Novel EGR2 mutation R359Q is associated with CMT type 1 and progressive scoliosis

Mutations in the early growth response 2 gene (EGR2) cause demyelinating neuropathies differing in severity and age of onset. We tested 46 unrelated Czech patients with dominant or sporadic demyelinating CMT neuropathy for mutations in the EGR2 gene. One novel de-novo mutation (Arg359Gln, R359Q) was identified in heterozygous state in a patient with a typical CMT1 phenotype, progressive moderate thoracolumbar scoliosis and without clinical signs of cranial nerve dysfunction. This patient is presently less affected compared to previously described Dejerine-Sottas neuropathy (DSN) patients carrying another substitution at codon 359 (Arg359Trp, R359W). This report shows that EGR2 mutations are rare in Czech patients with demyelinating type of CMT and suggests that different substitutions at codon 359 of EGR2 can cause significantly different phenotypes.     

A novel type of hereditary motor and sensory neuropathy characterized by a mild phenotype.

BACKGROUND: Three loci for autosomal dominant hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1) have been identified on chromosomes 17p11.2 (CMT1A), 1q21-q23 (CMT1B), and 10q21.1-q22.1 (designated here as CMT1D). The genes involved are peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), and the early growth response element 2 (EGR2), respectively. Probably a fourth locus (CMT1C) exists since some autosomal dominant HMSN I families have been excluded for linkage with the CMT1A and CMT1B loci. Four loci for autosomal dominant hereditary motor and sensory neuropathy type II (HMSN II) or Charcot-Marie-Tooth disease type 2 (CMT2) have been localized on chromosomes 1p35-p36 (CMT2A), 3q13-q22 (CMT2B), 7p14 (CMT2D), and 3p (HMSN-P). OBJECTIVE: To describe the clinical, electrophysiologic, and neuropathological features of a novel type of Charcot-Marie-Tooth disease. PATIENTS AND METHODS: We performed linkage studies with anonymous DNA markers flanking the known CMT1 and CMT2 loci. Patients and their relatives underwent clinical neurologic examination and electrophysiologic testing. In the proband, a sural nerve biopsy specimen was examined. RESULTS: Linkage studies excluded all known CMT1 and CMT2 loci. The clinical phenotype is mild and almost all affected individuals remain asymptomatic. Electrophysiologic and histopathological studies showed signs of a demyelinating neuropathy, but the phenotype is unusual for either autosomal dominant HMSN I or HMSN II. CONCLUSION: Our findings indicate that the HMSN in this family represents a novel clinical and genetic entity.     

A novel mutation of LRSAM1 in a Chinese family with Charcot‐Marie‐Tooth disease

Charcot‐Marie‐Tooth (CMT) disease is the most common inherited peripheral neuropathy characterized by progressive distal muscle weakness and atrophy with decreased or absent tendon reflexes. Mutations in LRSAM1 have been identified to cause CMT disease type 2P. We report a novel LRSAM1 mutation c.2021‐2024del (p.E674VfsX11) in a Chinese autosomal dominant CMT disease type 2 family. The phenotype was characterized by late onset and mild sensory impairment. Electrophysiological findings showed normal or mildly to moderately reduced motor and sensory nerve conduction velocities in lower and upper limb nerves.     

Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease

Mutations in the ganglioside-induced-differentiation-associated protein 1 gene (GDAP1) can cause Charcot-Marie-Tooth (CMT) disease with demyelinating (CMT4A) or axonal forms (CMT2K and ARCMT2K). Most of these mutations present a recessive inheritance, but few autosomal dominant GDAP1 mutations have also been reported. We performed a GDAP1 gene screening in a clinically well-characterized series of 81 index cases with axonal CMT neuropathy, identifying 17 patients belonging to 4 unrelated families in whom the heterozygous p.R120W was found to be the only disease-causing mutation. The main objective was to fully characterize the neuropathy caused by this mutation. The clinical picture included a mild-moderate phenotype with onset around adolescence, but great variability. Consistently, ankle dorsiflexion and plantar flexion were impaired to a similar degree. Nerve conduction studies revealed an axonal neuropathy. Muscle magnetic resonance imaging studies demonstrated selective involvement of intrinsic foot muscles in all patients and a uniform pattern of fatty infiltration in the calf, with distal and superficial posterior predominance. Pathological abnormalities included depletion of myelinated fibers, regenerative clusters and features of axonal degeneration with mitochondrial aggregates. Our findings highlight the relevance of dominantly transmitted p.R120W GDAP1 gene mutations which can cause an axonal CMT with a wide clinical profile.     

