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Disorders In Depth

Charcot-Marie-Tooth disease - Advanced Description of Diseases

Hereditary Motor Neuropathies (HMN)

The current classification is based on the seven types of “distal hereditary motor neuronopathies” proposed by Harding (Harding, 1993), according to their clinical features and pattern of inheritance.  “Distal spinal muscular atrophy” is an alternative name. They can be conceptualized as length-dependent neuropathies of only motor axons, although sensory axons may be minimally involved. If a myelopathy is also present (presumably caused by a length-dependent axonopathy of descending axons to the spinal cord), as occurs in HMN V, HMN Jerash, and ALS4, then this must be distinguished from hereditary amyotrophic lateral sclerosis. A genetic cause could be found in 17/110 probands (15%) of patients with HMN, somewhat higher for those associated with myelopathy (Dierick et al., 2008), so that many causes remain to be discovered. Altogether, HMN may account for ~10% of patients who have been labeled as CMT (Harding and Thomas, 1980). Whereas one can conceptually account for the selective vulnerability of sensory and autonomic neurons in HSAN4 and 5, why they shoud be spared in the various forms of HMN remains unexplained.

HMN I (OMIM 182960)

HMN I was proposed to be a dominant inherited motor neuropathy with onset between 2-20 years. Although there are scattered clinical reports of individuals with this phenotype, the only genetic cause that has been found is one patient with a Pro182Ser mutation in HSPB1, who had foot drop before age 10 (Kijima et al., 2005).

HMN II (OMIM 158590, 608634, 613376)

HMN II was proposed to be a dominant inherited motor neuropathy with adult onset. Dominant mutations in HSPB8, HSPB1, and HSPB3 cause this phenotype, and are called HMN IIa, IIb, and IIc, respectively. HSPB8, HSPB1, and HSPB3 encode heat shock protein 22 (HSP22), 27 (HSP27), and 27 kDa, respectively, all of which encode a member of the family of 11 small HSPs. These proteins form oligomeric complexes with each other and serve diverse cellular functions, but the common phenotype of these different dominant mutations suggests a final common pathway to an axonal neuropathy.

Two different missense mutations that affect the same amino acid (Lys141Asn and Lys141Glu) in HSPB8 have been identified in four families with HMN IIa (Irobi et al., 2004). The Lys141Asn mutation was found in two large families. In one family, the age of onset ranged from 14-35 years. Clinical neurophysiology demonstrated length-dependent denervation and no sensory nerve involvement, and a sensory nerve biopsy in one patient was normal. (Note that the Lys141Asn mutation was also reported in the only CMT2L family reported to date (Tang et al., 2005); unlike the HMN IIa patients, affected individuals had clinical, electrophysiological, and histological evidence of sensory axonal involvement). The HSP22 mutants show enhanced interaction with HSP27, leading to the formation of aggregates in transfected cells.

Nine different dominant, missense mutations in HSPB1 cause HMN IIb (Evgrafov et al., 2004; Houlden et al., 2008); one mutation (Ser135Phe) was also reported to cause CMT2F. The clinical onset varies between 20 and 50 years, except for one patient (with a Pro182Ser mutation), who had foot drop before age 10 (Kijima et al., 2005); this could be considered to be the one genetically confirmed example of HMN I. A homozygous recessive mutation (Leu99Met) produced a similar phenotype, which should probably be called HMN III, although the age of onset is older than the 2-20 years used in Harding's (1993) classification. EMG shows severe denervation in distal weak muscles, and sensory findings are minimal to none, although some patients had diminished sural amplitudes (Houlden et al., 2008), again underscoring the difficulty of separating HMN II from CMT2. HSP27 mutants form abnormal aggregates and may have abnormal interactions with cytoskeletal proteins.

