Phenotype of Charcot-Marie-Tooth disease Type 2.

Objective: To investigate the clinical and electrophysiologic phenotype of Charcot-Marie-Tooth disease (CMT) Type 2 in a large number of affected families.

Methods: We excluded CMT Type 1, hereditary neuropathy with liability to pressure palsies, and CMT due to Cx32 gene mutations by DNA analysis. We performed genetic analysis of the presently known CMT Type 2 genes.

Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations.

Background: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked, and autosomal recessive (AR) CMT. A locus responsible for the demyelinating form of ARCMT was assigned to the 5q23-q33 region (CMT4C) by homozygosity mapping. Recently, 11 mutations were identified in the SH3TC2 (KIAA1985) gene in 12 families with demyelinating ARCMT from Turkish, Iranian, Greek, Italian, or German origin.

Neurophysiologic studies in early-onset cerebellar ataxia.

The discovery of the gene for Friedreich's ataxia (FRDA) has not only broadened the FRDA phenotype, but has also identified patients with early-onset cerebellar ataxia who resemble FRDA clinically but who do not carry a mutation in the frataxin gene. In order to identify subgroups that may represent a uniform underlying disorder, we performed neurophysiologic studies, including nerve conduction studies, electromyography, and transcranial magnetic stimulation, in 15 patients with a slowly progressive, unexplained, early-onset cerebellar ataxia (EOCA). In addition, sural nerve biopsy data were available in four patients.

Late onset axonal Charcot-Marie-Tooth phenotype caused by a novel myelin protein zero mutation.

A late onset axonal Charcot-Marie-Tooth phenotype is described, resulting from a novel mutation in the myelin protein zero (MPZ) gene. Comparative computer modelling of the three dimensional structure of the MPZ protein predicts that this mutation does not cause a significant structural change. The primary axonal disease process in these patients points to a function of MPZ in maintenance of the myelinated axons, apart from securing stability of the myelin layer.

Macrophage clustering as a diagnostic marker in sural nerve biopsies of patients with CIDP.

Background: In adult patients with a slowly progressive demyelinating neuropathy, it may be difficult to distinguish between a hereditary neuropathy and chronic inflammatory demyelinating polyneuropathy (CIDP). The authors previously observed clustering of macrophages around endoneurial blood vessels in sural nerve biopsies from patients with CIDP.

Objectives: To quantitate macrophage clustering around endoneurial blood vessels in CIDP vs hereditary neuropathies.

Sensorineural hearing impairment in patients with Pmp22 duplication, deletion, and frameshift mutations.

Objective: To characterize and distinguish the types of sensorineural hearing impairment (SNHI) that occur in hereditary motor and sensory neuropathy Type 1a (HMSN-1a) and hereditary neuropathy with liability to pressure palsies (HNPP), which are caused by deletion or frameshift mutation.

Study Design: Prospective study.

Setting: Ambulatory patients in a university hospital.

Histology of hereditary neuralgic amyotrophy.

We report the findings in five muscle and three sural nerve biopsies, and in one postmortem plexus specimen, from six patients with hereditary neuralgic amyotrophy (HNA). We found that the sensory nerves are definitely involved in HNA despite the mainly motor symptoms, and that lesions in nerves and muscles are more widespread throughout the peripheral nervous system than clinically presumed, but, simultaneously, very focally affect isolated fascicles within individual nerves.

Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy.

Background: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot-Marie-Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis.

Methods: The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1.

Secondary axon atrophy and neurological dysfunction in demyelinating neuropathies.

Purpose Of The Review: Secondary axonal atrophy is common in most if not all demyelinating neuropathies and is likely responsible for the majority of clinical symptoms. We review clinical, electrophysiological and morphological evidence for secondary axonal atrophy in demyelinating neuropathies and summarize recent hypotheses on possible pathomechanisms.

Recent Findings: Elucidation of genetic defects responsible for hereditary demyelinating neuropathies and insights into axon-Schwann cell interactions have allowed longitudinal studies of genetically defined demyelinating neuropathies and research into the pathomechanism of secondary axonal atrophy.

Hereditary neuropathy with liability to pressure palsies with a small deletion interrupting the PMP22 gene.

Hereditary neuropathy with liability to pressure palsies is associated with a deficiency in the Peripheral Myelin Protein 22 (PMP22). Most hereditary neuropathy with liability to pressure palsies cases are caused by a deletion of a 1.5 Mb region on chromosome 17p11.

