CMT1A Patients Research Articles

Neurotrophin-3 therapy for Charcot–Marie–Tooth disease type 1A

Charcot–Marie–Tooth disease type 1A (CMT1A), a common inherited peripheral neuropathy (estimated prevalence 1 in 7,000 to 8,000), is caused by intrachromosomal duplication of a 1.4-megabase segment of chromosome 17p12. This large segment of duplicated DNA contains more than 20 genes, for each of which CMT1A patients have three copies, rather than the normal two.1 However, the excess copy number of only one of these genes, peripheral myelin protein 22 ( PMP22 ), seems to be responsible for all of the phenotypic features of CMT1A. Thus, rodents engineered to express multiple additional copies of the PMP22 gene, and hence to synthesize excess amounts of PMP22 protein, develop widespread peripheral nervous system (PNS) segmental demyelination and distal PNS sensorimotor axonopathy closely resembling the PNS pathology seen in patients with CMT1A.2 PMP22 is a Schwann cell transplasma membrane protein that, by virtue of adhesive interactions with the principal myelin glycoprotein, P0, contributes to the organization and stabilization of compact myelin.3 Important recent evidence in support of a cause-and-effect relationship between excess PMP22 protein expression in CMT1A was provided by …

Median nerve motor conduction velocity is concordant with myelin protein zero gene mutation

Myelin protein zero gene (MPZ) mutations may account for a small proportion of cases of Charcot-Marie-Tooth disease (CMT). Different MPZ mutations may be associated with different clinical and electrophysiological phenotypes. To expand our understanding of the characteristics of nerve conduction velocity (NCV) in patients with different MPZ mutations, the authors collected and analysed the NCV values from patients with MPZ mutations. The NCVs of fourteen patients from six families carrying MPZ mutations of Val58Asp, Ser63Phe, Thr65Ile,Arg98Cys, Arg98His, and Ser233fs were collected retrospectively. Five of them had received nerve conduction studies (NCS) twice. The mutations were verified by polymerase chain reaction (PCR) amplifications and nucleotide sequencing. Scatterplot analyses of median motor NCV (MNCV) versus specific MPZ mutation were performed. The median MNCV varied widely, with a mean of 16.3 m/s (SD = 7.7 m/s) and a range of 5.1-32.9 m/s. Median MNCVs of patients with particular MPZ mutations were similar. Moreover, Median MNCV did not change significantly over time. There was concordance between median MNCV and specific MPZ mutations. However, median MNCV is not an ideal measure with which to distinguish CMT1B patients with MPZ mutations from CMT1A patients with PMP22 mutations.

Early abnormalities in sciatic nerve function and structure in a rat model of Charcot-Marie-Tooth type 1A disease

We investigated early peripheral nervous system impairment in PMP22-transgenic rats (“CMT rat”), an established animal model for Charcot-Marie-Tooth disease 1A, at postnatal day 30 (P30), when the clinical phenotype is not yet apparent. Hemizygous CMT1A rats and wildtype littermates were studied by means of behavioral examination, electrophysiology, molecular biology, and light microscopy analysis. Behavioral studies only showed, a mild, but significant, decrease in toe spread 1–5, suggesting a weakness of distal foot muscles in CMT1A rats compared with normal littermates. Nerve conduction studies disclosed a severe slowing in motor conduction velocity, a temporal dispersion and a dramatic decrease of amplitude of motor waves in P30 transgenic animals. Coherently with a demyelinating process, affected nerves showed a significant thinning of myelin. Interestingly, axonal diameter and area were unchanged, but expression of non-phosphorylated neurofilaments was increased in CMT1A rats compared with normal controls. Our results confirm the fidelity of this animal model to human disease. Similarly, in young CMT1A patients, the MCV is significantly reduced and the muscle weakness is confined to distal segments, whereas morphological and morphometrical signs of axonal atrophy are absent. However, the presence of a molecular and functional damage of the axons suggests that this may be the correct moment to start neuroprotective therapies.

Is clinical variability in CMT1A related to epigenetic factors?

