The phenotype of the Gly94fsX222 PMP22 insertion

Point mutations in PMP22 are relatively rare and the phenotype may vary from mild hereditary neuropathy with liability to pressure palsies (HNPP) to severe Charcot-Marie-Tooth type 1 (CMT1). We describe the phenotype of the Gly94fsX222 mutation in the PMP22 gene. Medical records of all patients were reviewed and 11 patients were re-examined. EMG was carried out in nine patients and nerve biopsy in one. Thirteen patients originating from seven families with a Gly94fsX222 mutation were included and consisted of 10 women and 3 men with a median age of 41 years (range 7-67). Five index patients were originally suspected of CMT1. Ten patients had abnormal motor skills during childhood. Nine patients had a history of pressure palsies. Involvement of the olfactory, trigeminal, facial, and pudendal nerves occurred in three patients. Twelve patients had pes cavus and one scoliosis. Distal anterior leg and distal arm weakness were found in 12 and 4 patients, respectively. Twelve patients had distal leg sensory abnormalities. Electrophysiological examination revealed a demyelinating sensorimotor neuropathy, both resembling CMT1 and HNPP. Sural nerve biopsy showed demyelinating neuropathy with presence of tomacula. More than three-fourths of the patients with Gly94fsX222 mutation demonstrated a CMT1 phenotype combined with transient deficits. Clinicians should test for this mutation in those patients exhibiting a generalised neuropathy combined with compressive like episodes.     

A novel EGR2 mutation within a family with a mild demyelinating form of Charcot-Marie-Tooth disease

Mutations of the early growth response 2 (EGR2) gene have been reported in a variety of severe demyelinating neuropathies such as autosomal recessive congenital hypomyelinating neuropathy, autosomal dominant child-onset Dejerine-Sottas neuropathy, and autosomal dominant adult-onset Charcot-Marie-Tooth disease (CMT). Here, we report on a heterozygous mutation in EGR2 (c.1160C>A), which results in threonine at position 387 being changed to asparagine, in a family with a mild demyelinating form of adult-onset CMT. Of note, both the proband and her asymptomatic son exhibited neither pes cavus nor champagne-bottle leg atrophy, suggesting that the heterozygous T387N mutation may result in a relatively mild phenotype of demyelinating CMT.     

Distal hereditary motor neuropathy type II with mutation in heat shock protein 27 gene. A case report]

A 48-year-old man was admitted to our hospital with a tendency to stumble during walking. The family history indicated that the father was diagnosed with Charcot-Marie-Tooth disease (CMT) at the age of 55 and his younger sister (aunt) had similar symptoms that were considered to reflect autosomal dominant inheritance. Examination showed no pes cavus or inverted champagne-bottle thighs. In addition, the patient walked with foot drop due to weakness and atrophy of the distal parts of the lower extremities. Sensory examination revealed no deficits or abnormalities. Nerve conduction study and needle electromyography indicated pure motor axonal neuropathy. The diagnosis of distal hereditary motor neuropathy (distal HMN) type II was made. Genetic analysis detected mutation in the heat shock protein 27 (HSP27) gene. A recent report indicated that mutations in the HSP27 gene cause both distal hereditary motor neuropathy and CMT2F. In Japan, there are only a few reports of distal hereditary motor neuropathy with mutation in the HSP27 gene. Distal HMN should be considered in the differential diagnosis of patients with CMT like distal amyotrophy.     

