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

Amyotrophic lateral sclerosis (ALS)

April 11, 2017

Disease summary:

Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disorder characterized by 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 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)
  • Bulbar findings (dysarthria, dysphagia)
  • Muscle fasciculations
  • Muscle cramps
  • Lability of affect and changed mood

Various subtypes of ALS may be identified 1, 5:

  • Progressive bulbar palsy (presents with speech disturbance and swallowing difficulties)
  • Limb-onset ALS
  • Progressive muscular atrophy (involves only lower motor neurons)
  • UMN-predominant ALS                  

Presence of the following clinical features 1, 5:

  • Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination
  • Evidence of upper motor neuron (UMN) degeneration by clinical examination
  • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination

Together with the absence of both of the following 1, 5:

  • Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration
  • Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiologic signs.

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 treatment for ALS 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.
  • Riluzole (FDA-approved) reduce some of the 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.


Overview of the genes in CENTOGENE´s ALS panel

Gene (OMIM) ALS type (Locus) Inheritance Protein % of Individuals with FALS
ALS2 (606352) ALS 2 (2q33.2) AR Alsin Rare
ANG (105850) ALS 9 (14q11.2) AD Angiogenin Rare, certain ethnic groups only
ATXN2 (601517) ALS 13 (12q24) AD Ataxina 2 Rare, polyQ repeats (23–34)
C9orf72 (614260) ALS-FTD (9p21.2) AD Uncharacterized protein C9orf72 23%-30%
CHCHD10 (615903) FTD ALS2 (22q11.23) AD Coiled-coil-helix-coiled.cild helixc domain protein 10 Rare
CHMP2B (609512) ALS 17 (3p12.1) AD Chromatine modifying protein 2B <1%
DCTN1 (601143) ALS1-FTD (2p13.1) AD, AR Dynactin 1 Rare
ERBB4 (600543) ALS19 (2q34) AD Oncogene ERBB4 Rare
FIG4 (609390) ALS 11 (6q21) AD Polyphosphoinositide phosphatase Rare
FUS (137070) ALS 6 (16q11.2) AD; AR; de novo RNA-binding protein FUS ~4%
HNRNPA1 (164017) ALS20 (12q13.13) AD HNRNPA1 Rare
MATR3 (164015) ALS21 (22q11.23) AD Matrin 3 Rare
NEFH (162230) ALS1-DTD (22q12.2) AD; AR Neurofilament heaviy polypeptide protein Rare
OPTN (602432) ALS 12 (10p13) AD; AR Optineurin Rare
PFN1 (176610) ALS 18 (17p13.2) AD Profilin 1 Rare
PRPH (170710) ALS-susceptibility (12q13.12) AD, AR Peripherin Rare
SETX (608465) ALS 4 (9q34) AD Senetaxin Rare
SIGMAR1 (601978) ALS 16 (9p13.3) AD Sigma receptor 1 Rare
SOD1 (147450) ALS 1 (21q22.1) AD; AR, de novo Superoxide dismutase (Cu-Zn) 20%
SPG11 (610844) ALS5 (15q21.1) AR Spatascin Rare
SQSTM1 (601530) FTD ALS3 (5q35.3) AD Sequestosome 1 Rare
TARDBP ALS 10 (1p36.22) AD; AR TAR DNA-binding protein 43 1%-4%
TBK1 (604834) FTD ALS4 (12q1.2) AD Tank-binding kinase 1 Rare
TUBA4A (191110) ALS22 (2q35) AD Tubulin alpha 1 Rare
UBQLN2 (300264) ALS 15 (Xp11.21) XD Ubiquilin Rare
VAPB (605704) ALS 8 (20q13.3) AD Vesicle-associated membrane protein-associated protein B/C Rare
VCP (601023) ALS 14 (9p13) AD Transitional endoplasmic reticulum ATPase Unknown

More information on CENTOGENE´s amyotrophic lateral sclerosis (ALS) panel can be found in our genetic test catalogue.