Comprehensive ALS Testing at PreventionGenetics
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We are pleased to announce our updated testing options for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The Amyotrophic Lateral Sclerosis Panel and Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Panel have all been expanded to include more genes involved in ALS and FTD.
Amyotrophic Lateral Sclerosis (ALS)
ALS is a progressive, neurological disease caused by the degeneration of motor neurons. Major clinical features are muscle weakness, atrophy, and eventually paralysis (Hardiman et al. 2017). The annual incidence of ALS is 2-3 per 100,000. Disease progression is rapid with respiratory failure occurring 3-4 years after symptom onset. Median symptom onset for familial ALS is 55 years of age compared to sporadic ALS being 65 years of age. Spinal ALS presenting as limb muscle weakness is most common but patients can have bulbar involvement resulting in difficulty in speech, swallowing, or both. Dementia also is present in ~15% of ALS cases (van Es et al. 2017). When features of ALS and FTD are present, the condition is referred to as ALS-FTD.
Frontotemporal Dementia (FTD)
FTD clinically and genetically overlaps with ALS and is characterized by progressive degeneration and atrophy of the frontal and temporal lobes of the brain. When degeneration begins in the frontal lobes, behavioral changes result (Rascovsky et al. 2011); when degeneration begins in the temporal lobes, difficulties with communication or language comprehension occur (Gorno-Tempini et al. 2011). These two major forms are behavioral variant FTD (bvFTD) and primary progressive aphasia (PPA). PPA is subdivided further depending on the type of language difficulties experienced. Additionally, some disorders on the FTD spectrum display primarily motor symptoms, though patients still experience cognitive issues (Olney et al. 2017). Symptom onset is gradual and usually begins during the fourth and sixth decades of life. The annual incidence of FTD is 3-4 people per 100,000 (Onyike and Diehl-Schmid. 2013).
Genetics of ALS and FTD
While about 40% of FTD is inherited (Rosso et al. 2003), 90% of ALS cases are sporadic, with no known affected relatives. Age related penetrance is also observed. Some sporadic cases for either ALS or FTD may be inherited with low penetrance. Familial ALS and sporadic ALS present similarly, but the onset of symptoms is typically earlier in familial cases (Kinsley and Siddique 2015). Heritable forms of both ALS and FTD may be caused by variants in any of several different genes that are genetically heterogeneous. They are primarily inherited in an autosomal dominant manner, but autosomal recessive or X-linked dominant inheritance has been documented in some families.
Why Genetic Testing?
Due to the varying clinical presentation and disease progression, ALS can be challenging to diagnose (van Es et al. 2017). Genetic testing can be beneficial for confirming a clinical diagnosis, and may help determine whether additional family members may be at risk for ALS or FTD.
• A genetic cause for ALS is detected in 55-68% of familial and 8-11% of sporadic cases from people of European descent and 40% of familial and 3% of people of Asian descent (Renton et al. 2014. PubMed ID: 24369373; Zou et al. 2017. PubMed ID: 28057713).
• C9orf72 hexanucleotide repeat expansion of within intron 1 is the most common cause of ALS and FTD. This expansion is not readily detected by typical Sanger and Next Generation Sequencing tests. These expansions are found in ~1/3 of familial ALS and FTD cases in patients of European descent (van der Zee et al. 2013. PubMed ID: 23111906).
• Pathogenic variants in the SOD1 gene is the most common cause of familial ALS in patients of Asian descent and is found in ~1/3 of cases (Zou et al. 2017. PubMed ID: 28057713).
• ATXN2 expansions of the exon 1 poly glutamine track ranging from 29-32 CAG repeats have also been associated with an increased risk for development of ALS (Van Damme et al. 2011. PubMed ID: 21562247).
• With the emergence of ALS precision therapeutics, understanding the genetic etiology of ALS/FTD is more important than ever (Brown and Al-Chalabi. 2017. PubMed ID: 28700839; van Es et al. 2017. PubMed ID: 28552366). Precision therapeutics including antisense oligonucleotides are being developed for patients with either SOD1 pathogenic variants, FUS pathogenic variants, C9orf72 repeat expansions, or ATXN2 repeat expansions.
Genetic Testing for ALS and FTD at PreventionGenetics
Our Amyotrophic Lateral Sclerosis Panel now includes 33 genes shown when altered to cause ALS and is appropriate for testing individuals with upper and lower motor neuron impairment. The 40 gene Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Panel is a good fit for patients with ALS, FTD, and ALS-FTD. PreventionGenetics’ panels will detect pathogenic variants in at least 68% of patients with familial ALS and 11% of apparently sporadic cases of ALS (Renton et al. 2014). Pathogenic variants in up to 65% of patients with familial FTD will also be detected.
Testing Strategy
Because a pathogenic expansion of the GGGGCC hexanucleotide repeat in an intron of C9orf72 has been reported as the most common genetic cause of ALS, FTD, and ALS-FTD (Renton et al. 2011. PubMed ID: 21944779; DeJesus-Hernandez et al. 2011. PubMed ID: 21944778; Byrne et al. 2012. PubMed ID: 22305801), we first screen the patients’ DNA for the presence or absence of this expansion. In cases where we find a pathogenic expansion, we stop testing and only bill for C9orf72 repeat expansion (Test # 151). When there is no evidence for the pathogenic expansion, the sequencing panel and ATXN2 CAG repeat expansion testing is performed.
| ALS and Related Testing Options at PreventionGenetics | |
| Amyotrophic Lateral Sclerosis (ALS) Panel | |
| Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) Panel | |
| C9orf72 Gene Hexanucleotide Repeat Expansion | |
| Dementia Panel | |
References
Brown and Al-Chalabi. 2017. PubMed ID: 28700839
Byrne et al. 2012. PubMed ID: 22305801
DeJesus-Hernandez et al. 2011. PubMed ID: 21944778
Gorno-Tempini et al. 2011. PubMed ID: 21325651
Hardiman et al. 2017. PubMed ID: 28980624
Kinsley and Siddique 2015. PubMed ID: 20301623
Olney et al. 2017. PubMed ID: 28410663
Onyike and Diehl-Schmid. 2013. PubMed ID: 23611343
Rascovsky et al. 2011. PubMed ID: 21810890
Renton et al. 2011. PubMed ID: 21944779
Renton et al. 2014. PubMed ID: 24369373
Rosso et al. 2003. PubMed ID: 12876142
Van Damme et al. 2011. PubMed ID: 21562247
van der Zee et al. 2013. PubMed ID: 23111906
van Es et al. 2017. PubMed ID: 28552366
Zou et al. 2017. PubMed ID: 28057713