Nerve Biopsy Is Still Useful in Some Inherited Neuropathies

J Neuropathol Exp Neurol Vol. 77, No. 2, February 2018, pp. 88–99 doi: 10.1093/jnen/nlx111 REVIEW ARTICLE Nerve Biopsy Is Still Useful in Some Inherited Neuropathies Mathilde Duchesne, MD, Stéphane Mathis, MD, PhD, Laurence Richard, PhD, Corinne Magdelaine, MD, Philippe Corcia, MD, PhD, Sonia Nouioua, MD, Meriem Tazir, MD, PhD, Laurent Magy, MD, PhD, and Jean-Michel Vallat, MD In hereditary neuropathies, next-generation sequencing techniques are producing a vast number of candidate gene mutations that need to be verified or excluded by careful genotype–phenotype correlation analysis. In most cases, clinical acumen is still important but needs to be combined with data from nerve conduction studies and, in some cases, from nerve biopsy examinations. Indeed, characteristic clinical, electrophysiological, and sometimes pathological features may be suggestive of a particular subtype of Charcot– Marie–Tooth (CMT) disease. Microscopical (mainly ultrastructural) human nerve biopsy patterns may be related to CMT diseases and gene defects. Even today, it is important to recognize these characteristic lesions in the context of a chronic idiopathic neuropathy as they may help search for or reveal a sporadic form of CMT. In practice, these different types of lesions are often linked to the known function of the mutated genes. Only a few patients diagnosed or suspected as having a CMT disease need a nerve biopsy that can help find or confirm the causative gene mutation. The indication for this procedure should be based on a case-by-case discussion. Key Words: Charcot–Marie–Tooth, Genotype, Nerve biopsy, Next-generation sequencing, Phenotype, Ultrastructural. INTRODUCTION Hereditary neuropathies comprise various disorders encompassing Charcot–Marie–Tooth disease (CMT), hereditary neuropathy with liability to pressure palsy (HNPP), hereditary motor neuropathy (HMN), hereditary sensory autonomic neuropathy (HSAN), as well as various other forms of inher- ited neuropathy such as familial amyloid polyneuropathy (FAP) (1). CMT, or “hereditary motor and sensory neuropathy” (HMSN), is a heterogeneous group of inherited disorders sharing a characteristic clinical phenotype and a progressive course (2). It represents the most common degenerative disorder of the peripheral nervous system (PNS), affecting up to 1 out of 1,214 individuals in some countries (3, 4). This incurable disorder may be “demyelinating,” “axonal,” or “intermediate,” based on electrophysiological and sometimes pathological criteria (5). One century after the clinical description by Jean-Martin Charcot and Pierre Marie (France) (6) and Howard Tooth (Great Britain) (7) of the “peroneal muscular atrophy syndrome,” the first genes were identified in patients with CMT (8, 9). Since the 1990s, progress in molecular genetics and more recently the use of next-generation sequencing (NGS) have generated a vast number of candidate gene mutations that need to be verified or excluded by careful genotype–phenotype correlation analysis, which in turn complicates the current classification of CMT (1). In most cases, clinical acumen is still essential, but needs to be combined with data from nerve conduction studies and, in some cases, from nerve biopsy findings. Characteristic clinical, electrophysiological, and sometimes pathological features may be suggestive of a particular subtype of CMT. From our personal experience and study of the medical literature, our aim is to highlight data showing the usefulness of nerve biopsy studies in the clinical diagnosis of some hereditary neuropathies of any age, and also provide more evidence that a mutated gene detected by molecular biology is the cause of the neuropathy. STEPS FOR DIAGNOSIS From the Department and Laboratory of Neurology, ‘Centre de Référence Neuropathies Périphériques Rares’, University Hospital, Limoges, France (MD, LR, LM, JMV); Department of Pathology, University Hospital, Limoges, France (MD); Nerve-Muscle Unit, Department of Neurology, CHU Bordeaux (Pellegrin Hospital), University of Bordeaux, Bordeaux, France (SM); Department of Genetics, University Hospital, Limoges, France (CM); Department of Neurology, CHU Tours (Bretonneau Hospital), Tours, France (PC); and Department of Neurology, CHU Algiers (Mustapha Pacha Hospital), Algiers, Algeria (MT) Send correspondence to: Jean-Michel Vallat, MD, Department and Laboratory of Neurology, CHU Limoges, 2 Avenue Martin Luther King, 87042 Limoges, France; E-mail: The authors declare that they have no competing financial interest. The authors have no duality or conflicts of interest to declare. 88 The objective of the first part of the review is to discuss how to select patients who could benefit from a nerve biopsy in routine clinical practice. In most cases, clinical, electrophysiological, and family data are sufficient to diagnose the type of genetic neuropathy (mainly CMT) and sometimes to confirm a suspected mutated gene. Although there are reports of the value of a skin biopsy for detecting ultrastructural lesions, our experience is that biopsy of a sensory nerve (usually the sural nerve) is of more value. Examination of a skin biopsy can only detect tiny fascicules in the dermis, which even in normal individuals contain few myelinated and unmyelinated fibers. In most cases, the axons are not sufficiently C 2017 American Association of Neuropathologists, Inc. All rights reserved. V Abstract J Neuropathol Exp Neurol • Volume 77, Number 2, February 2018 variant in the 3 other most common genes (GJB1, MPZ, and MFN2). If these first tests are negative, with the rapid development of NGS, it is now possible to test all known CMT genes for several patients in a single test, although there may be problems with interpretation of the identified variants. The causative nature of a new sequence variant or the presence of several genetic variants in the same individual (oligogenic inheritance or rare “private” polymorphisms in >1 CMT genes) may not be straightforward. Nevertheless, in 2 separate recent studies (employing either a 56- or 70-gene CMT panel in patients negative for the common CMT mutations), diagnostic rates of only 12% and 27%, respectively, were found (16, 17). Thus, in some familial cases and even more so in sporadic cases, the clinical, electrophysiological, and molecular data may be unable to confirm that the patient has a genetic neuropathy or specify its subtype if the mutated gene is not identified. In such conditions, nerve biopsy can be helpful, its indication relying on a case-by-case discussion. By demonstrating the presence of characteristic pathological lesions (mainly by electron microscopy [EM]) of either axons, myelin, or nodes of Ranvier, nerve biopsy may point to particular mutations in some genes; these various microscopical lesions in nerve biopsies often being linked to the known function of the mutated genes (Table). Nerve biopsy may also be helpful to orientate genetic testing in spo (...truncated)