Background to disease

OMIM #160900 (gene OMIM #605377)

Myotonic dystrophy 1 (DM1) is one of the most frequent neuromuscular genetic diseases. It is an autosomal dominant, multi-systemic disorder affecting skeletal muscle, eyes, brain, heart, endocrine system and testes. Clinically DM1 is highly variable but can be categorised into three main groups; mildly affected which has a later age of onset, classical adult onset and severe congenital onset. In the mildest cases, the only symptoms may be characteristic bilateral cataracts, whilst in the most severely affected congenital cases, babies are born with severe hypotonia and mental retardation. Congenitally affected infants who survive the neonatal period subsequently develop the classical symptoms of DM1, which include myotonia, muscle wasting, premature frontal balding, testicular atrophy, endocrine disturbances, neuropsychological deficits and cardiac conduction defects. 98% of skeletal muscle is dystrophic by histology.

The incidence of DM1 is approximately 1 in 8000 in most European populations. DM1 accounts for 98% of myotonic dystrophy cases.

The disease affects the 3’ untranslated region of the DMPK gene, through a (CTG)_n repeat expansion. Mutant alleles (>50 repeats) leads to transcription of RNA but no translation into protein. Previously it was thought the repeat resulted in haploinsufficiency of DMPK and the surrounding genes causing the multi-systemic effects. However with the discovery of the DM2 locus in 2001, it has been determined that over-expression of CUG, CCUG, CUG-BP or depletion of muscleblind proteins results in splicing alterations resulting in the downstream characteristics of both types of DM.

Laboratory Analysis

Analysis for this disease is now carried out by the Northern Genetics Service under a reciprocal arrangement (GENLYNC). Please contact them directly regarding information regarding turnaround time and sensitivity. Local samples should still be sent via the Yorkshire Regional Genetic Laboratory where they will be forwarded as whole blood as appropriate. DNA from these samples can be stored in the Yorkshire Regional Genetic Laboratory if it is anticipated that future tests may be required (please indicate clearly on referral card if required).