Building on the observation that mutations in two different HSPs caused HMN II, Kolb et al (Kolb et al., 2010) sequenced the genes for 10 different small HSPs in a cohort of 28 patients who had an unexplained axonal neuropathy. They identified a heterozygous mutation in HSPB3 in two sisters with HMN. The proband developed distal leg weakness in her 20s and had minimal sensory findings at age 51, including a normal sural sensory amplitude. EMG showed acute and chronic denervation in distal muscles.

HMN III (no OMIM) and HMN IV (OMIM 607088)

HMN III and IV were proposed to be recessively inherited forms of HMN that were separated by their age of onset and severity. They are also called Spinal Muscular Atrophy, Distal, Autosomal Recessive, 3 (DSMA3) in OMIM. In addition to the patient with a homozygous (Leu99Met) mutation, a gene causing this phenotype has been mapped to 11q13 in one large family, in which affected members had their clinical onset from infancy to adulthood (Viollet et al., 2002), thus encompassing both HMN III and IV.

HMN V (OMIM 600794)

HMN V was proposed to be dominantly inherited HMN with upper limb predominance. Dominant mutations in GARS (Antonellis et al., 2003) or BSCL2 (Windpassinger et al., 2004) cause this phenotype. GARS catalyzes the aminoacylation of glycine to its tRNA, and is an essential enzyme and is expressed in all cells. How dominant mutations cause a motor neuropathy (or CTM2D) is unknown.

Patients with GARS mutations typically present with weakness in the intrinsic hand muscles, followed by the distal legs, with clinical onset from the second to fourth decades, with slow progression. Some patients have reduced sensation, perhaps to different degrees depending on the mutation, adding to the difficulty in discerning HMN V from CMT2D.

BSCL2 encodes seipin. Homozygous, loss of function mutations cause congenital generalized lipodystrophy type 2, whereas two different dominant mutations (Asn88Ser and Ser90Leu), both of which affect glycosylation, cause HMN V. The unglycosylated mutants accumulate in the endoplasmic reticulum and likely induce an unfolded protein response that is presumably detrimental to certain neuronal types (e.g., motor neurons) that have the longest axons (Ito and Suzuki, 2007).

Concurrent myelopathy is often present with BSCL2 mutations (Auer-Grumbach et al., 2005); this is known as Silver syndrome (OMIM 270685). Even in the same kindred, a dominant BSCL2 mutation can produce a clinical picture of prominent weakness of intrinsic hand muscles, with or without spastic paraparesis, and others had a spastic paraparesis without hand weakness (SPG17). Taking all of these phenotypes together, the clinical onset is rare before age 10, and some patients did not have clinical manifestations until their 60s. Extremely slow progression is the rule; only one patient lost ambulation.


Recessive mutations in IGHMBP2 cause HMN VI/SMARD1 (spinal muscular atrophy with respiratory distress type 1)/Distal Spinal Muscular Atrophy Type 1. IGHMBP2 is a DNA and RNA helicase that is associated with ribosomes in the cytoplasm of neurons (Guenther et al., 2009). Mutations associated with HMN VI cause the loss of helicase activity.

Affected infants have low birth weights, difficulty breathing, distal weakness, contractures, diaphragmatic eventration. In a hierarchical cluster analysis, “the combination of ‘manifestation of respiratory failure between 6 weeks and 6 months’ AND (‘presence of diaphragmatic eventration’ OR ‘preterm birth’) predicted the presence of IGHMBP2 mutations with 98% sensitivity and 92% specificity” (Guenther et al., 2007). Sensory responses are absent, and motor responses, if present, show slowed conduction that is probably explained by the underdeveloped axonal diameters seen in nerve biopsies (similar to patients with homozygous, recessive NEFL mutations). Biopsies also show axonal loss. In one autopsied case, motor neurons did not appear to be lost. Thus, HMN VI appears to be a lethal, congenital axonal neuropathy, but there may be exceptional patients who survive with a severe neuropathy (Joseph et al., 2009).

