Werdnig-Hoffmann Disease; Infantile Muscular Atrophy; Kugelberg-Welander Syndrome; Juvenile Muscular Atrophy; Proximal SMA

Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by progressive muscle weakness caused by the degeneration of anterior horn cells of the spinal cord and the brain stem nuclei. Onset ranges from before birth to young adulthood. Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications. Subtypes include: SMA 0 (proposed name; also referred to as prenatal), with prenatal onset and severe joint contractures, facial diplegia, and respiratory failure; SMA 1, with onset before six months of age; SMA 2, with onset between six and 12 months; SMA3, with onset in childhood after 12 months; and SMA 4, with adult onset.

Two adjacent genes, SMN1 and SMN2, are associated with SMA. The two genes differ by only five base pairs and none of these base pair differences change the amino acids encoded by the genes. Nonetheless, the two genes do not encode identical proteins. SMN1 produces full-length transcripts while SMN2 primarily produces transcripts that lack exon 7 because one of the base pair changes in exon 7 disrupts SMN2 gene splicing.

SMN1 is the SMA disease gene. Approximately 95 – 98% of individuals with a clinical diagnosis of SMA are homozygous for an apparent deletion of exon 7 in SMN1. The remaining 2 – 5% are compound heterozygotes for an apparent deletion of exon 7 of SMN1 and an intragenic point mutation in SMN1.

The copy number of the SMN2 gene varies, ranging from zero to five. Although SMN2 does not produce the full length transcript with high efficiency, some full length transcript is produced. In some individuals with SMA who also have an increased copy number of the SMN2 gene, the small amount of full-length transcript generated SMN2 may help to produce a milder phenotype.

1. Confirmation of diagnosis:
   1. In individuals with clinical features suggestive of SMA.
2. Carrier testing:
   1. Adults at risk to be carriers of SMA due to a family history.
      NB: For the most accurate assessment of carrier status, please provide the results of SMN1 molecular analysis of the parents of the affected individual.
3. Prenatal testing (prenatal diagnosis requests are not normally accepted from physicians other than Medical Geneticists):
   1. Pregnancies at risk of SMA, where the parents have been confirmed by molecular analysis to each carry an SMN1 deletion.
      NB: If only one of the parents has been confirmed to be a carrier, contact the Molecular Geneticist on-service to discuss options.
4. Presymptomatic testing:
   1. Adults at risk of developing a milder form of SMA due to a family history confirmed to be due to SMN1 deletions.

The copy number of exons 7 and 8 of both the SMN1 and SMN2 genes is assessed by multiplex ligation-dependent probe amplification (MLPA) using the P060 probe mix (MRC-Holland).

Pregnancy-related/Prenatal

If pregnancy management will be altered, 3 weeks; otherwise, routine TAT.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: NOT ACCEPTED

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). 

Prenatal Specimens
Prenatal testing REQUIRES LABORATORY CONSULTATION PRIOR TO THE PROCEDURE and can only be ordered by a Medical Geneticist. Contact the laboratory at 604-875-2852 and choose the appropriate option for the Molecular Geneticist on service.
Chorionic Villi: 20 mg.
Direct Amniotic fluid: 25 mL collected in two separate tubes of equal volume.
Cultured Amniocytes: Two (2) 100% confluent T-25 flasks.

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth. Ship samples by overnight courier with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays) as follows:

• Villi – on wet ice or in media at room temperature
• Amniocytes, Amniotic fluid, DNA – at room temperature

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, promoter mutations, and regulatory element mutations). In rare cases, a point mutation could be detected.

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.

Rare single nucleotide variants or polymorphisms could lead to false-negative 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.