Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of the upper and lower motor neurons. Most cases appear to be sporadic, but 5-10% of cases have a family history of the disease (FALS) 1. To date, more than a dozen causative genes have been identified in hereditary ALS and more than 30 potential causative or disease-modifying genes have also been identified 2, 3.
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.
Table 1. Overview of genes in Amyotrophic lateral sclerosis panel
|Gene||OMIM (Gene)||Associated diseases (OMIM)||Inheritance||CentoMD® exclusive variant numbers (++)|
|ALS2||606352||amyotrophic lateral sclerosis 2; Spastic paralysis, infantile onset ascending||AR||20|
|ANG||105850||amyotrophic lateral sclerosis 9||9|
|CHCHD10||615903||Frontotemporal dementia and/or amyotrophic lateral sclerosis 2||AD||2|
|CHMP2B||609512||Dementia, familial, nonspecific; amyotrophic lateral sclerosis 17||AD||3|
|DCTN1||601143||amyotrophic lateral sclerosis 1; Perry syndrome; Neuronopathy, Distal Hereditary Motor, Type Viib||AD, AR||12|
|ERBB4||600543||Amyotrophic lateral sclerosis 19||AD||2|
|FIG4||609390||Yunis-Varon syndrome; type 4J Charcot-Marie-Tooth disease; amyotrophic lateral sclerosis 11; Polymicrogyria, bilateral temporooccipital||AD, AR||34|
|FUS||137070||amyotrophic lateral sclerosis 6; Tremor, hereditary essential, 4||AD||26|
|HNRNPA1||164017||Amyotrophic lateral sclerosis 20||AD||1|
|MATR3||164015||Myopathy, Distal, 2||AD||0|
|NEFH||162230||amyotrophic lateral sclerosis 1; Charcot-Marie-Tooth disease, axonal, type 2CC||AD, AR||8|
|OPTN||602432||Adult-onset primary open angle glaucoma; Glaucoma, normal tension, susceptibility to; amyotrophic lateral sclerosis 12||AD||7|
|PFN1||176610||amyotrophic lateral sclerosis 18||4|
|PRPH||170710||amyotrophic lateral sclerosis 1||AD, AR||0|
|SETX||608465||amyotrophic lateral sclerosis 4; autosomal recessive spinocerebellar ataxia 1||AD, AR||78|
|SIGMAR1||601978||distal spinal muscular atrophy type 2; amyotrophic lateral sclerosis 16||AR||18|
|SOD1||147450||amyotrophic lateral sclerosis 1||AD, AR||6|
|SPG11||610844||Amyotrophic lateral sclerosis 5, juvenile; spastic paraplegia type 11; Charcot-Marie-Tooth disease, axonal, type 2X||AR||68|
|SQSTM1||601530||Frontotemporal dementia and/or amyotrophic lateral sclerosis 3; Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset||AD, AR||5|
|TARDBP||605078||amyotrophic lateral sclerosis 10||AD||11|
|TBK1||604834||Frontotemporal dementia and/or amyotrophic lateral sclerosis type 4||AD||1|
|TUBA4A||191110||amyotrophic lateral sclerosis 22||AD||2|
|UBQLN2||300264||amyotrophic lateral sclerosis 15||XLD||1|
|VAPB||605704||Finkel type late-onset spinal muscular atrophy; amyotrophic lateral sclerosis 8||AD||3|
|VCP||601023||amyotrophic lateral sclerosis 14; Charcot-Marie-Tooth disease type 2Y||AD||14|