In the context of a neuromuscular disease diagnostic evaluation, the clinician still must be able to obtain a relevant patient and family history and perform focused general, musculoskeletal, neurologic and functional physical examinations to direct further diagnostic evaluations. The basis for the use of molecular genetic studies for diagnosis is well-described by Arnold and Flanigan in their article “A Practical Approach to Molecular Diagnostic Testing in Neuromuscular Diseases” in this issue 5. 58 In fact, the gene loci for over 500 distinct neuromuscular and mitochondrial disorders have been identified at the time this manuscript went to press. For example, at least 70 genetically distinct subtypes of Charcot Marie Tooth have been described, some with undetermined gene loci over 14 genetically distinct subtypes of autosomal recessive limb girdle muscular dystrophy have been identified and 3 genetically distinct subtypes of Emery Dreifuss exist. Clinical NMD syndromes described over the decades in the literature have recently been redefined based molecular genetic advances and documentation of genetic heterogeneity within specific syndromes. Hereditary NMDs are also quite common and include such disorders as spinal muscular atrophy (SMA), Charcot Marie Tooth disease, congenital myasthenia, and Duchenne muscular dystrophy. Other acquired NMDS include amyotrophic lateral sclerosis (ALS), poliomyelitis, Guillain Barre syndrome, myasthenia gravis, and polymyositis.
The most common NMDs are acquired peripheral neuropathies. For example, RNA toxicity generated from expansion of trinucleotide repeat sequences in myotonic muscular dystrophy gives rise to skeletal muscle, smooth muscle, myocardial, endocrine, brain and ocular abnormalities Duchenne muscular dystrophy gives rise to abnormalities of skeletal and cardiac muscle, the cardiac conduction system, smooth muscle and the brain Fukuyama congenital muscular dystrophy affects skeletal muscle and brain mitochondrial encephalomyelopathies may affect the mitochondria of multiple tissues.
Many neuromuscular diseases are multi-system disorders affecting multiple organ systems. The notion that a pathologic abnormality in a neuromuscular disease may be purely isolated to one anatomic region of the lower motor neuron with primary or secondary changes isolated to muscle is only true for selected conditions. Progressive acquired or hereditary neuromuscular diseases (NMDs) are disorders caused by an abnormality of any component of the lower motor neuron - anterior horn cell, peripheral nerve, neuromuscular junction (pre-synaptic or post-synaptic region), or muscle.
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