Mutational mechanisms in MFN2‐related neuropathy: compound heterozygosity for recessive and semidominant mutations

Mitofusin‐2 (MFN2) mutations are the most common cause of autosomal dominant axonal Charcot‐Marie‐Tooth disease (CMT, type 2A), sometimes complicated by additional features such as optic atrophy (CMT6) and upper motor neuron involvement (CMT5). Several pathogenic mutations are reported, mainly acting in a dominant fashion, although few sequence variants behaved as recessive or semidominant in rare homozygous or compound heterozygous patients. We describe a 49‐year‐old woman with CMT5 associated with compound heterozygosity for two MFN2 variants, one already reported missense mutation (c.748C>T, p.R250W) and a novel nonsense sequence change (c.1426C>T, p.R476*). Her mother, carrying the p.R250W variant, had very late‐onset minimal axonal neuropathy, whilst the father harboring the nonsense sequence change had neither clinical nor electrophysiological neuropathy. The missense mutation is likely pathogenic according to in silico analyses and a previous report, while the nonsense variant is predicted to behave as a null allele. The p.R250W variant behaves as semidominant by causing only a mild, almost subclinical, neuropathy when heterozygous; the nonsense mutation in the father was phenotypically silent, suggesting that haploinsufficiency for MFN2 is not disease causative, but was deleterious in the daughter who had only one active mutated MFN2 allele.     

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.     

Inherited peripheral neuropathy

Hereditary disorders of the peripheral nerves constitute a group of frequently encountered neurological diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is genetically heterogeneous and characterized by demyelination with moderately to severely reduced nerve conduction velocities, absent muscle stretch reflexes and onion bulb formation. Genetic loci for CMT1 map to chromosome 17 (CMT1A), chromosome 1 (CMT1B), and another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1 B result from point mutations in the myelin protein zero (Po or MPZ) gene. The molecular defect in CMT1 C is unknown. Mutations in the early growth response 2 gene (EGR2) are also associated with demyelinating neuropathy. Other rare forms of demyelinating peripheral neuropathies map to chromosome 8q, 10q, and 11q. X-linked Charcot-Marie-Tooth neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is characterized by normal or mildly reduced nerve conduction velocity with decreased amplitude and axonal loss without hypertrophic features. One form of CMT2 maps to chromosome 1 p36 (CMT2A), another to chromosome 3p (CMT2B) and another to 7p (CMT2D). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy that may be associated with point mutations in either the PMP22 gene or the Po gene and shares considerable clinical and pathological features with CMT1. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and results from reduced expression of the PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis.     

A novel autosomal dominant GDAP1 mutation in an Italian CMT2 family

We report the clinical, electrophysiological, and skin biopsy findings of an Italian Charcot-Marie-Tooth disease type 2 (CMT2) family with a novel heterozygous GDAP1 mutation. We observed a marked intra-familial phenotypic variability, in age at onset and disease severity which ranged from a typical CMT phenotype to an asymptomatic status. Electrophysiological study, consistent with an axonal sensory-motor neuropathy, confirmed a different degree of severity and disclosed minimal electrophysiological abnormalities also in the asymptomatic subjects. Skin biopsy findings showed a variable loss of large and small somatic nerve fibers. Molecular analysis identified a novel heterozygous missense mutation (Arg120Gly) in the GDAP1 gene which co-segregated with the disease within the pedigree. In conclusion, our findings confirm that the GDAP1 autosomal dominant mutations underlie a pronounced phenotypic variability, mimicking the effects of reduced penetrance. Notably, electrophysiological study in this family allowed to reveal hidden positive family history and assess a dominant inheritance pattern, revealing subclinical neuropathy in asymptomatic mutation carriers.     

A French family with Charcot-Marie-Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations

Either dominantly inherited mutations in MFN2 encoding mitofusin 2 or GDAP1 encoding ganglioside-induced differentiation associated protein 1 may be associated with mild neuropathy. The proband, a 41-year-old woman, and her daughter present a severe axonal form of Charcot-Marie-Tooth (CMT) disease. Both are heterozygous for the well-described mild variant p.R120W in GDAP1, which was transmitted by the pauci symptomatic proband's mother. Given that they had an early onset in the first decade and delayed walking acquisition, the other genes implicated in axonal forms of CMT disease were analyzed. A second mutation truncating MFN2 (p.Val160fsX26) was found in the proband and her daughter. This mutation was transmitted by the proband's father who has normal neurological examination. The proband underwent two nerve biopsies which showed an axonal degeneration, myelin modifications, and intra-axonal mitochondria with distorted cristae. Such abnormal mitochondria have been reported in cases with autosomal dominant MFN2 mutations and in one patient with an autosomal recessive GDAP1 mutation. Our two cases show that heterozygous truncation of MFN2, which is silent at least until the sixth decade, when combined with the mild p.R120W GDAP1 variant, leads to a severe neuropathy. This supports the emerging hypothesis of cumulative effects of MFN2 and GDAP1 mutation.     

