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, juvenile; Primary lateral sclerosis, juvenile; Spastic paralysis, infantile onset ascending||AR||17|
|ANG||105850||Amyotrophic lateral sclerosis 9||9|
|CHCHD10||615903||Spinal muscular atrophy, Jokela type; Frontotemporal dementia and/or amyotrophic lateral sclerosis 2; ?Myopathy, isolated mitochondrial, autosomal dominant||AD||0|
|CHMP2B||609512||Dementia, familial, nonspecific; Amyotrophic lateral sclerosis 17||AD||3|
|DCTN1||601143||Amyotrophic lateral sclerosis, susceptibility to; Perry syndrome; Neuropathy, distal hereditary motor, type VIIB||AD, AR||11|
|ERBB4||600543||Amyotrophic lateral sclerosis 19||AD||1|
|FIG4||609390||Yunis-Varon syndrome; Charcot-Marie-Tooth disease, type 4J; Amyotrophic lateral sclerosis 11; ?Polymicrogyria, bilateral temporooccipital||AD, AR||34|
|FUS||137070||Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia; Essential tremor, hereditary, 4||AD||26|
|HNRNPA1||164017||?Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3; Amyotrophic lateral sclerosis 20||AD||0|
|MATR3||164015||Amyotrophic lateral sclerosis 21||AD||0|
|NEFH||162230||?Amyotrophic lateral sclerosis, susceptibility to; Charcot-Marie-Tooth disease, axonal, type 2CC||AD, AR||7|
|OPTN||602432||Glaucoma 1, open angle, E; Glaucoma, normal tension, susceptibility to; Amyotrophic lateral sclerosis 12||AD||7|
|PFN1||176610||Amyotrophic lateral sclerosis 18||4|
|PRPH||170710||Amyotrophic lateral sclerosis, susceptibility to||AD, AR||0|
|SETX||608465||Amyotrophic lateral sclerosis 4, juvenile; Spinocerebellar ataxia, autosomal recessive 1||AD, AR||79|
|SIGMAR1||601978||?Spinal muscular atrophy, distal, autosomal recessive, 2; ?Amyotrophic lateral sclerosis 16, juvenile||AR||19|
|SOD1||147450||Amyotrophic lateral sclerosis 1||AD, AR||6|
|SPG11||610844||Amyotrophic lateral sclerosis 5, juvenile; Spastic paraplegia 11, autosomal recessive; Charcot-Marie-Tooth disease, axonal, type 2X||AR||68|
|SQSTM1||601530||Paget disease of bone 3; Frontotemporal dementia and/or amyotrophic lateral sclerosis 3; Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset; Myopathy, distal, with rimmed vacuoles||AD, AR||3|
|TARDBP||605078||Amyotrophic lateral sclerosis 10, with or without FTD; Frontotemporal lobar degeneration, TARDBP-related||AD||11|
|TBK1||604834||Frontotemporal dementia and/or amyotrophic lateral sclerosis 4; Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8||AD||1|
|TUBA4A||191110||Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia||AD||2|
|UBQLN2||300264||Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia||XL D||1|
|VAPB||605704||Spinal muscular atrophy, late-onset, Finkel type; Amyotrophic lateral sclerosis 8||AD||3|
|VCP||601023||Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1; Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia; Charcot-Marie-Tooth disease, type 2Y||AD||13|