Muscle & peripheral nerve nontumor

Muscular dystrophies

Myotonic dystrophy

Topic Completed: 1 March 2018

Minor changes: 14 May 2021

Copyright: 2018-2021, Inc.

PubMed Search: Myotonic dystrophy [title] muscle Review[ptyp]

Wesley Hiser, M.D.
Jesse L. Kresak, M.D.
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Cite this page: Hiser W. Myotonic dystrophy. website. Accessed November 27th, 2021.
Definition / general
  • Inherited muscular dystrophy characterized by muscle weakness, myotonia and additional systemic manifestations including cardiac and neurologic
  • Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are caused by differing nucleotide repeat expansions but have similar pathophysiologic mechanisms
  • DM1 is the most common type of adult onset muscular dystrophy
Essential features
  • Autosomal dominant (AD) muscular dystrophy caused by expansions of different nucleotide repeats which affect RNA splicing and processing, leading to muscle weakness, myotonia and systemic effects
  • Variable clinical course, from late onset of mild symptoms to death in infancy
  • Frequently involves cardiac conduction system and CNS
  • Significantly increased internal nuclei on histologic examination
  • Dystrophia myotonica (DM)
  • Classic type DM1 was first clinically described in 1909 by German physician Hans Steinert and termed, "Steinert's disease" (Biochim Biophys Acta 2015;1852:594)
ICD coding
  • G71.11: myotonic muscular dystrophy
  • Prevalence varies by region and is most common in individuals of European descent
  • DM1 is more common than DM2 in the U.S. but some studies suggest similar prevalence of DM1 and DM2 in Europe (Neurol Clin 2014;32:705)
  • Combined prevalence reported as 1 in 8,000 (12.5 per 100,000) but this is likely an underestimate due to clinical heterogeneity (Curr Opin Genet Dev 2017;44:30)
  • DM1:
    • Involvement of distal limb muscles with preferential involvement of finger, wrist and ankle flexors
    • Diaphragm involvement can occur early in disease course
    • Neck flexors involved
    • Facial muscles involved with wasting of temporalis muscles (hatchet appearance)
  • DM2:
    • Proximal musculature affected including limb girdle, neck flexors and elbow extensor muscles (Neurol Clin 2014;32:705)
    • Less involvement of facial or respiratory musculature
  • Both forms are a result of toxicity from abnormal mRNA caused by expanded repeats
  • DM1 has been more extensively studied
  • Mutant RNA with expanded repeats is not exported to cytoplasm but is retained in the nucleus where it forms multiple clumps or foci
  • RNA binding proteins such as MBNL1 and DDX6 exhibit high affinity for the mutant RNA and become sequestered in the nucleus
    • These proteins are normally involved in splicing, as well as mRNA transport, stability and decay
  • Protein function is lost once sequestered, leading to incorrect splicing and defects of proteins including insulin receptor, dystrophin, BIN1 and ClC-1 and L type calcium channels
  • Mutated RNA may also produce peptides which are directly cytotoxic (Neurol Clin 2014;32:705)
  • Autosomal dominant (AD) inheritance in both DM1 and DM2
  • DM1 is caused by expansion of a CTG repeat in the 3' noncoding region of the DMPK gene on chromosome 19q13.3, which codes for myotonic dystrophy protein kinase
    • Normal individuals have between 5 and 37 repeats but symptomatic patients typically have > 50 repeats
    • Anticipation is frequently seen
      • Symptoms appear earlier and with greater severity in successive generations
      • Individuals with borderline elevated CTG repeats (> 50) may be asymptomatic but offspring are at risk
    • Clinical presentation correlates with CTG repeat size (Neurol Clin 2014;32:705)
  • DM2 is caused by expansion of a CCTG repeat in the first intron of the CNTB gene (previously ZNF9) on chromosome 3q21, which codes for CCHC type zinc finger nucleic acid binding protein
    • Normal individuals typically have between 10 and 33 repeats but symptomatic patients usually have greater than 1,000 repeats (range, 75 to greater than 11,000)
    • Anticipation is less prominent
    • No correlation between repeat size and clinical presentation (Neurol Clin 2014;32:705)
Clinical features
  • DM1 is typically broken down into four subtypes: congenital, childhood, classic and minimal / late onset
    • Spectrum of clinical severity: from death in infancy to onset in late adulthood with extremely mild symptoms
    • Congenital DM1: fetal onset, involving musculature and CNS; severe
      • Prenatal features: decreased fetal movement, polyhydramnios
      • Neonatal features: hypotonia with feeding or respiratory distress
      • Childhood: delayed motor milestones, intellectual impairment, prominent oropharyngeal weakness with tenting of upper lip
      • Degenerative features develop by second or third decade, resembling classic DM1
      • More than half of mothers do not carry DM1 diagnosis so diagnosis can be delayed (Neurol Clin 2014;32:705)
    • Childhood DM1: between 1 and 10 years of age
      • Predominantly cognitive and behavioral issues
      • Facial weakness and conduction abnormalities
      • Approximately half with intellectual impairment
      • Range of psychiatric disorders
    • Classic DM1: onset usually between second and fourth decades
      • Myotonia is the most common presenting symptom
        • More pronounced after rest, improves with activity
        • Involves forearms and hands (grip), tongue and jaw
      • Muscle weakness of distal limbs and craniofacial muscles
      • Wasting of fascial muscles with characteristic ptosis and hatchet appearance
      • Respiratory distress secondary to diaphragmatic involvement
      • Cardiac conduction abnormalities common
          • Risk of sudden cardiac death as high as 1.1% per year
      • Cataracts located on the posterior lens capsule with a multicolored, iridescent appearance on slit lamp examination (Neurol Clin 2014;32:705)
      • Sleep disturbances (80% with daytime hypersomnolence)
      • Gastrointestinal involvement: cholelithiasis, intestinal dysmotility
      • Insulin resistance, metabolic syndrome, frontal balding and hypogonadism in men
      • Evidence for increased risk of malignancy (thyroid, ovarian, colorectal, endometrial, Mayo Clin Proc 2012;87:130, JAMA 2011;306:2480)
    • Minimal / late onset DM1: small expansions (70 - 100 repeat) with mild weakness, myotonia and development of cataracts, usually after age 40 (range 20 to 70 years, Neurol Clin 2014;32:705)
  • DM2: overall milder disease; most often presents in the third decade of life (range second to sixth decades)
    • Presents with proximal muscle weakness as well as myotonia
      • May resemble limb girdle dystrophy
    • Less muscle wasting and respiratory involvement than DM1
    • Frontal balding, hypogonadism, cataracts and insulin resistance
    • Less cardiac and CNS involvement than DM1 (Yachnis: Neuropathology - A Volume in the High Yield Pathology, 1st Edition, 2014)
    • Some patients exhibit calf and thigh hypertrophy (true hypertrophy)
    • Patients often have a history of unexplained pain and may have a diagnosis of fibromyalgia (Neurol Clin 2014;32:705)
  • Molecular testing is definitive and may be the only test performed in the appropriate clinical setting
  • PCR is most commonly used for detection of repeat expansion
  • Southern blot is sometimes utilized in addition to PCR testing (Eur J Hum Genet 2012;20:1203)
  • Muscle biopsy is infrequently performed if clinical suspicion is high
Radiology description
  • No specific imaging features of the involved musculature have been identified
  • Imaging of CNS may show alterations in the white matter signal intensity, most notable in the frontotemporal region
  • Prenatal ultrasound in congenital DM1 patients may show borderline ventriculomegaly or talipes equinovarus (club foot) (Neurol Clin 2014;32:705)
Prognostic factors
  • Classic DM1 has a slowly progressive course
  • Respiratory failure is the leading cause of death in DM1, followed by sudden cardiac death (Neurol Clin 2014;32:705)
  • Congenital DM1 patients may live to adulthood and typically die of cardiorespiratory complications (similar to classic DM1)
  • DM2 patients typically have a milder clinical course
Case reports
  • No curative treatment - supportive therapy only
  • Many patients require nighttime respiratory support
  • May require pacemaker or defibrillator placement
  • Ongoing research into curative genetic therapies
Microscopic (histologic) description
  • Variation in myofiber size, ranging from 10 um to 100 um
  • Ring fibers and sarcoplasmic masses (dark staining regions) are frequently seen in DM1
  • DM1: type 1 myofiber atrophy with type 2 hypertrophy
  • DM2: greater variation in both type 1 and 2 fibers with predominantly type 2 myofiber atrophy (Yachnis: Neuropathology - A Volume in the High Yield Pathology, 1st Edition, 2014)
  • Pyknotic nuclear clumps in atrophic fibers
  • May see moth eaten or whorled fibers
  • Microscopic (histologic) images

