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ALS2-Related Disorders via the ALS2 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8005 ALS2 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8005ALS281479 81479,81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Luke Drury, PhD

Clinical Features and Genetics

Clinical Features

Amyotrophic lateral sclerosis (ALS, OMIM 105400) is a neurodegenerative disease characterized by selective loss and dysfunction of both upper motor neurons (UMN) of the motor cortex and lower motor neurons (LMN) of the brainstem and spinal cord (Tandan and Bradley Ann Neurol 18:271-280, 1985; Brooks J Neurol Sc 124(Sup):96-107, 1994). The dysfunction and loss of UMN result in spasticity in the legs leading to difficulty in walking, lack of movement coordination and brisk reflexes. Damage to LMN results in weakness, muscle wasting, and fasciculation. Symptoms usually begin with asymmetric involvement of the muscles. Juvenile ALS (ALSJ, OMIM 205100) is distinguished from classical ALS by its early onset and slow progression. In ALSJ, the age of onset varies between 3 and 10 years of age, and the mean disease duration ranges between 2 and 28 years (Ben Hamida et al. Brain 113(Pt 2):347-363, 1990). As is the case for classical ALS, ALSJ is clinically heterogeneous, and its phenotype is influenced by the relative ratio of UMN and LMN involvement (Yang et al. Nat Genet 29:160-165, 2001).

Infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM 607225) is a motor neuron disease characterized by a degeneration of the UMN of the corticospinal tract. The clinical hallmark of IAHSP is a slow, progressive, ascending spastic paralysis. Spasticity usually begins in the lower limbs, extending to the upper limbs and bulbar muscles and, eventually, to a severe spastic paralysis. The onset of symptoms typically occurs during the first two years of life, with most patients being wheelchair-bound by the age of ten. The disease progresses to tetraplegia (complete paralysis of both upper and lower limbs), anarthria (total or partial loss of articulate speech), dysphagia (difficulty in swallowing) and slow eye movements in the second decade of life. Despite the progressive nature of the disease, life expectancy is not affected (Eymard-Pierre et al. Am J Hum Genet 71:518-527, 2002; Lesca et al. Neurology 60:674-882, 2003).

Primary lateral sclerosis (PLS) is characterized by neurological dysfunction limited to the UMN of the corticospinal tract (Russo Arch Neurol 39:662-664, 1982). The most common features of PLS are spastic quadriparesis, hyperactive muscle-stretch reflexes, and bilateral Babinski's sign. Additional features include spastic dysarthria, dysphagia, and exaggerated affective responses such as weeping or loathing. PLS is typically characterized by a gradual onset, slow and steady progression, and long duration (Beal and Richardson Arch Neurol 38:630-633, 1981). Two forms of PLS, juvenile and adult, are recognized based on the age of onset. In juvenile PLS (JPLS, OMIM 606353) symptoms begin in early childhood, sometimes before twelve months of age (Grunnet et al. Neurology 39:1530-1532, 1989); in adult PLS (PLSA1, OMIM 611637) the age of onset varies between 35 and 66 years of age (Pringle et al. Brain 115 (Pt 2):495-520, 1992). JPLS is always inherited with an autosomal recessive manner, while adult PLS is either sporadic or autosomal dominant.

Genetics

Juvenile amyotrophic lateral sclerosis (ALSJ) is most often inherited in an autosomal recessive pattern and has been generally reported in North African (Hentati et al. Nat Genet 7:425-428, 1994) and Middle Eastern populations (Kress et al. Ann Neurol 58:800-803, 2005). ALSJ is caused by variants in the ALS2 gene (Yang et al. Nat Genet 29:160-165, 2001; Hadano et al. Nat Genet 29:166-173, 2001; Kress et al. Ann Neurol 58:800-803, 2005; Bertini et al. GeneReviews, 2005). To date, three small homozygous deletions were reported in patients with ALSJ from consanguineous families. All deletions resulted in a predicted truncated protein with loss of function. In addition to ALSJ, variants in the ALS2 gene have been reported in patients with juvenile primary lateral sclerosis (PLSJ), infantile-onset ascending spastic paralysis (IAHSP), and complicated hereditary spastic paraplegia (cHSP, Gros-Louis et al. Ann Neurol 53:144-145, 2003).

IAHSP is transmitted in an autosomal recessive pattern and is genetically heterogeneous. Variants in the ALS2 gene cause IAHSP in a subset of patients (Eymard-Pierre et al. Am J Hum Genet 71:518-527, 2002). At least eight ALS2 variants have been reported in patients with IAHSP (Devon et al. Clin Genet 64:210-215, 2003; Verschuuren-Bemelmans et al. Eur J Hum Genet 16:1407-1411, 2008; Bertini et al. GeneReviews, 2005). Except in one compound heterozygote case (Sztriha et al. Clin Genet 73:591-593, 2008), all variants were homozygous and resulted in a predicted truncated protein. In some cases, parents were closely related, while a history of consanguinity was absent in others. These variants occurred in patients of North African and European origins.

