Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic Lateral Sclerosis (ALS), also referred to as Lou Gehrig’s Disease or Charcot’s Disease, is one of the most common adult-onset neuromuscular disorders worldwide.
PrintAmyotrophic Lateral Sclerosis (ALS), also referred to as Lou Gehrig’s Disease or Charcot’s Disease, is one of the most common adult-onset neuromuscular disorders worldwide.
Approximately 10% of ALS cases are referred to as familial ALS (FALS), in which individuals have at least one affected family member. Amyotrophic Lateral Sclerosis is characterized by the degeneration and death of both the upper and lower motor neurons in the cerebral cortex, brainstem, and spinal cord. Of the eleven FALS types, five types of autosomal dominant ALS (AD-ALS) have been associated with mutations in single genes. Twenty percent (20%) of FALS cases have identified mutations in the SOD1 gene, ~5% have identified mutations in the TARDBP gene, with mutations in FUS, ANG, and FIG4 representing a combined 5%.
The Ambry SEQUENCE™: ALS detects >96% of all described SOD1 mutations, >97% of all described TARDBP and >99% of described mutations in FUS, ANG, and FIG4. Testing is arranged into two steps to control costs and prevent unnecessary testing.
Amyotrophic Lateral Sclerosis (ALS), also referred to as Lou Gehrig’s or Charcot’s disease, is one of the most common adult-onset neuromuscular disorders worldwide. ALS is a rapidly progressive and fatal neurodegenerative disease affecting all ethnicities with an annual incidence ~1 to 2 per 100,000 and an estimated prevalence from 2-8 per 100,000.1 The mean age at onset is 60 years old with death usually resulting within 1-5 years of onset due to respiratory failure.2 There is a slight male preference (M: F ratio~1.5:1), however studies now suggest that as the incidence age increases both sexes are equally affected.3,4 Roughly 90% of ALS patients have no family history of ALS and are referred to as having sporadic ALS (SALS). The remaining 10% of ALS cases are referred to as familial ALS (FALS) in which individuals have at least one affected family member.5 FALS is divided into eleven different types of ALS (ALS1-11) and all types, with the exception of ALS2 and ALS5, are inherited in an autosomal dominant manner with high penetrance.3
Of the eleven FALS types, five types of autosomal dominant ALS (AD-ALS) have been associated with mutations in single genes. These five genes are: SOD1 (ALS1), TARDBP (ALS10), ANG (ALS9), FUS (ALS6), and FIG4 (ALS11). Twenty percent (20%) of FALS cases have identified mutations in the SOD1 gene5, ~5% have identified mutations in the TARDBP gene3,6, with mutations in FUS, ANG, and FIG4 representing a combined 5%.2,7,8
ALS is characterized by the degeneration and death of both the upper and lower motor neurons in the cerebral cortex, brainstem, and spinal cord.2,3 Some of the hallmarks of the disease include progressive muscle weakness, muscle atrophy, and fasciculations. Initial symptoms are dependent on whether the patient presents the limb (classic) or bulbar onset form.1 Approximately two thirds of patients will present symptoms of the limb form which includes asymmetric focal muscle weakness, muscle twitches or cramps, or fasciculations. Patients presenting bulbar ALS symptoms usually manifest with dysarthria or dysphagia. As the disease progresses, patients will develop both limb and bulbar symptoms along with increasing issues ultimately leading to paralysis. Prognosis for ALS patients is poor with an average survival time of 2-3 years for the bulbar form and 3-5 years for the limb form upon the onset of symptoms.3
Diagnostic testing for individuals known or suspected to have Amyotrophic Lateral Sclerosis (ALS); carrier screening for relatives of ALS patients; carrier testing for known familial mutations; prenatal testing of at-risk pregnancies.
The Ambry Test: Amyotrophic Lateral Sclerosis is a gene sequence analysis performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for the following ranges of each gene plus at least 20 bases into the 5’ and 3’ ends of all the introns: SOD1: exons 1-5. TARDBP: exons 1-6. ANG: exon 2. FUS: exons 1-15. FIG4: exons 1-23. All are sequenced bidirectionally with the exception of FUS exons 8 and 15, which are limited to a unidirectional read. Specific mutation analysis for individual ALS gene mutations known to be in the family is also available.
The Ambry Sequence: ALS is capable of detecting >96% of all described SOD1 mutations, >97% of all described TARDBP and >99% of described mutations in ANG, FUS, and FIG4 (analytical sensitivity).
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Minimum DNA Amount of 5μg of DNA at a concentration of ~100ng/μl in 50μl TE (10mM Tris-Cl pH 8.0, 1mM EDTA); preferred 20μg. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.
| Test Code | Technique |
|---|---|
| 8620 | ALS SOD1, Reflex to ANG, FIG4, FUS, TARDBP |
| 8642 | ALS SOD1, Concurrent to ANG, FIG4, FUS, TARDBP |
| 8622 | ALS SOD1 Gene Sequence Analysis |
| 8624 | ALS Step 2: 4 Genes |
| Technique | Days |
|---|---|
| ALS SOD1, Reflex to ANG, FIG4, FUS, TARDBP | 7-28 |
| ALS SOD1, Concurrent to ANG, FIG4, FUS, TARDBP | 14-21 |
| ALS SOD1 Gene Sequence Analysis | 7-14 |
| ALS Step 2: 4 Genes | 14-21 |
1. Cleveland D, Rothstein J. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci. 2001;2:806-819. [PMID: 11715057]
2. Vance C et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323:1208. [PMID: 19251628]
3. Wijesekera L, Leigh PN. Amyotrophic lateral sclerosis. Orphanet Journal of Rare Diseases. 2009;4:3. [PMID: 19192301]
4. Worms P. The epidemiology of motor neuron diseases: a review of recent studies. Journal of the Neurological Sciences. 2001;191:3–9. [PMID: 11676986]
5. Rosen D et al. Genetic linkage analysis of familial amyotrophic lateral sclerosis using human chromosome 21 microsatellite DNA markers. Am J Med Genet. 1994;362:59-62. [PMID: 7913294]
6. Ayala Y et al. Structural determinants of the cellular localization and shuttling of TDP-43. Journal of Cell Science. 2008;121:3778-3785. [PMID: 18957508]
7. Chow C et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet. 2009;84:85-88. [PMID: 19118816]
8. Fernandez-Santiago R et al. Identification of novel Angiogenin (ANG) gene missense variants in German patients with amyotrophic lateral sclerosis. J Neurol. 2009;256:1337-1342. [PMID: 19363631]