Primary Lateral Sclerosis, Adult, 1

Description

Although primary lateral sclerosis (PLS) is similar to amyotrophic lateral sclerosis (ALS; 105400), they are considered to be clinically distinct progressive paralytic neurodegenerative disorders. Following a period of diagnostic confusion, the clinical distinction between ALS and PLS became clear and diagnostic criteria were established (Pringle et al., 1992). PLS is characterized by degeneration of the upper motor neurons and the corticospinal and corticobulbar tracts, whereas ALS is a more severe disorder characterized by degeneration of both the upper and lower motor neurons.

See 606353 for autosomal recessive juvenile-onset PLS, which is caused by mutations in the ALS2 gene (606352).

Clinical Features

Pringle et al. (1992) reported 8 unrelated patients with adult-onset sporadic PLS and suggested diagnostic criteria. Clinical features were limited to those associated with the descending motor tracts and included spastic tetraparesis, pseudobulbar affect, spastic dysarthria, hyperreflexia, and extensor plantar responses. The mean age at onset was 50 years, and the disorder was slowly progressive. Neuropathologic findings showed selective involvement of the motor cortex with atrophy of pyramidal cells and degeneration of the lateral corticospinal tracts. Lower motor neurons were spared.

Dupre et al. (2007) reported a 3-generation French-Canadian family in which 8 living members had primary lateral sclerosis inherited in an autosomal dominant pattern. Four decreased family members were reportedly affected. Age at onset ranged from 30 to 60 years, with an average of 48.4 years. The disorder began with progressive asymmetric spastic paraparesis and weakness of the lower limbs followed by upper limb involvement. Bulbar symptoms developed later with spastic dysarthria and dysphagia. Reflexes were diffusely increased and sensation was normal. Nerve conduction abnormalities consistent with an axonal neuropathy occurred in some patients later in the disease. Brain MRI was normal in all, but 2 patients showed mild spinal cord atrophy. The disorder appeared to involve only upper motor neurons. Linkage analysis excluded multiple loci including ALS2.

Mapping

By genomewide scanning of a large French Canadian family with adult PLS (Dupre et al., 2007), Valdmanis et al. (2008) identified a 23.17-cM candidate region on chromosome 4ptel-4p16.1 (maximum lod score of 3.01 at D4S2936) that they termed PLS1.

Molecular Genetics

Exclusion Studies

Brugman et al. (2007) found no mutations in the ALS2 gene among 51 presumably unrelated Dutch patients with adult-onset PLS.

In a large French Canadian family with adult PLS, Valdmanis et al. (2008) excluded mutations in the MYL5 gene (160782) by molecular analysis.

Nomenclature

Valdmanis et al. (2008) referred to the locus on chromosome 4ptel-p16.1 as 'PLS1'; however, this symbol has been reserved for the plastin-1 gene (602734).