Abstract
The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary “myopathic” changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions.
Highlights
Histopathological analysis of muscle is not required for the diagnosis of amyotrophic lateral sclerosis (ALS) and neurologists rarely perform muscle biopsy on motor neuron disease patients when the diagnosis is not in doubt
We recently described a new slowly progressive type of adult-onset spinal muscular atrophy caused by a c.197G>T p.G66V mutation in CHCHD10 [1] (SMAJ, OMIM #615048)
As expected in a neurogenic disorder, fetal myosin heavy chain (MHCd) positive fibers were much less frequent, with a median of 1% of fibers in all groups, ranging between 0%-5%, 0.5%-10% and 0%-20% of fibers in c9orf72-mutated amyotrophic lateral sclerosis (c9ALS), spinal and bulbar muscular atrophy (SBMA) and SMAJ biopsies, respectively
Summary
Histopathological analysis of muscle is not required for the diagnosis of amyotrophic lateral sclerosis (ALS) and neurologists rarely perform muscle biopsy on motor neuron disease patients when the diagnosis is not in doubt. Several neurogenic entities may clinically simulate myopathies, and some myopathies such as LMNA- mutated muscular dystrophies and inclusion body myositis may show neurogenic features In these cases muscle biopsy is likely to provide diagnostically useful information. Because lower motor neurons define the fiber types of innervated muscle fibers (either fast or slow), reinnervation of denervated fibers by axonal sprouts from surviving motor neurons typically leads to grouping of muscle fibers of the same type. This is considered the myopathological hallmark of neurogenic change
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