Muscle Nogo-A Expression Is a Prognostic Marker in Lower Motor Neuron Syndromes Pierre-Franc ¸ois Pradat, MD, PhD, 1 Gaelle Bruneteau, MD, 1 Jose-Luis Gonzalez de Aguilar, PhD, 2,3 Luc Dupuis, PhD, 2,3 Natasa Jokic, PhD, 2,3 Franc ¸ois Salachas, MD, 1 Nadine Le Forestier, MD, 1 Andoni Echaniz-Laguna, MD, PhD, 2–4 Odile Dubourg, MD, PhD, 5 Jean-Jacques Hauw, MD, PhD, 5 Christine Tranchant, MD, 4 Jean-Philippe Loeffler, PhD, 2,3 and Vincent Meininger, MD, PhD 1 Objective: A proportion of patients with pure lower motor neuron syndrome (LMNS) progress to amyotrophic lateral sclerosis (ALS). Early detection of this progression is impossible, which delays the patient’s access to treatment. Muscle expression of Nogo-A is a new candidate marker of ALS. We tested whether detection of Nogo-A in a muscle biopsy from patients with LMNS predicts progression to ALS. Methods: Thirty-three patients who had undergone a muscle biopsy during the diagnostic workup of spinal LMNS were observed for 12 months. Nogo-A expression was measured by Western blot in muscle biopsy samples and compared with the final diagnosis. Results: Nogo-A expression was detected in 17 patients and was absent in 16 patients. The detection of Nogo-A in muscle biopsy samples from LMNS patients correctly identified patients who further progressed to ALS with 91% accuracy, 94% sensitivity, and 88% specificity. In patients who later developed typical ALS, Nogo-A may be detected as early as 3 months after the onset of symptoms. Interpretation: Nogo-A test is able to identify ALS early in the course of the disease when diagnosis is difficult, requiring further progression. Use of the test in clinical practice may shorten the delay before introduction of neuroprotective drugs or inclusion in clinical trials. Ann Neurol 2007;62:15–20 Lower motor neuron syndrome (LMNS) refers to the presence of lower motor neuron (LMN) signs (muscle weakness, atrophy, fasciculations) together with motor neurogenic abnormalities on electromyographic (EMG) examination in the absence of upper motor neuron (UMN) signs. In many patients, LMNS represents the initial features of amyotrophic lateral sclerosis (ALS), with the patient eventually demonstrating the typical evolution of ALS with a progressive spreading of weak- ness leading to death. A proportion of patients with rapidly progressive characteristics of ALS never demon- strate UMN signs at any stage of their illness. In other patients, LMNSs are related to degenerative LMN dis- orders that can be sporadic, commonly classified as progressive spinal muscular atrophy (PSMA), or herita- ble, such as adult-onset SMN1-linked spinal muscular atrophy (SMA). 1,2 Various disease processes, such as multifocal motor neuropathy or postpoliomyelitis syn- drome, may cause or mimic LMNS (eg, inclusion body myositis). 3,4 Discovering biological markers for early detection of ALS in LMNS patients is critical to evaluate prognosis and start neuroprotective drugs as early as possible. A possible candidate is the presence of Nogo-A protein in muscle. Muscle expression of Nogo-A, a protein mainly involved in preventing neurite outgrowth and nerve regeneration in the central nervous system, 5 was always detected in a series of typical ALS patients, but absent in healthy control subjects and patients with sensorimotor peripheral neuropathy or myopathy. 6 In addition, Nogo-A is expressed at levels that correlate with the severity of clinical disability. 7 Expression also promotes denervation in a mouse model of ALS and induces neuromuscular junction instability when over- expressed in muscle fibers. 8 Muscle expression of Nogo-A is therefore a new candidate marker of ALS. From the 1 Fe ´de ´ration des Maladies du Syste `me Nerveux, Centre re ´fe ´rent maladie rare SLA, Ho ˆpital de la Pitie ´-Salpe ˆtrie `re, Paris; 2 In- stitut National de la Sante et de la Recherche Me ´dicale U692, Labo- ratoire de Signalisations Mole ´culaires et Neurode ´ge ´ne ´rescence; 3 Fac- ulte ´ de Me ´decine, Universite ´ Louis Pasteur; 4 De ´partement de Neurologie, Centre Hospitalier Universitaire de Strasbourg, Stras- bourg; and 5 Service de Neuropathologie, Ho ˆpital de la Pitie ´- Salpe ˆtrie `re, Paris, France. Received October 13, 2006, and in revised form Feb 6, 2007. Ac- cepted for publication Feb 9, 2007. This article includes supplementary materials available via the Inter- net at http://www.interscience.wiley.com/jpages/0364-5134/supp- mat Published online Apr 23, 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.21122 Address correspondence to Pr Meininger, Fe ´de ´ration des Maladies du Syste `me Nerveux, Centre re ´fe ´rent maladie rare SLA, Ho ˆpital de la Pitie ´-Salpe ˆtrie `re, 47-83, Boulevard de l’Ho ˆpital, 75651 Paris, France. E-mail: vincent.meininger@psp.aphp.tz ORIGINAL ARTICLES © 2007 American Neurological Association 15 Published by Wiley-Liss, Inc., through Wiley Subscription Services