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Amyotrophic lateral sclerosis (ALS)
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.