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Predicting ALS Progression
Abstract & Commentary
By Michael Rubin, MD, Professor of Clinical Neurology, NewYork-Presbyterian Hospital, Weill Cornell Medical Center. Dr. Rubin is on the speaker's bureau for Athena Diagnostics, and does research for Pfizer and Merck.
Synopsis: Muscle Nogo-A may be a useful biomarker for the early diagnosis of ALS.
Source: Pradat PF, et al. Muscle Nogo-A expression is a prognostic marker in lower motor neuron syndromes. Ann Neurol 2007;62:15-20.
Harel NY, Strittmatter SM. Nogo-A marks motor neuron disease. Editorial. ibid 1-2.
The diagnosis of amyotrophic lateral sclerosis (ALS) is devastating for patient and family alike. Nevertheless, the ability to predict which patients with lower motor neuron disease will progress to full blown ALS would be beneficial by enabling earlier enrollment into clinical trials, offering added hope, and potentially therapeutic benefit. Thirty-three patients, evaluated at the Paris or Strasbourg Motor Neuron Disease Center between 2003 - 2005 for a purely lower motor neuron syndrome, were followed prospectively over 12 months to determine whether progression to ALS could be predicted by positive Nogo-A expression in muscle biopsy. Lower motor neuron involvement was documented clinically by the presence of weak, wasted, fasciculating muscles, and confirmed electrodiagnostically by reduced motor evoked potential amplitudes on nerve conduction studies, or spontaneous activity (positive sharp waves and fibrillation potentials), or a reduced interference pattern on needle electromyography. At entry, no patient demonstrated upper motor neuron signs (spasticity, hyperreflexia, retained reflexes in weak wasted muscles, Hoffman or Babinski signs, loss of superficial abdominal reflexes), bulbar involvement, respiratory compromise, or sensory signs. All underwent spinal magnetic resonance imaging, sedimentation rate, serum immunoelectrophoresis and immunofixation, anti-GM1 and anti-poliovirus antibodies, and thyroid and parathyroid function. Muscle biopsy, usually of the deltoid (n = 28) unless it was deemed too atrophic, was performed as part of the routine workup, and Nogo-A expression was measured by Western blot techniques. Neurologists blinded to Nogo-A test results performed quarterly neurologic examinations to determine disease progression.
Strikingly, among 17 patients who tested positive for Nogo-A on muscle biopsy, found as early as 3 months following onset, 15 progressed to a definite ALS diagnosis, yielding 91% accuracy, 94% sensitivity, and 88% specificity. Among 16 Nogo-A negative patients, only 1 progressed to ALS over a mean follow-up of 25 months (14-37 months). Final diagnoses in this group included progressive spinal muscular atrophy (n = 6), lumbosacral root compression (n = 4), postpolio syndrome (n = 2), and one each of chronic inflammatory demyelinating polyneuropathy, idiopathic brachial plexopathy, and SMN1-linked spinal muscular atrophy. The authors conclude that muscle Nogo-A expression may accurately and specifically predict progression of lower motor neuron disease to ALS.
Were that it were so! Nogo, comprising isoforms Nogo-A, Nogo-B, and Nogo-C, is part of the reticulon family of integral membrane proteins demonstrated to inhibit axonal sprouting and regeneration in the adult nervous system. Though initially found in muscle biopsies from amyotrophic lateral sclerosis but not neuropathy or myopathy patients, suggesting it might be a specific marker for ALS, more recent evidence indicates that it is expressed in a host of neuromuscular disorders including peripheral neuropathies, polymyositis, dermatomyositis and histologically nonspecific myopathies (Wojcik S et al. Acta Myol. 2000;25:116-118). 20 kDa proteolytic Nogo-A product was also detected in 110/114 (96%) cerebrospinal fluid samples from patients with multiple sclerosis, compared to 0/18 patients with meningo-encephalomyelitis, 0/125 controls with other neurologic diseases, and 0/10 patients with central nervous system autoimmune diseases (Jurewicz A et al. Neurology 2007:68:283-287). Nogo-A appears not to be as specific as hoped for. Nevertheless, in the correct clinical setting, it may help predict early diagnosis of ALS. The jury is still out.