A Newly Described Motor Neuron Disease Mimic
Abstract & Commentary
By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports no financial relationships relevant to this field of study.
Synopsis: A new autosomal-dominant genetic disorder is described that has similarities to sporadic motor neuron disease.
Source: Jokela M, et al. Late-onset lower motor neuronopathy: A new autosomal dominant disorder. Neurology 2011;77:334-340.
Spinal muscular atrophies (SMA) constitute a group of hereditary degenerative lower motor neuron disorders, the most common and severe of which is SMA Type 1 (Werdnig-Hoffmann disease), presenting in the infantile period, with later-onset, less severe forms including Type 2 (intermediate form) and Type 3 (Kugelberg-Welander disease). Inheritance is autosomal recessive, with nearly all young-onset forms resulting from deletions or mutations in the survival motor neuron 1 (SMN1) gene on chromosome 5q12.2. Adult-onset SMN1 SMA is rare, whereas LMNA mutations, designated as laminopathies, may underlie up to 10% of autosomal dominant (AD) SMA. Two families are now reported with a previously undescribed phenotype of adult-onset, autosomal-dominant SMA, possibly representing a new disorder.
Muscle cramps and fasciculations, with onset in the third decade, were the presenting symptoms among 12 patients in these eastern Finland families. Subsequently, usually after age 50 years, proximal and distal weakness progressed slowly, over decades, in the absence of manifest atrophy, with absent deep tendon reflexes at the knees and ankles. Myalgias, usually in the neck and back but also in the limbs, were reported in six of 12 patients. Upper motor neuron signs were not found, but five had mild pes cavus, three had moderate hammer toes, and one had pes planus, consistent with longstanding neurogenic disease. Only mildly decreased vibratory loss in the feet was seen in five patients, usually asymmetrically, and of two patients with more prominent sensory findings, one had diabetes. All were ambulatory, with only one patient requiring a cane. Coarse hand tremor was demonstrable in four patients, and two experienced drop attack-like episodes. Serum creatine kinase was mildly elevated in all but one, usually two- to three-fold above normal, but did not correlate with disease severity or progression. Needle electromyography revealed neurogenic changes in all limbs in all patients, comprising positive waves, fibrillation potentials, and/or complex repetitive discharges, with motor unit potentials of increased amplitude and duration. Muscle biopsy confirmed this pattern, demonstrating fiber type grouping, group atrophy, nuclear clump fibers, and type II atrophy. Muscle magnetic resonance imaging of the leg muscles revealed diffuse fatty degenerative changes, with the medial gastrocnemius the earliest and most severely affected. Molecular genetic analysis failed to reveal any significant linkage with known motor neuronopathy loci.
As noted in the accompanying editorial,1 the classification of spinal muscular atrophies that do not localize to chromosome 5q is quite confusing and this report, if confirmed, will necessarily make it more so. Of importance to the clinician is that this disorder begins with fasciculations, raising the specter of amyotrophic lateral sclerosis (ALS). Weakness, however, is a much-delayed symptom, and atrophy is mild, indicating that this is not typical motor neuron disease. Family history will help, for although 5% of ALS is autosomal-dominant, those patients will not have survived as long as would be expected with this disorder. As always, clinicians beware, and make sure to examine family members when in doubt.
1. Darras BT. Non-5q spinal muscular atrophies: The alphanumeric soup thickens. Neurology 2011;77:312-314.