ALS2-Related Disorders via the ALS2 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
108 ALS2$1650.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Currently unknown.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 ALS2$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

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, ALS2, ARALS OMIM 205100) is distinguished from the 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 upper motor neurons 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 upper motor neurons (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. 
Juvenile Amyotrophic Lateral Sclerosis (ALSJ) is most often inherited with 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 mutations 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, mutations in the ALS2 gene were 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 with an autosomal recessive pattern and is genetically heterogeneous.  Mutations 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 mutations 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 for one case of compound heterozygote mutation (Sztriha et al. Clin Genet 73:591-593, 2008), all mutations were homozygous and resulted in a predicted truncated protein.  In some cases parents were closely related, while history of consanguinity was absent in others.  These mutations occurred in patients of North African and European origins.  In addition to IAHSP, mutations in the ALS2 gene were reported in patients with Juvenile Amyotrophic Lateral Sclerosis (JALS, OMIM 205100), Juvenile Primary Lateral Sclerosis (JPLS, OMIM 606353), and complicated Hereditary Spastic Paraplegia in a large consanguineous Pakistani family (Gros-Louis et al. Ann Neurol 53:144-145, 2003).

JPLS is caused by mutations 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 mutations 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 mutation (c.1619 G>A) in an Italian family (Panzeri et al. Brain 129(Pt 7):1710-1719, 2006) and a splice site mutation (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 history of consanguinity.  Patients from all families showed the first symptoms before the age of two years.  All four mutations resulted in a predicted truncated protein with loss of function.  In addition to JPLS, mutations in the ALS2 gene were reported in patients with juvenile amyotrophic lateral sclerosis (JALS, ALS2, AR-ALS OMIM 205100), infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM 607225) and complicated hereditary spastic paraplegia (cHSO, Gros-Louis et al. Ann Neurol 53:144-145, 2003).
Testing Strategy
The ALS2 gene encodes the Alsin protein. This test involves bidirectional DNA sequencing of all 33 coding exons and splice sites of the ALS2 gene. The full coding sequence of each exon plus ~ 20 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.
Indications for Test
All patients with symptoms suggestive of ALSJ, IAHSP, and PLS  as described above.


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


Genetic Counselors
  • 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., (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., (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, (2005). "ALS2-Related Disorders." PubMed ID: 20301421
  • Eymard-Pierre, E., (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., (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., (1989). "Primary lateral sclerosis in a child." Neurology 39(11): 1530-2. PubMed ID: 2812336
  • Hadano, S., (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., (1994). "Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35." Nat Genet 7(3): 425-8. PubMed ID: 7920663
  • Kress, J. A., (2005). "Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis." Ann Neurol 58(5): 800-803. PubMed ID: 16240357
  • Lesca, G., (2003). "Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families." Neurology 60(4): 674-82. PubMed ID: 12601111
  • Mintchev, N., (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., (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., (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., (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., (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., (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
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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