JPLS is caused by variants in the ALS2 gene (Hadano et al. Nat Genet 29:166-173, 2001; Yang et al. Nat Genet 29:160-165, 2001; Bertini et al. GeneReviews, 2005). To date, four homozygous variants in the ALS2 gene were found in patients with JPLS. These include two 2 bp deletions in families from Saudi Arabia (1867delCT; Yang, 2001) and Kuwait (1425delAG; Hadano, 2001), a nonsense variant (c.1619 G>A) in an Italian family (Panzeri et al. Brain 129(Pt 7):1710-1719, 2006), and a splice site variant (c.2980-2A>G) in a Cypriot family (Mintchev et al. Neurology 72:28-32, 2009). While consanguinity was documented in the families from Saudi Arabia, Kuwait and Cyprus, the Italian family did not illustrate a history of consanguinity. Patients from all families showed the first symptoms before the age of two years. All four variants resulted in a predicted truncated protein with loss of function.

Clinical Sensitivity - Sequencing with CNV PGxome

Currently unknown.

Testing Strategy

This test provides full coverage of all coding exons of the ALS2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

All patients with symptoms suggestive of ALSJ, IAHSP, and PLS. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ALS2.

Gene

Official Gene Symbol OMIM ID
ALS2 606352
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Beal, M. F., Richardson, E. P., Jr. (1981). "Primary lateral sclerosis: a case report." Arch Neurol 38(10): 630-3. PubMed ID: 7295106
  • Ben Hamida, M., et.al. (1990). "Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy." Brain 113 ( Pt 2): 347-363. PubMed ID: 2328408
  • Brooks, B. R. (1994). "El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial Clinical limits of amyotrophic lateral sclerosis" workshop contributors." J Neurol Sci 124 Suppl: 96-107." PubMed ID: 7807156
  • Devon, R. S., et.al. (2003). "The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings." Clin Genet 64(3): 210-5. PubMed ID: 12919135
  • Enrico S Bertini, et.al. (2005). "ALS2-Related Disorders." PubMed ID: 20301421
  • Eymard-Pierre, E., et.al. (2002). "Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene." Am J Hum Genet 71(3): 518-27. PubMed ID: 12145748
  • Gros-Louis, F., et.al. (2003). "An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred." Ann Neurol 53(1): 144-5. PubMed ID: 12509863
  • Grunnet, M. L., et.al. (1989). "Primary lateral sclerosis in a child." Neurology 39(11): 1530-2. PubMed ID: 2812336
  • Hadano, S., et.al. (2001). "A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2." Nat Genet 29(2): 166-73. PubMed ID: 11586298
  • Hentati, A., et.al. (1994). "Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35." Nat Genet 7(3): 425-8. PubMed ID: 7920663
  • Kress, J. A., et.al. (2005). "Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis." Ann Neurol 58(5): 800-803. PubMed ID: 16240357
  • Lesca, G., et.al. (2003). "Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families." Neurology 60(4): 674-82. PubMed ID: 12601111
  • Mintchev, N., et.al. (2009). "A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family." Neurology 72(1): 28-32. PubMed ID: 19122027
  • Panzeri, C., et.al. (2006). "The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function." Brain 129(Pt 7): 1710-9. PubMed ID: 16670179
  • Pringle, C. E., et.al. (1992). "Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria." Brain 115 ( Pt 2): 495-520. PubMed ID: 1606479
  • Russo, L. S., Jr. (1982). "Clinical and electrophysiological studies in primary lateral sclerosis." Arch Neurol 39(10): 662-4. PubMed ID: 7125980
  • Sztriha, L., et.al. (2008). "First case of compound heterozygosity in ALS2 gene in infantile-onset ascending spastic paralysis with bulbar involvement." Clin Genet 73(6): 591-3. PubMed ID: 18394004
  • Tandan, R. and Bradley, WG. (1985). "Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management." Ann Neurol 18(3): 271-280. PubMed ID: 4051456
  • Verschuuren-Bemelmans, C. C., et.al. (2008). "Novel homozygous ALS2 nonsense mutation (p.Gln715X) in sibs with infantile-onset ascending spastic paralysis: the first cases from northwestern Europe." Eur J Hum Genet 16(11): 1407-11. PubMed ID: 18523452
  • Yang, Y., et.al. (2001). "The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis." Nat Genet 29(2): 160-165. PubMed ID: 11586297

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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