Comparison of a new pmp22 transgenic mouse line with other mouse models and human patients with CMT1A.

Charcot-Marie-Tooth disease type 1A is a dominantly inherited demyelinating disorder of the peripheral nervous system. It is most frequently caused by overexpression of peripheral myelin protein 22 (PMP22), but is also caused by point mutations in the PMP22 gene. We describe a new transgenic mouse model (My41) carrying the mouse, rather than the human, pmp22 gene.

Dejerine-Sottas syndrome grown to maturity: overview of genetic and morphological heterogeneity and follow-up of 25 patients.

Dejerine-Sottas syndrome (DSS) is an early onset demyelinating motor and sensory neuropathy with motor nerve conduction velocities below 12 m s(-1). The phenotype is genetically heterogeneous, and autosomal dominant (AD) as well as autosomal recessive (AR) inheritance is described. Nerve pathology is highly variable.

Two amino-acid substitutions in the myelin protein zero gene of a case of Charcot-Marie-Tooth disease associated with light-near dissociation.

Charcot-Marie-Tooth disease caused by mutations of the myelin protein zero gene demonstrates considerable phenotypical variability. We describe a 45-year-old female with a peripheral neuropathy with demyelinating and axonal features, pes cavus and pupillary light-near dissociation. She was heterozygous for two mutations in the myelin protein zero gene (His81Tyr and Val113Phe), both present on the same allele.

Axon damage in CMT due to mutation in myelin protein P0.

We describe a family carrying the Thr148Met mutation in the P0 gene. Contrary to other neuropathies caused by myelin gene defects, no demyeliantion could be found in our biopsies. Based on follow up examinations, extensive morphometry and immunohistochemical analysis we suggest that the mild hypomyelination documented in our family secondarily causes axonal degeneration and axonal loss of large and small fibers which predominates the clinical picture.

Mononeuropathy multiplex as the initial manifestation of neurofibromatosis type 2.

The authors report a patient with neurofibromatosis type 2 (NF2) presenting with an axonal mononeuropathy multiplex. Sural nerve biopsy showed small scattered groups of Schwann cells transformed into irregular branching cells with abnormal cell-cell contacts. The authors hypothesize that defective Schwann cell function, due to inactivation of the NF2 gene product merlin, leads to changes in morphology, cell-cell contact, and growth, and finally to degeneration of axons.

Intermediate CAG repeat lengths (53,54) for MJD/SCA3 are associated with an abnormal phenotype.

We report on a Dutch family in which 4 members in 2 generations have intermediate repeat lengths (53 and 54) for Machado-Joseph Disease/Spinocerebellar Ataxia (MJD/SCA3). All but the youngest have a restless legs syndrome with fasciculations and a sensorimotor axonal polyneuropathy. Central neurological abnormalities are only present in 2.

Cerebrotendinous xanthomatosis. Controversies about nerve and muscle: observations in ten patients.

Neuromuscular characteristics were documented in ten patients with biochemically and genetically confirmed cerebrotendinous xanthomatosis. An array of genotypes was found in these patients. Only one patient complained of muscle weakness, while clinical signs of peripheral neuropathy were present in six patients.

Abeta fibers mediate cutaneous reflexes during human walking.

During human gait, transmission of cutaneous reflexes from the foot is controlled specifically according to the phase of the step cycle. These reflex responses can be evoked by nonnociceptive stimuli, and therefore it is thought that the large-myelinated and low-threshold Abeta afferent fibers mediate these reflexes. At present, this hypothesis is not yet verified.

Mutation-dependent alteration in cellular distribution of peripheral myelin protein 22 in nerve biopsies from Charcot-Marie-Tooth type 1A.

The hereditary demyelinating neuropathy Charcot-Marie-Tooth type 1A is caused by duplication or by point mutations of the PMP22 gene. Histopathological differences in these genotypes suggest distinct disease mechanisms. In the present investigation we demonstrate a pathologically altered cellular distribution of PMP22 in sural nerve biopsies of patients with PMP22 point mutations.

Human nerve pathology caused by different mutational mechanisms of the PMP22 gene.

The study of the morphological phenotypes in patients with different mutations of the PMP22 gene gives additional insights into the role of the protein in myelin function. The pathology in young patients is in some aspects different from the pathology in older patients, providing essential and additional information about the early disease processes in humans induced by different PMP22 mutational mechanisms. Duplication of chromosome 17p11.