phenotype in 2 brothers and a sister, with onset between 3 and 5 years of age. They stated that the condition was indistinguishable from amyotrophic lateral sclerosis (ALS; 105400).

Hentati et al. (1992, 1994) reported a Tunisian family in which 10 members had juvenile-onset ALS with symptoms beginning between ages 3 and 23 years. The disorder was characterized by progressive spasticity of the limb, facial, and pharyngeal muscles with spastic gait and spastic dysarthria. Some patients had amyotrophy of the hands and peroneal muscles. Several patients had uncontrolled laughter and weeping, consistent with pseudobulbar symptoms. This family had also been reported in a larger series of affected families by Ben Hamida et al. (1990).

Kress et al. (2005) reported a Turkish man, born of consanguineous parents, with juvenile ALS confirmed by mutation in the ALS2 gene (606352.0011). He had a severe disease course with onset at age 2 years of difficulty walking, spastic gait, hyperreflexia, and extensor plantar responses. Spastic tetraparesis and pseudobulbar paralysis developed at ages 12 and 15 years, respectively. He became wheelchair-bound at age 16 and anarthric at 18. He also had mild distal amyotrophy of the upper and lower limbs.

Shirakawa et al. (2009) reported 2 Japanese brothers, born of unrelated parents, with juvenile ALS. The older brother, who was more severely affected, started walking on tiptoes at age 13 months and had never run. He developed dysarthria at age 11 years and lost the ability to speak at 14. At age 32, he had lower limb spasticity, extensor plantar responses, and complete paralysis of the tongue. He had mild signs of lower motor neuron involvement, with distal muscle atrophy of the limbs, and normal cognition. The younger brother had a milder disease course, with walking at age 3 years, but ability to participate in gym during elementary school. At age 23, he had unintelligible speech, mild muscle atrophy in the extremities, and normal cognition.

Clinical Variability

Sheerin et al. (2014) reported 2 unrelated consanguineous families in which a sib pair had ALS2 manifest as severe spastic quadriparesis and generalized dystonia. Two sibs of Bangladeshi descent had upper and lower limb spasticity that began in early childhood. The sister had global developmental delay and did not walk by age 2 years, whereas the brother had normal motor milestones and started toe-walking at age 12 months. At age 13 years, the sister was wheelchair-bound with marked limb spasticity, contractures, dystonia, nystagmus, anarthria, and distal lower-limb wasting, suggesting lower motor neuron involvement. At age 7 years, the brother had limb spasticity with clonus and dystonia, ataxia, and hyperreflexia. Both patients also had mild microcephaly. An unrelated 32-year-old Turkish man was severely affected. He had difficulty walking at age 2 to 3 years and became wheelchair-bound at age 8. The disorder was progressive, and he became anarthric with dysphagia, profound muscle weakness and atrophy, contractures, spasticity, dystonia, opisthotonus, and retrocollis. Deep-brain stimulation did not result in improvement. Cognition appeared intact. His sister was reportedly similarly affected. Sheerin et al. (2014) noted that these patients exhibited dystonia in addition to classic signs of ALS, thus expanding the phenotypic spectrum associated with ALS2.

Mapping

By linkage analysis of a large consanguineous Tunisian family with juvenile ALS, Hentati et al. (1992) established linkage to chromosome 2q33-q35 (maximum lod score of 7.67 at marker D2S72). Haplotype analysis indicated a 20- to 25-cM interval between CRYG (123660) and COL3A1 (120180). By further linkage analysis in this family, Hentati et al. (1994) refined the ALS2 locus to an 8-cM region between D2S115 and D2S155. By linkage and haplotype analyses, Hosler et al. (1998) refined the ALS2 locus to a 1.7-cM region. Hadano et al. (1999) assigned the ALS2 gene to 2q33-q34 by inclusion within a YAC contig.

Molecular Genetics

In affected members of the Tunisian family reported by Ben Hamida et al. (1990) and Hentati et al. (1992, 1994), Yang et al. (2001) and Hadano et al. (2001) identified a homozygous mutation in the ALS2 gene (606352.0001).

In 2 pairs of sibs from 2 unrelated consanguineous families with severe juvenile ALS associated with dystonia, Sheerin et al. (2014) identified 2 different homozygous truncating mutations in the ALS2 gene (G668X, 606352.0016 and c.4573dupG, 606352.0017). The mutation in 1 family was found by whole-exome sequencing, whereas the mutation in the other family was found by candidate gene sequencing. Functional studies of the variants were not performed.