Clinical correlates of charcot–marie–tooth disease in patients with pes cavus deformities

Introduction: Given its association with Charcot–Marie–Tooth disease (CMT), pes cavus is a common reason for referral to a neurologist. We investigated clinical features that may predict CMT in children with pes cavus. Methods: In this study we retrospectively reviewed pes cavus patients referred to Boston Children's Hospital in the past 20 years. Patients were categorized as idiopathic or CMT, based on EMG/genetic testing, and their clinical features were compared. Results: Of the 70 patients studied, 33 had idiopathic pes cavus, and 37 had genetically confirmed CMT. Symptoms of weakness, unsteady gait, family history of pes cavus and CMT, and signs of sensory deficits, distal atrophy and weakness, absent ankle jerks, and gait abnormalities were associated with CMT. Conclusions: In children with pes cavus, certain clinical features can predict CMT and assist in selection of patients for further, potentially uncomfortable (EMG) and expensive (genetic) confirmatory investigations. Muscle Nerve, 2013     

Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland

We describe a founder mutation in the gene encoding ganglioside-induced differentiation associated-protein 1 (GDAP1), leading to amino acid change p.H123R, as a common cause of autosomal dominant axonal Charcot-Marie-Tooth (CMT2) neuropathy in Finland. The mutation explains up to 14 % of CMT2 in Finland, where most patients with axonal neuropathy have remained without molecular diagnosis. Only three families out of 28 were found to carry putative disease mutations in the MFN2 gene encoding mitofusin 2. In addition, the MFN2 variant p.V705I was commonly found in our patients, but we provide evidence that this previously described mutation is a common polymorphism and not pathogenic. GDAP1-associated polyneuropathy caused predominantly a mild and slowly progressive phenotype. Besides distal leg muscle weakness, most patients showed mild proximal weakness, often with asymmetry and pes cavus. Our findings broaden the understanding of GDAP1 mutations in CMT2 phenotypes and provide support for the use of whole-exome sequencing in CMT gene diagnostics.     

Myelin protein zero Val102fs mutation manifesting with isolated spinal root hypertrophy

The Val102fs mutation of the myelin protein zero gene (MPZ) has been associated with Charcot–Marie–Tooth disease type 1B (CMT1B). Here we describe an unusual presentation of the Val102fs mutation characterized by symptoms of spinal root hypertrophy with no overt peroneal muscular atrophy. Two sisters aged 41 and 35 years complained of neck pain and presented only pes cavus or deep-tendon hyporeflexia. In both of them magnetic resonance imaging revealed non-enhancing hypertrophy of spinal roots misdiagnosed as neurofibromatosis; neurophysiology disclosed a demyelinating neuropathy and addressed the correct molecular diagnosis. This report adds new data concerning the clinical presentations of MPZ mutations.     

Episodic neurological dysfunction in hereditary peripheral neuropathy

Episodic transient neurological symptoms are an important set of problems presenting to a neurologist in his routine practice. Occasionally, detailed clinical history including past and family history supplemented with focused examination can bring out a rare cause for such symptoms. We describe in this report in a young male presenting with episodic focal neurological dysfunction, with family history of similar episodes in mother and brother. Examination showed features of pes cavus and peripheral neuropathy for which patient was asymptomatic. Mother and brother were established cases of hereditary neuropathy. Imaging on multiple occasions showed reversible white matter abnormalities. Clinical suspicion of X-linked Charcot-Marie-Tooth disease type 1 (CMT1X) was confirmed with detection of mutation in Gap Junction B1 (GJB1) gene, which codes for connexin 32 protein (c.425G>A; p.R142Q hemizygous mutation). Though this mutation has been already reported in CMTX patients, it has not been associated with transient neurological dysfunctions. This is probably the first reported case of CMTX patient with transient neurological dysfunction from India, whose family members had similar episodes.     