HMN VII (OMIM 158580)

Dominant mutations in DCTN1 cause HMN VIIa, which is characterized by distal weakness and vocal cord paralysis. DCTN1 encodes the p150Glued subunit of dynactin, which is the motor for retrograde axonal transport. The Gly59Ser mutant protein has reduced binding to microtubules, and likely results in reduced retrograde axonal transport (Puls et al., 2003). Other DCTN1 mutations have been found in patient with sporadic motor neuron disease; whether these are causal remains to be shown.

Only a single family has been reported (Puls et al., 2005). Dysphagia, stridor, or hand weakness are the initial sympthoms, with onset between 23 and 44 years; weakness subsequently develops in the legs but patients do not require wheelchairs. Abduction of the the left vocal cord was weaker than the right, likely related to the greater length of the left recurrent laryngeal nerve. The (median-innervated) abductor pollicus brevis is weaker and had a smaller compound muscle action potential than does the (ulnar-innervated) adductor digiti minimi. Sensory exams and sensory responses are normal, but skin biopsies show some mild abnormalities. An autopsy on one affected patient showed “more intense staining and coarser and more irregularly shaped granules” of dynactin and dynein in hypoglossal motor neurons.

A mutation on 2q14 causes HMN VIIb (McEntagart et al., 2001). In the single reported family, weakness and atrophy typically develop in the second decade, followed by weakness in the distal legs. Hoarseness develops before or after the onset of hand weakness.

X-linked HMN associated with ATP7A mutations (no OMIM)

Some mutations in ATP7A cause X-linked HMN (Kennerson et al., 2010). ATP7A encodes a copper transporter. Complete loss of function ATP7A mutations cause Menkes disease (OMIM 309400), and partial loss of function mutations cause Occipital Horn Syndrome (OMIM 304150); motor neuropathy has not been reported with either disorder. Further, unlike the latter disorders, serum copper and ceruloplasmin levels are normal in patients the X-linked distal HMN. The ATP7A mutants associated with X-linked distal HMN are missense mutations of amino acides in the transmembrane domain; the mutants had delayed movement from the trans-Golgi to the plasma membrane in response to a copper challenge.

Distal weakness and atrophy and minimal sensory findings are the clinical findings, beginning at age1-10 years for the Thr994Ile mutation and 10-60 years for the Pro1386Ser mutation. The electrophysiology data mirror these clinical findings.

ALS4 (OMIM 602433)

Dominant mutations in SETX cause HMN/ALS4 (Chen and el., 2004). These mutations are distinct from the autosomal recessive mutations that cause Ataxia-Oculomotor Apraxia Type 2 (OMIM 208920), a syndrome that includes a prominent axonal neuropathy (Anheim et al., 2009). SETX encodes senataxin, a DNA and RNA helicase related to IGHMBP2. Senataxin is localized throughout the cell, but is particularly concentrated in the nucleolus of differentiated, non-dividing cells (Chen et al., 2006).

Patients typically become symptomatic in the second decade, with difficulty walking, followed by weakness and atrophy of distal muscles in the arms and legs. The patients who believed they were asymptomatic had physical findings of upper and lower motor neuron involvement (Rabin et al., 1999). Weakness was progressive in symptomatic patients, and involved proximal muscles. Increased deep tendon reflexes and extensor plantar responses are frequently noted. Sensory exams are minimally altered and sensory nerve responses are normal. Distal motor responses have reduced or absent amplitudes, with length-dependent denervation on needle exam. Autopsies show loss of myelinated axons in motor as well as sensory nerves/roots, and mild involvement of the lateral corticospinal tract.

HMN Jerash type (OMIM 605726)

HMN Jerash type is an autosomal recessive distal HMN that was found in one Jordanian kindred and mapped to 9p21.1-p12 (Christodoulou et al., 2000). Clinical onset is age 6-10 years, with distal atrophy and weakness. Younger patients have a myelopathy, but these findings progressively disappear as the disease progresses. Sensory exams are normal, sensory nerve responses are normal, and sural nerve biopsies showed mild loss of myelinated axons.  Motor responses are reduced or absent in distal muscles, with slowing of conduction.


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