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Myotonic Dystrophy - DMPK Gene

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Gene Symbol: DMPK  

Chromosomal Locus: 19q13.32  

Protein: dystrophia myotonica-protein kinase

Pseudonyms: DM, DM1, myotonin-protein kinase

TURNAROUND TIME: 15 days

TESTING METHODOLOGY:

Polymerase chain reaction (PCR) that brackets the DMPK CTG trinucleotide repeat region. The expansions in positive samples can be very large so a Southern procedure is required for this phase of the analysis.

SPECIMEN REQUIREMENTS:

  • Collect: Prefer two 5ml whole blood EDTA (lavender top) tube.  
  • Min. Collection: 0.7 ml whole blood EDTA.
  • Transport: blood EDTA at Room Temp shipped next day air (No Saturday delivery; store specimen refrigerated and ship Monday). 
  • Stability: Ambient: up to 7 days; Refrigerated: 2 weeks. Frozen: unacceptable
  • Unacceptable Conditions: Serum. Frozen or severely hemolyzed blood. Clotted blood.         
  • Prenatal Testing: Direct: 5ml direct unspun amniotic fluid or 15mg CVS tissue with a backup flask growing. Culture: confluent T25 flask.  Maternal blood sample is required for maternal cell contamination studies.

A Molecular Genetics Laboratory Test Requisition must accompany the specimen. Contact the Molecular Laboratory at 918-502-1721 to obtain further information.

Note: Counseling and informed consent are recommended for genetic testing. A consent form is available as a resource but not required.

INTERPRETATIVE DATA:

Incidence: 1 in 20,000.

Inheritance: Autosomal dominant. Variable age of onset but complete penetrance.

Disease Characteristics:

Myotonic dystrophy (DM1) is a multisystem disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system.  DM1 has 3 distinct presentations. The mild form has cataracts and mild myotonia but life span is normal. Classic DM1 is characterized by muscle weakness and wasting, myotonia, cataracts, and often cardiac conduction abnormalities resulting in a shortened life span.

Congenital DM1 is characterized by hypotonia at birth, often with respiratory insufficiency and early death; intellectual disability is also frequent. The presentation of hypotonia in a newborn are common symptoms of 3 different inherited diseases; a hypotonia panel including DM1, SMA and Prader-Willi syndrome should be considered.

Molecular Genetic Mechanism: Myotonic Dystrophy Type 1 (DM1) is the result of an insertion of CTG trinucleotide repeats in the 3’ – untranslated region (UTR) of the DMPK gene. Normal and clinically unaffected individuals can vary in the number of CTG triplets ranging between 5 – 34 repeats. Mutable alleles that are not disease causing are associated with 35 – 49 CTG repeats. Fully penetrant abnormal alleles contain 50 or more CTG repeats; however the age of onset and severity vary dramatically within that range.

Patients with “Mild” DM1 have 50 - 150 repeats with onset in adulthood. Patients with “Classical” DM1 have 100 to 1500 repeats with onset in childhood and early adulthood. Patients with “Congenital” DM have 1000 – 4000 repeats with onset at birth or childhood. The age of onset and increase of CTG size often increases each generation (anticipation) and is most common in mother-to-child inheritance.

Reference Ranges:

  • Normal alleles: 5 to 34 CTG repeats
  • Mutable Normal Alleles: 35 to 49 CTG repeats
  • “Mild” Abnormal Alleles: 50 to 150 CTG repeats
  • “Classical” Abnormal Alleles: 100 to 1500 CTG repeats
  • “Congenital” Abnormal Alleles: > 1000 CTG repeats

Related Tests:   Hypotonia panel, SMA, and Prader-Willi syndrome

Clinical Sensitivity: 99%

Analytical Sensitivity: 99%

Test Limitations: This test examines the CTG trinucleotide repeat region, exclusively. However, no other mechanism has been described for DM1 and the test is considered diagnostic. Myotonia caused by DM2 will not be detected with this test.

INDICATIONS FOR USE:

  • Individuals with a family history of DM1 who want to determine their true risk.
  • Prenatal testing for individuals at risk
  • To determine whether a neonate with hypotonia has DM1
  • To differentiate from DM2 in individuals with myotonia

ADDITIONAL RESOURCES:

OMIM – Myotonic dystrophy: http://omim.org/entry/160900
OMIM – DMPK: http://omim.org/entry/605377
MedLine : http://www.nlm.nih.gov/medlineplus/ency/article/001190.htm
GeneReviews: http://www.ncbi.nlm.nih.gov/books/NBK1165/
Genetics Home Reference: http://ghr.nlm.nih.gov/condition/myotonic-dystrophy