Peripheral neuropathy as initial sign of mitochondrial disorder

Charcot‐Marie‐Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. On the basis of electrophysiologic properties and histopathology, CMT has been divided into demyelinating (type 1) and axonal (type 2) neuropathies. The form of Charcot‐Marie‐Tooth neuropathy that maps to Xq13 may present mild electrophysiological changes (NCV > 40 M/s), mixed neuropathy (NCV: Intermediate (30–40 M/s), or demyelinating neuropathy (NCV: Slow (<37 M/s). On molecular grounds, CMTX is caused by mutations in GJB1 gene, coding for Connexin 32 protein. A 42‐year‐old man, with no other affected family members, was clinically evaluated for CMT. Three years ago he noticed thumb abductor atrophy and then leg muscle atrophy. He presented with hand and leg muscle atrophy, bilateral pes cavus, areflexia, and apallesthesia. The median and ulnar motor NVC were 35–38 m/s, and the median sensory NVC was 35 m/s. Both motor and sensory nerve action potentials were markedly reduced. After exclusion of CMT1A and 1B, analysis for CMTX was performed. The mutation screening of GJB1 gene showed a 9bp insertion upstream the 194ATG codon (Met194) with preservation of the downstream sequence. The three new amino acids (Thr‐Val‐Phe) inserted are localized between the end of the second extracellular domain and the beginning of the fourth transmembrane domain. This is the first 9bp insertion found in GJB1 gene; a genotype‐phenotype correlation may be deduced.     

Charcot–Marie–Tooth disease type 2J with <Emphasis Type="Italic">MPZ</Emphasis> Thr124Met mutation: clinico-electrophysiological and MRI study of a family

The purpose of the present study was to describe clinico-electrophysiological features and lower limb muscle MRI findings in a CMT2J pedigree due to MPZ Thr124Met mutation. We examined the proband, aged 56 years, and her affected daughter and son, aged 30 and 29 years. Disease severity in terms of ability to walk and run was established using a nine-point functional disability scale (FDS). We administered the CMT neuropathy score (CMTNS) based on patient’s symptoms, neurologic examination and neurophysiologic testing. All three patients had non-symptomatic Adie’s pupil. The proband and her son presented with late-onset lower limb sensorimotor neuropathy and pes cavus; the proband’s daughter had no signs of polyneuropathy. FDS score was 4 in the proband, 2 in her son, and 0 (normal) in her daughter. In both symptomatic patients, electrophysiological study showed a pattern of length-dependent axonal neuropathy mainly involving lower limb nerves; this was normal in the other patient. CMTNS was 18 in the proband, 12 in her son, and 0 (normal) in her daughter. MRI of foot and leg musculature was normal in the proband’s daughter, whereas the other two patients showed massive fatty atrophy of intrinsic foot musculature, extensive and diffuse fatty atrophy of leg muscles in the proband, and mild distally accentuated fatty infiltration of calf muscles in her son. Muscle edema, detected only in the proband’s son, was present in 7 out of 22 (33%) of visualized leg muscles, whereas contrast enhancement occurred in 6 of them. The reported mutation may manifest with either isolated Adie’s pupil or pupil abnormalities with late-onset sensorimotor length-dependent axonal polyneuropathy, though the presence of pes cavus might indicate an earlier onset. MRI examination helps to delineate an accurate extent of muscle involvement in the disease.     

Gene dosage sensitivity of a novel mutation in the intracellular domain of P0 associated with Charcot-Marie-Tooth disease type 1B

Autosomal dominant Charcot-Marie-Tooth disease type 1B (CMT1B) is caused by heterozygous mutations in the extracellular domain of P0. Here, we investigated clinically, electrophysiologically and pathologically a pedigree with a novel mutation in the intracellular domain of P0 (P0ic). The mutational analysis included denaturing high performance liquid chromatography (DHPLC) and nucleotide sequencing. Two patients from subsequent generations were homozygous for an Asp195Tyr mutation in the intracellular domain of P0 (P0ic), whereas two healthy individuals with minimal electrophysiological changes were heterozygous for the same mutation. The authors conclude that mutations of P0ic may undergo a gene dosage effect manifesting semidominant inheritance.     

Myelin uncompaction in Charcot-Marie-Tooth neuropathy type 1A with a point mutation of peripheral myelin protein-22.

