Amyotrophic lateral sclerosis and primary lateral sclerosis (ALS-PLS) [38 genes]

• Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a prevalence of 5.4/100,000 (Chiò et al., 2013). Even though most cases are of sporadic presentation, previous family history exists in 10% of patients. Pathogenic variants in the C9orf72, SOD1, TARDBP, and FUS genes explain almost two-thirds of the familial forms (25%, 20%, 5%, and 5% respectively). In the C9orf72 gene, a single genetic alteration associated with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia has been detected, consisting of a (GGGGCC)n repeat expansion not detectable by NGS.
• Primary lateral sclerosis (PLS) is characterized by isolated involvement of upper motor neurons, which distinguishes it from amyotrophic lateral sclerosis, where lower motor neurons are also compromised. The diagnosis of PLS is made by excluding disease causes such as spastic paraplegia, multiple sclerosis, metabolic disease, or myelopathy.

Pathogenic variants in the genes C9orf72, SOD1, TARDBP and FUS explain almost two-thirds of the familial forms (25%, 20%, 5% and 5% respectively). In the C9orf72 gene, a single genetic alteration has been identified, associated with ALS and/or frontotemporal dementia, consisting of a GGGGCC hexanucleotide expansion, not quantifiable using NGS techniques.

Diagnosis, prognosis and genetic counseling in affected patients and family members.

• ALS2, FIG4, SPG11, TBK1: Primary lateral sclerosis
• CHCHD10, SQSTM1, TBK1: Primary lateral sclerosis with/without frontotemporal dementia
• SLC52A2, SLC52A3: Brown-Vialetto-Van Laere/Fazio-Londe syndrome

Patients with clinical suspicion of amyotrophic lateral sclerosis or primary lateral sclerosis.