back to the list

Amyotrophic Lateral Sclerosis - C9orf72, SOD1, TARDBP, FUS, FIG4, ANG

Lou Gehrig's disease

Clinical Features

Amyotrophic lateral sclerosis is a progressive degenerative disease affecting the motor neurons of the brain and spinal cord. ALS is characterized by the symptom triad:

• spinal muscle atrophy
• bulbar paresis and
• spastic spinal paralysis

The mean age of onset for "sporadic" ALS (i.e., ALS occurring in individuals with no family history of ALS) is 56 years. Approximately 10 to 15% of the cases have a positive family history for ALS. Familial ALS (FALS) is clinically very similar to sporadic ALS. The mean age of onset is earlier at about 46 years.

There may be a substantial clinical overlap of ALS with other genetic disorders affecting motor neuron functions, in particular  distal hereditary motor neuropathies (dHMN), adult onset spinal muscular atrophy (SMAIV; e.g. by mutations in VAPB, ALS8), or in males – spinal and bulbar muscular atrophy (SBMA). If there is a predominant affection of central motor neurons, symptoms may resemble primary lateral sclerosis (PLS) that may be caused by mutations in FIG4 or the alsin gene (ALS2, juvenile type). If a spasticity of the lower extremities is prominent, there may be a clinical overlap with the hereditary spastic paraparesis (HSPs).

Genetic Information

In the majority of cases FALS  is an autosomal dominant disorder but other modes of inheritance (autosomal recessive, X-linked) are possible. The genetic causes of ALS are heterogeneous:

• C9ORF72 gene (chromosome 9p21): Recently, a hexanucleotide repeat expansion of the C9ORF72 gene has been identified as underlying genetic cause in chromosome 9p21 linked FLTD (frontotemporal lobar degeneration) and ALS (Renton AE et al, Neuron 2011). The mutation in C9ORF72 has been frequently identified in different patient cohorts of familial (up to 46%) and sporadic forms (up to 21% in Finnish cohort)

• In up to 12-20% of the affected individuals with autosomal dominant inheritance, and in about 3% of patients with sporadic ALS, mutations are found in the copper zinc superoxide dismutase-gene (SOD1;  ALS1; chromosome 21q22.1).

• Mutations of the TAR DNA binding protein 43-gene (TARDBP; ALS10; chromosome 1p36.2) account for about 4% of all FALS and are transmitted in an autosomal dominant fashion.

• Mutations of the fused in sarcoma-gene (FUS; ALS6; chromosome 16p11.2)) account for about 4% of all FALS and are transmitted in an autosomal dominant fashion.

In addition, there are several other genes/gene loci known as causative for FALS that – acoording to current knowledge – contribute to only a small fraction of ALS patients, among them:

• FIG4 gene (SAC domain containing inositol phosphatase 3; SAC3, chromosome 6q21, ALS 11): Mutations in FIG4 have been originally described in patients with autosomal rezessive hereditary neuropathy (CMT4J). Subsequently, dominant mutations have been found in 1-2% of an ALS cohort (FALS/and SALS patients).

• Mutations of the angiogenin-gene (ANG; ALS9; chromosome 14q11) have been described as a cause of ALS in less than 1% of familial and sporadic ALS. Frequently, these patient had early and prominent bulbar symptoms. ANG mutations may be  transmitted in an autosomal dominant fashion or represent risk factors in certain populations.

Prevalence

Approximately 1 : 25 000 in the European population

Diagnostic