BACKGROUND: The peripheral myelin protein-22 (PMP22) gene has four transmembrane domains, two extracellular loops, and a short cytoplasmic tail. Its roles in the peripheral nervous system remain unclear. The most common cause of Charcot-Marie-Tooth neuropathy type 1A (CMT1A) is a PMP22 gene duplication. Missense point mutations in the transmembrane domains are rare alternative causes that have undetermined pathogenetic mechanisms. OBJECTIVE: To investigate the phenotype-to-genotype correlations in a pedigree with unusual CMT1A. METHODS: We identified a pedigree with an autosomal dominant motor-sensory neuropathy and severely reduced nerve conduction velocities who did not have the PMP22 duplication. Specimens from sural nerve biopsies from two patients of different ages were evaluated morphometrically. By automated direct nucleotide sequencing we analyzed PMP22 and the gene of the major structural myelin protein zero (P0). RESULTS: Nucleotide 159 of PMP22 showed an A-to-T heterozygous mutation, predicted to cause an aspartate-to-valine substitution at codon 37 in the first extracellular loop of the protein. The mutation co-segregated with the disease in the pedigree and was absent in 80 healthy controls. The histopathologic phenotype was a de-remyelinating neuropathy with onion bulb formations, characterized by prominent uncompaction of the myelin sheath in the majority of fibers and by frequent tomacula. CONCLUSION: We have described a novel mutation in the first extracellular loop of PMP22 associated with an atypical CMT1A that overlaps pathologically with CMT1B caused by point mutations in the extracellular domain of P0.     

New insights into the pathophysiology of pes cavus in Charcot–Marie–Tooth disease type 1A duplication

Forefoot pes cavus is a cardinal sign of Charcot–Marie–Tooth disease (CMT). This review is focused on the pathophysiology of pes cavus in CMT1A duplication, which is the most common subtype of the disease. Assessment of foot deformities in CMT1A, their prevalence and proposed mechanisms, and recent contributions of magnetic resonance imaging studies of lower-leg and foot musculature are revised. Special attention is given to papers on foot deformities at initial stages of the disease. We conclude that pes cavus is an early and age-dependent manifestation of CMT1A duplication. Selective denervation of intrinsic foot musculature, particularly of the lumbricals, and not imbalance of lower-leg muscles, seems to be the initial mechanism causing reduced ankle flexibility and forefoot cavus deformity.     

X-LINKED DOMINANT CHARCOT-MARIE-TOOTH NEUROPATHY: ANALYSIS OF A PEDIGREE WITH A NOVEL MUTATION OF CONNEXIN 32

Objective: To report a family with X-linked Charcot-Marie-Tooth neuropathy (CMTX) with a novel mutation of connexin 32 (Cx32).
Background: Cx32, a gap-junction protein, is expressed in various neural and non-neural tissues. In the peripheral nervous system (PNS), Cx32 is expressed by the Schwann cell and it is believed to form reflexive gap-junctions at the Schmidt-Lantermann incisures and paranodes; in the central nervous system, Cx32 is expressed by neurons and oligodendrocytes. Mutations of Cx32 causes an apparently tissue-specific disorder of PNS: CMTX.
Methods: We examined, clinically and electrophysiologically, 2 brothers with CMT and their asymptomatic mother. We performed a sural nerve biopsy in the 29-year-old proband and analysed the Cx32 gene (GJB1) by direct nucleotide sequencing.
Results: We detected a novel GTA→GAA of GJB1 that is predicted to cause a Val23Glu substitution in the first transmembrane domain of Cx32. NCV studies disclosed features of a demyelinating neuropathy in the severely-affected hemizygous brother, and slowing of the sensory conduction velocity in the sural nerve in the mother who showed pes cavus and areflexia. In all three examined patients, BAEPs showed both delayed wave 1 and prolonged interpeak-latency-time (IPL I-V); central motor conduction time by MEPs was normal. The nerve biopsy in the proband was consistent with a primary axonal degeneration.
Conclusions: Cx32 mutations may lead also to a dysfunction of the CNS. Electrophysiological abnormalities of the CNS pathways may orientate the diagnosis of CMT towards Cx32.     