The phenotype of Charcot–Marie–Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy

Charcot–Marie–Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies. The locus responsible for CMT4C was previously assigned to the chromosome 5q23 region by homozygosity mapping and mutations in the SH3TC2 (KIAA1985) gene have been subsequently identified mainly in families around the Mediterranean basin but also frequently in European Gypsies. No English families have been reported to date. To determine the frequency, phenotype and neuropathology of CMT due to SH3TC2 mutations we screened 23 English autosomal recessive (AR) demyelinating CMT families. Five families with AR demyelinating CMT and SH3TC2 mutations were identified, four families were homozygous for the R954X mutation and the fifth family was compound heterozygous for the R954X and E657K mutations. There was significant clinical variation between these families with some cases presenting with a severe childhood onset neuropathy with respiratory and cranial nerve involvement, compared to other families with mild scoliosis and foot deformity. Characteristic sural nerve neuropathology was seen in three families with frequent demyelinating fibres surrounded by excess Schwann cell lamellae forming basal lamina onion bulbs and abnormally long and attenuated Schwann cell processes. One patient homozygous for the R954X mutation had a 20-year history of an inflammatory neuropathy that was superimposed onto the hereditary form, indicating that structural alterations to the SH3TC2 gene could possibly predispose to peripheral nerve inflammation.     

A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family

Charcot-Marie-Tooth (CMT) disease is the most-common form of inherited motor and sensory neuropathy. The autosomal dominant axonal form of the disease (CMT2) is currently subdivided into seven types based on genetic localization. These are CMT2A (1p35-p36), CMT2B (3q13-q22), CMT2C (unknown), CMT2D (7p14), CMT2E (8p21), HMNSP (3q13.1), and CMT2F (7q11-q21). Two loci have thus far been identified for autosomal recessive CMT2; ARCMT2A (1q21.1-q21.3) and ARCMT2B (19q13.3). Mutations in four genes (connexin 32, myelin protein zero, neurofilament-light, and kinesin) have been associated with the CMT2 phenotype. We identified a novel neurofilament-light missense mutation (C64T) that causes the disease in a large Slovenian CMT2 family. This novel mutation shows complete co-segregation with the dominantly inherited CMT2 phenotype in our family. Electronic Publication     

A novel NDRG1 mutation in a non‐Romani patient with CMT4D/HMSN‐Lom

Charcot‐Marie‐Tooth disease type 4D (CMT4D), also known as hereditary motor and sensory neuropathy Lom type (HMSNL), is an autosomal recessive, early onset, severe demyelinating neuropathy with hearing loss, caused by N‐Myc downstream‐regulated gene 1 (NDRG1) mutations. CMT4D is rare with only three known mutations, one of which (p.Arg148Ter) is found in patients of Romani ancestry and accounts for the vast majority of cases. We report a 38‐year‐old Italian female with motor development delay, progressive neuropathy, and sensorineural deafness. Magnetic resonance imaging showed slight atrophy of cerebellum, medulla oblongata, and upper cervical spinal cord. She had a novel homozygous NDRG1 frameshift mutation (c.739delC; p.His247ThrfsTer74). The identification of this NDRG1 mutation confirms that CMT4D is not a private Romani disease and should be considered in the differential diagnosis of recessive demyelinating CMT.     

Charcot-Marie-Tooth neuropathy due to a novel EGR2 gene mutation with mild phenotype--usefulness of human mapping chip linkage analysis in a Czech family

Charcot-Marie-Tooth neuropathies (CMT) are a group of clinically and genetically heterogeneous disorders of the peripheral nervous system. Selection of candidate disease genes for mutation analysis is sometimes difficult since more than 40 genes and loci are known to be associated with CMT neuropathies. Hence a Czech family Cz-CMT with demyelinating type of autosomal dominant CMT disease was investigated by genome-wide linkage analysis by means of single-nucleotide polymorphism (SNP) arrays. Among 35 regions with linkage, five carried known CMT genes. In the final result a novel early growth response 2 - missense mutation c.1235 A>G, p.Glu412Gly was found. Surprisingly, the more severely affected proband carried an additional heterozygous myelin protein zero variant p.Asp246Asn detected previously, which may modify the phenotype. However, this MPZ variant is benign in heterozygous state alone, because it is also carried by the patient's healthy father.     

Phenotypic variation of a novel nonsense mutation in the P0 intracellular domain.

Mutations in the gene for the peripheral myelin protein zero (P0, MPZ) cause type 1B of Charcot-Marie-Tooth sensorimotor neuropathy (CMT1B). Here we report a German family with a novel heterozygous P0 nonsense mutation (G206X) that supposedly removes four-fifths of the amino acid residues constituting the P0 intracellular domain. The 12-year-old propositus had childhood-onset CMT1B associated with bilateral pes cavus, moderate lower limb weakness, and mildly reduced sensory qualities in the distal legs. The electrophysiology was consistent with a demyelinating neuropathy. He inherited the mutation from his mother who had no complaints but slight pes cavus deformity and slow nerve conduction velocities (NCV). Conclusively, truncating mutations within the P0 intracellular domain do not necessarily cause a severe phenotype such as Dejerine-Sottas syndrome (DSS) or congenital hypomyelinating neuropathy (CHN), but can result in mild or moderate CMT1B with intrafamilial clinical variability.