CMT1A patients bear the same genetic defect but often present with a wide range of clinical disability. Knowing the relationship between the phenotypic variability and other parameters, such as electrophysiological findings, age, gender, disease duration and environmental factors may be important for understanding the pathogenetic mechanisms underlying CMT1A. We studied 15 families and 7 sporadic cases affected by CMT1A (27 adults and 9 children) from the clinical, neurophysiological and genetic standpoint. A detailed patient history included: disease onset and progression, distribution of weakness, additional symptoms, life habits, genealogical tree, exposure to toxic substances, geographic provenance, instruction grade, job, use of drugs, and concurrent diseases. A questionnaire about diet was administered. The disability was evaluated by modified Rankin scale, deambulation index, functional independence measure and Barthel index. As previously reported, disease onset was in the first decade in 50% of cases and before the age of 20 years in 70% of cases. Severe disability was rarely observed, only 2 patients walking with a cane. No clear influence of gender over clinical severity was observed. Interestingly, genetic anticipation was observed in all the families. Data on the influence of environmental factors will also be presented.

Auditory processing in patients with Charcot-Marie-Tooth disease type 1A.

It is unclear whether Charcot-Marie-Tooth (CMT) disease, type 1A, causes auditory processing disorders. Therefore, auditory processing abilities were investigated in five CMT1A patients with normal hearing. Previous studies have failed to separate peripheral from central auditory processing disorders. Five genetically confirmed CMT1A cases in patients with normal hearing underwent behavioral and objective testing. Pure tone audiometry, speech audiometry, and OAE assessment were followed-up by an auditory processing test battery comprising sentences-in-noise test, pattern recognition tests, words-in-noise test, dichotic digit test, filtered speech test, binaural fusion test, and categorical speech perception test. Subsequently, ABR and ERP measurements were conducted. Either the behavioral or objective test scores of 4 out of the 5 CMT1A patients did not differ significantly from those of subjects with normal hearing. Significantly lower scores of one patient on auditory processing tests and ABR measurements could be ascribed to subnormal hearing. The authors conclude that CMT1A patients with normal peripheral hearing have auditory processing abilities that were not indicative for an auditory processing disorder. Furthermore, the presence of a peripheral hearing loss complicates the interpretation of auditory processing abilities.

ALTERED DOSAGE OF PERIPHERAL MYELIN PROTEIN 22 (PMP22) AFFECTS MYELIN PERIODICITY

Peripheral myelin protein 22 (PMP22) plays a dual role in regulating cells growth and peripheral myelin compaction. Charcot‐Marie‐Tooth 1A neuropathy (CMT1A) and Hereditary Neuropathy with liability to Pressure Palsies (HNPP) are respectively due to a duplication and a deletion of the PMP22 gene, leading to over and underexpression of the protein. It is unknown how the altered PMP22 dosage impairs peripheral myelination. By means of transmission electron microscopy (TEM) morphometry we found that myelin periodicity is significantly increased in CMT1A patients (9.79 ± 0.9 nm) and compared to normal sural nerves (9.1 ± 0.7 nm). Conversely, myelin periodicity was slightly reduced in HNPP patients (8.9 ± 0.7 nm). Interestingly, the difference between CMT1A and HNPP patients was highly significant. Moreover, we found an increased myelin periodicity in sciatic nerves of a transgenic rat model of CMT1A (8.9 ± 0.08) and in organotypic dorsal root ganglia cultures (10.1 ± 0.1 nm) established from this rat line, compared to control animals (8.6 ± 0.1) and cultures (9.6 ± 0.1 nm). Since TEM studies suffer considerably from radiation damage, we also used small‐angle X‐ray scattering (SAXS) with a synchrotron radiation microbeam (5 m diameter) for in‐situ experiments on single sural nerves of CMT 1A and HNPP patients and of normal controls. For comparison with the TEM‐data, the periodicities were divided by two. Myelin periodicities ranged from 8.4 to 8.9 nm (mean: 8.7 ± 0.3) in CMT 1A nerves, from 8.0 to 8.4 nm (mean: 8.1 ± 0.3) in normal controls, and from 6.9 to 7.2 nm (mean 7.1 ± 0.3) in HNPP. In conclusion, altered PMP22 levels induce significant changes in myelin lamellae spacing, which may be recorded by appropriate morphometric techniques, and in particular by microbeam SAXS. Differences in term of myelin periodicity between TEM morphometry and x‐ray microbeam analysis may be due to the higher resolution and accuracy of the latter technique to measure periodic structures. Having an altered myelin period could lead to demyelination and subsequent remyelination. Therefore, the pathomechanism of both CMT1A and HNPP may be also related to a dysfunction of PMP22 as a structural protein of peripheral myelin.

