Amyotrophic lateral sclerosis (ALS)

Autosomal dominant, autosomal recessive, X-linked dominant

Prevalence: 4-8/100,000 ^{1, 4}

Major clinical symptoms ^{1, 5}:

• Asymmetric focal weakness of the extremities (stumbling or poor handgrip)
• Dysarthria
• Dysphagia)
• Muscle fasciculations
• Muscle cramps

Presence of all of the following clinical features ^{1, 5}:

• Signs of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination
• Signs of upper motor neuron (UMN) degeneration by clinical examination
• Progressive spread of symptoms or signs within a region or to other regions
• Absence of evidence of other diseases that could cause UMN or LMN degeneration and/or explain the electrophysiologic or neuropathologic results

For familial cases of ALS: Identification of a heterozygous pathogenic variant in one of the following genes ^{2, 3} (Table 1):

• SOD1 (frequency of pathogenic variants approximately 20%) ^1-3
• C9orf72 (23%-30%) ^1-3
• TARDBP (1%-4%) ^1-3
• FUS (4%) ^1-3
• SETX, FIG4, ANG and others (Table 1).

There is no cure for ALS to date, but symptomatic treatment can relieve symptoms ^{1, 6}.

• Care by a multidisciplinary team (neurologist, pulmonologist, speech, physical and occupational therapist, nutritionist, psychologist, social worker, and genetics professional) ⁶.
• The two FDA–approved drugs riluzole and edaravone, slow the progression of symptoms
• Antidepressants, bensodiazepines, baclofen, for muscle cramps and spasticity
• Ventilator assistance

• Spinal and bulbar muscular atrophy
• Spinal muscular atrophy
• Distal hereditary motor neuronopathy type VIIB
• Primary lateral sclerosis
• Hereditary spastic paraplegia
• Hexosaminadase A deficiency
• Inclusion body myopathy associated with Paget disease of bone and/or frontotemporal dementia 

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for ALS using NGS Panel Genomic:

Step 1: Whole genome sequencing from a single filter card (drop of blood), covering the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the ALS panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variant is identified in Step1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.   

• Individuals with a positive family history of ALS
• Individuals with most common symptoms of ALS (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of ALS can allow for genetic counseling and may direct medical management.