Recent Advances in Charcot–Marie–Tooth Disease

Jonathan Baets; Peter De Jonghe; Vincent Timmerman

Disclosures

Curr Opin Neurol. 2014;27(5):532-540. 

In This Article

Abstract and Introduction

Abstract

Purpose of review This article focuses on recent advances in Charcot–Marie–Tooth disease, in particular additions to the genetic spectrum, novel paradigms in molecular techniques and an update on therapeutic strategies.

Recent findings Several new Charcot–Marie–Tooth disease-causing genes have been recently identified, further enlarging the genetic diversity and phenotypic variability, including: SBF1, DHTKD1, TFG, MARS, HARS, HINT1, TRIM1, AIFM1, PDK3 and GNB4. The increasing availability and affordability of next-generation sequencing technologies has ramped up gene discovery and drastically changed genetic screening strategies. All large-scale trials studying the effect of ascorbic acid in Charcot–Marie–Tooth 1A have now been completed and were negative. Efforts have been made to design more robust outcome-measures for clinical trials. Promising results with lonaprisan, curcumin and histone deacetylase 6 inhibitors have been obtained in animal models.

Summary Charcot–Marie–Tooth is the most common form of inherited peripheral neuropathy and represents the most prevalent hereditary neuromuscular disorder. The genetic spectrum spans more than 70 genes. Gene discovery has been revolutionized recently by new high-throughput molecular technologies. In addition, the phenotypic diversity has grown tremendously. This is a major challenge for geneticists and neurologists. No effective therapy is available for Charcot–Marie–Tooth. Several large trials with ascorbic acid were negative but research into novel compounds continues.

Introduction

Inherited peripheral neuropathies (IPNs) are a large group of disorders characterized by length-dependent progressive degeneration of the peripheral nervous system (PNS). Clinical and genetic heterogeneity is extensive and with a prevalence of one in 2500 individuals, they represent the most common group of inherited neuromuscular disorders.[1] The most prevalent subgroup of IPN is hereditary motor and sensory neuropathies (HMSN) or Charcot–Marie–Tooth disease (CMT) named after the 19th Century neurologists who made seminal descriptions.[2] CMT is closely related to two more rare subgroups of IPN characterized by selective involvement of the motor nerves (hereditary motor neuropathies, HMN) or the sensory and autonomic nerves (hereditary sensory and autonomic neuropathies, HSAN). Both HMN and HSAN will be discussed elsewhere.

Disease onset in CMT is usually in the first 2 decades; symptoms typically start in the feet and progress in a distal to proximal pattern. Patients present with distal weakness and muscle atrophy in the lower limbs, resulting in gait difficulties. Distal involvement in the upper limbs is seen later and is usually less pronounced. Patients develop skeletal abnormalities, for example pes cavus, hammer toes and scoliosis. In addition, distal sensory loss is present; positive sensory symptoms are less common. Deep tendon reflexes typically are reduced or absent. Most often the disease progression is slow and results in mild-to-moderate impairment, leaving life expectancy unaltered.[3]

Following pioneering studies by Harding and Thomas,[4] nerve conduction studies became the mainstay of HMSN classification. A key parameter is the motor nerve conduction velocity (NCV) in the median nerve, in which the pathological basis of NCV slowing is prominent Schwann cell pathology leading to demyelination.[5] Conversely, when the disease results in axonal degeneration, NCVs are near normal. By convention, demyelinating forms of neuropathy (CMT1) are defined by a median motor NCV less than 38 m/s (normal value >49 m/s). Axonal forms (CMT2) are characterized by normal or moderately slowed NCV > 38 m/s. CMT2 only accounts for 25–30% of all IPN.[6,7] In addition, CMT with an intermediate electrophysiology has been described: in some patients, NCVs fall within a range of 25–45 m/s spanning both CMT1 and CMT2.[2,8] In the same way, in a single family, some patients may present electrophysiologically as CMT1 whereas others as CMT2. Some genes are specific to these phenotypes, supporting 'intermediate HMSN' as a useful clinical category, even if it does not necessarily correspond to a precise pathological interpretation.

A positive family history is typical in CMT, but its absence does not argue against a genetic cause. Inheritance is usually autosomal dominant or X-linked in nonconsanguineous families. De-novo mutations are frequently encountered as well.[9] Autosomal recessive forms tend to start early in childhood and run a more severe course presenting with delayed motor milestones, loss of ambulation and more complex phenotypes. In Europe, autosomal recessive forms of CMT account for less than 10% of families, whereas in communities with a high rate of consanguineous marriages, this proportion is more than 40%.[10] A few CMT2 families have a mutation in a mitochondrial-encoded gene.[11]

There is a considerable variability in disease onset and severity, ranging from severe congenital-onset forms to mild subtypes with onset in the fourth decade.[12,13] Several subforms of CMT have specific clinical features that can sometimes guide molecular diagnosis, for example vocal cord paralysis, cranial nerve involvement, upper limb predominance, pyramidal tract signs or optic atrophy.[3]

Because of the extensive clinical and genetic heterogeneity, classification of IPN/CMT has become obscured by ever-expanding complexity. Historically, IPN were subdivided based on clinical features. Despite early attempts to classify IPN genetics according to specific clinical features, it is now generally recognized that the current unifying classification is no longer capable of combining all relevant clinical and genetic elements in a simple and flexible format.[14]

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