    Contributed by Jesse L. Kresak, M.D

    Scattered internal nuclei

    Increased internal nuclei

    Markedly increased internal nuclei

    Fatty replacement and ring fibers

    Positive stains
    Electron microscopy description
    Molecular / cytogenetics images

    Images hosted on other servers:

    DM2 muscle biopsy: FISH and MBNL1 immunofluorescence

    Differential diagnosis
    • Limb girdle dystrophy (DM2): often has significantly increased CK; molecular testing and immunohistochemistry on muscle biopsy can also be utilized to make the diagnosis
    • Other muscular dystrophies: molecular studies will aid in differentiation; myotonic dystrophy shows a greater number of and more consistent internal nuclei
    • Myotubular myopathy (in congenital DM1): greater number of internal nuclei in DM1 without peripheral halos seen in myotubular myopathy; can also look for MTM1 gene mutation
    • Myopathic conditions (i.e. inflammatory myopathies): degenerating and regenerating fibers, as well as inflammatory cell infiltrates, are not commonly seen in myotonic dystrophy
    Board review style question #1
    Myotonic dystrophy type 2 (DM2) is inherited in what pattern?

    1. Autosomal dominant
    2. Autosomal recessive
    3. Mitochondrial
    4. X linked
    Board review style answer #1
    A. Both DM1 and DM2 are inherited in an autosomal dominant pattern.

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