Mapping of the gene for X-linked dominant Charcot-Marie-Tooth neuropathy.

We performed a clinical study and linkage analysis on 278 subjects (66 affected) belonging to eight families with X-linked dominant Charcot-Marie-Tooth (CMT) neuropathy. This form affects 11.8% of CMT patients in Iowa. Motor nerve conduction velocities (MNCVs) were significantly slowed consistent with type 1 CMT. Fifty-six obligate carriers manifested mild distal weakness, localized areflexia, pes cavus, and slowing on MNCVs. Seven X-linked restriction fragment length polymorphisms mapping in the Xp11-q21 region were tested for linkage against CMT. Two-point linkage results showed the highest lod scores with PGK1, DXS159, and DXYS1. Multipoint linkage analysis excluded the CMT gene from being telomeric to either DXS14 or DXYS1, with over 1,000:1 odds. The highest location scores were at PGK1 and 1 cM proximal to DXS159.     

A NOVEL MYELIN PROTEIN ZERO MUTATION ASSOCIATED WITH CHARCOT-MARIE-TOOTH TYPE II DISEASE

Charcot-Marie-Tooth type II disease (CMT2) is a typical peroneal muscular atrophy syndrome and is characterised by normal or slightly reduced nerve conduction velocities with signs of axonal degeneration. CMT2 is genetically heterogeneous: linkage to 1p35–p36 (CMT2A; KIF1B gene), 3q13–q22 (CMT2B), 7p14 (CMT2D) and 8p21 (CMT2E; NF-L gene) loci has been reported for the autosomal dominant disease; however, the majority of CMT2 families do not link to any of the reported loci. Mutations of the myelin protein zero (MPZ) gene were found associated with demyelinating forms of hereditary neuropathies such as CMT1B, Dejerine-Sottas syndrome and congenital hypomyelination. So far, few CMT2 cases (CMT2F) were found to be caused by point mutations in the MPZ (see CMT Mutation Database, http://molgen-www.uia.ac.be/CMTMutations/ ) in 1q22 region.
We report a family in which three members are affected with a late-onset peripheral neuropathy. The index patient is a 68-year-old male who presents with pronounced distal muscle weakness of inferior limbs, bilateral pes cavus and absence of deep tendon reflexes. Electrophysiological findings were suggestive of an axonal form of peripheral neuropathy, thus allowing the diagnosis of CMT type 2. At the clinical and electrophysiological examination, two other family members (first cousins of the proband) resulted to be affected. MPZ gene direct sequencing revealed a heterozygous T/A transversion in the exon 3 of the gene, predicting an Asp103Glu aminoacid substitution in the extracellular domain of the protein. This variant was not found in unaffected relatives and in 100 normal chromosomes. This finding confirms the role of protein zero in axonal neuropathies and the phenotypic heterogeneity associated with MPZ mutations.
(The laboratory is a member of the European CMT Consortium; partially granted by Ministero della Sanitá to PM, MURST to FA)     

Parental mosaicism of a novel PMP22 mutation with a minimal neuropathic phenotype

Genetic germinal and somatic mosaicisms of dominant Charcot‐Marie‐Tooth disease (CMT) mutations are rarely reported and/or recognized. We describe a novel heterozygous p.Trp39Cys missense mutation in the extracellular domain of the peripheral myelin protein 22 (PMP22) associated with an early‐onset demyelinating CMT type 1 E (CMT1E) in two siblings born from asymptomatic non‐consanguineous parents. The 29‐year‐old mother, harboring approximately 20% of the mutant PMP22 allele in blood, had minor signs of distal polyneuropathy (pes cavus, decreased ankle jerk reflexes and vibration sense in legs) and slight reduction of sural nerve action potentials (SNAPs). Authors suggest that mutations of CMT‐related genes which originate in post‐zygotic stages may be associated with mild phenotypes of peripheral neuropathy.