Publications about genetic testing for neurological disorders
  1. NGS panel - Genetic testing for amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS)

May 11, 2018

Disease summary:

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


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.


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