A 21-year-old man comes to the clinic due to weakness and gait disturbance. For the past few months, he has noticed difficulty opening the lids on jars, along with trouble releasing his grip afterward. The patient has also tripped and fallen several times, particularly when walking up stairs. He has no known chronic medical conditions and takes no medications. Vital signs are normal. The patient has male pattern baldness. Cardiopulmonary examination is unremarkable. The abdomen is soft with no organomegaly. A muscle biopsy shows muscle atrophy involving mostly type 1 fibers. This patient most likely has a form of which of the following neuromuscular diseases?
Myotonic dystrophy | |
Pathogenesis |
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Clinical features |
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Diagnosis |
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*Repeat length correlates with earlier onset of more severe disease. | |
This patient has distal muscle weakness (eg, difficulty opening jar lids) with delayed muscle relaxation after contraction (myotonia), key features of myotonic dystrophy (DM).
DM is an autosomal dominant muscular dystrophy caused by a trinucleotide repeat expansion in the DMPK gene, which is then transcribed into mutant mRNA. The mutant mRNA is untranslatable and toxic to the expression of other genes, particularly those related to skeletal muscle chloride channels, resulting in myotonia. Grip myotonia is classic and characterized by impaired muscle relaxation after voluntary release of a contracted hand.
The toxic mRNA also affects T tubules, which usually facilitate synchronized release of calcium ions for organized muscle contraction, resulting in weakness due to impaired excitation-contraction coupling. Weakness classically involves the face (eg, long, narrow face with sagging) and distal skeletal muscles. This patient's recent falls are likely due to footdrop, but quadriceps involvement can occasionally occur and may be contributing to his difficulty walking up stairs. Muscular atrophy in DM preferentially affects the type I (slow-twitch) fibers, as seen on this patient's muscle biopsy.
Other common features of DM include cataracts, insulin resistance, and early-onset frontal balding.
(Choice A) Inflammatory myopathies (eg, dermatomyositis, polymyositis) present with symmetric proximal muscle weakness without myotonia. In addition, inflammatory cell infiltration is seen on muscle biopsy.
(Choice B) Certain ion channel myopathies can manifest with myotonia, but those that do so are associated with muscle hypertrophy (not atrophy) due to muscle overactivity. In contrast, the genetic defects causing muscular dystrophy result in progressive muscle damage that leads to atrophy of muscle fibers.
(Choice C) Mitochondrial myopathies are characterized by varying degrees of muscle weakness, typically presenting in infancy or early childhood with multisystem involvement (eg, seizures). In addition, ragged red fibers (due to bright red mitochondrial bundles) are classically seen on muscle biopsy.
(Choice D) Motor neuron disease (eg, amyotrophic lateral sclerosis) is characterized by progressive nerve degeneration, resulting in skeletal muscle weakness. Muscle wasting and a weak grip are common, but impaired muscle relaxation does not occur.
(Choice F) Myasthenia gravis, caused by postsynaptic acetylcholine receptor antibodies, is the most common neuromuscular junction disorder and presents with proximal muscle weakness. However, the weakness is fluctuating and fatigable, and hand weakness and relaxation impairment would not be expected.
Educational objective:
Myotonic dystrophy is characterized by muscle weakness and myotonia (impaired muscle relaxation) with muscle atrophy, particularly of the type I (slow-twitch) muscle fibers. Pathophysiology involves a trinucleotide repeat expansion causing mutant RNA that disrupts muscle contraction and relaxation.