Machado-Joseph Disease; Olivopontocerebellar Atrophy (OPCA); Cerebelloparenchymal Disease; Menzel type OPCA; Schut-Haymaker type OPCA; Holguin Ataxia; Wadia-Swami Syndrome; Azorean Ataxia; Spinopontine Atrophy; Nigrospinodentatal Degeneration

The spinocerebellar ataxias (SCA) are characterized by slowly progressive gait ataxia, and are often associated with poor coordination of hands, speech, and eye movement.

SCA type 1, 2, 3, 6, and 7 are autosomal dominant conditions caused by expansion of the CAG repeat in ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 respectively. 

SCA alleles are classified based on size, and reported based on classification, as outlined below.  Exact repeat sizes are not reported:

SCA1 (ATXN1):

• Normal: ≤38 repeats or 39-44 interrupted repeats
• Full Penetrance (pathogenic): 39-44 uninterrupted repeats or ≥45 repeats

SCA2 (ATXN2)

• Normal: ≤31 repeats
• Uncertain: 32-34 repeats
• Full Penetrance (pathogenic): ≥35 repeats

SCA3 (ATXN3)

• Normal: ≤44 repeats
• Uncertain: 45-~59 repeats*
• Full Penetrance (pathogenic): ≥~60 repeats*

           *The repeat size of the smallest full penetrance pathogenic allele is not well-defined.

SCA6 (CACNA1A)

• Normal: ≤18 repeats
• Uncertain: 19 repeats
• Full Penetrance (pathogenic): ≥20 repeats

SCA7 (ATXN7)

• Normal: ≤33 repeats
• Uncertain: 34-36 repeats
• Full Penetrance (pathogenic): ≥37 repeats

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of SCA1, 2, 3, 6 or 7.
2. Prenatal testing (prenatal diagnosis requests are not normally accepted from physicians other than Medical Geneticists; technically feasible, but not routinely performed – contact MGL to discuss):
   1. Pregnancies at risk of being affected with one of these ataxias
3. Presymptomatic testing:
   1. Adults at risk to develop one of these ataxias due to a molecularly confirmed family history. Predictive testing will only be performed following genetic counselling by a recognized genetic service.

Sizing of the CAG repeats associated with each gene is carried out on an ABI genetic analyzer following fluorescence-based PCR amplification.  Digestion with SfaN1 is performed on SCA1 alleles between 39 – 44 repeats to differentiate between interrupted (normal) and uninterrupted (pathogenic) repeats.  Alleles ≤44 CAG repeats that are interrupted by CAT repeats are normal, whereas alleles with 39-44 uninterrupted CAG repeats are considered fully penetrant (pathogenic).  As required, triplet-primed (tp) PCR is performed for SCA2 and SCA7.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., point mutations in the coding region of the gene, large genomic deletions, promoter mutations, regulatory element mutations). For some trinucleotide repeat disorders, repeat expansions have been described that cannot be amplified by PCR. Consideration should be given to this particularly in cases with severe clinical features or early onset; consult the on-service Molecular Geneticist to discuss specific repeat disorders.

For carrier/predictive testing due to family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

In certain scenarios of repeat size mosaicism, false negative results may occur. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

Rare single nucleotide variants or polymorphisms could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.