Proliferation of Schwann cells and regulation of cyclin D1 expression in an animal model of Charcot-Marie-Tooth disease type 1A.

Overexpression of PMP22 is responsible for the most common form of inherited neuropathy, Charcot-Marie-Tooth disease (CMT) type 1A. The PMP22-transgenic rat (CMT rat) is an animal model of CMT1A, and its peripheral nerves show the characteristic features of ongoing demyelination and remyelination that is also seen in CMT1A patients. Since Schwann cell proliferation is a prominent feature of peripheral nerves in inherited peripheral neuropathies, we examined proliferation and the expression of cyclin D1 in CMT rats. D-type cyclins are required for the initial steps in cell division and nuclear import is crucial for the function of cyclin D1 in promoting cell proliferation. Like normal myelinating Schwann cells in wild-type rats, remyelinating Schwann cells in CMT rats show perinuclear cyclin D1 expression. Schwann cells with nuclear cyclin D1 expression, as well as proliferating Schwann cells, were both associated with demyelinated axonal segments. Supernumerary onion bulb Schwann cells, however, do not express cyclin D1 and were not proliferating. Thus, cyclin D1 expression and its subcellular localization correlate directly with distinct physiological states of Schwann cells in this animal model of CMT1A.

Polymorphic Short Tandem Repeats for Diagnosis of the Charcot-Marie-Tooth 1A Duplication

A 1.5-Mb microduplication containing the gene for peripheral myelin protein 22 (PMP22) on chromosome 17p11.2-12 is responsible for 75% of cases of the demyelinating form of Charcot-Marie-Tooth disease (CMT1A). Methods for molecular diagnosis of CMT1A use Southern blot and/or amplification by PCR of polymorphic poly(AC) repeats (microsatellites) located within the duplicated region, or the detection of junction fragments specific for the duplication. Difficulties with both strategies have led us to develop a new diagnostic strategy with highly polymorphic short tandem repeats (STRs) located inside the CMT1A duplicated region. We tested 10 STRs located within the duplication for polymorphic behavior. Three STRs were selected and used to test a set of 130 unrelated CMT1A patients and were compared with nonduplicated controls. The study was then extended to a larger population of patients. Alleles of interest were sequenced. A manual protocol using polyacrylamide electrophoresis and silver staining and an automated capillary electrophoresis protocol to separate fluorescently labeled alleles were validated. We identified three new STRs covering 0.55 Mb in the center of the CMT1A duplication. One marker, 4A, is located inside the PMP22 gene. The two others, 9A and 9B, more telomerically positioned, have the highest observed heterozygosity reported to date for CMT1A markers: 0.80 for 9A, and 0.79 for 9B. Tetra- and pentanucleotide repeats offered clear amplification, accurate sizing, and easy quantification of intensities. Combined use of the three STRs allows robust diagnosis with almost complete informativeness. In our routine diagnosis for CMT1A, they have replaced the use of other polymorphic markers, either in a manual adaptation or combined with fluorescence labeling and allele sizing on a DNA sequencer.

CMT1A Associated With The 17p11.2 Duplication: Differential Features And Correlation

A duplication on chromosome 17p11.2 encompassing the gene coding for the peripheral myelin protein‐22 (PMP22) is the most common genetic abnormality underlying Charcot‐Marie‐Tooth disease (CMT). We report clinical and electrophysiologic features of our series of CMT1A patients harboring the duplication. There were 92 patients from 53 families representing 42% of all CMT index cases (n = 125) and 64% of CMT1 probands (n = 83). In CMT1A patients, mean age at onset was 9.7 ± 11.4 and was significantly lower than in non‐duplicated CMT1 cases (12.6 ± 9.7, p < 0.01) and CMT2 cases (21.5 ± 17, p < 0.001). Clinical severity was similar to that of CMT2 patients, but significantly milder than in non‐duplicated CMT1 cases. Pes cavus, upper limb involvement, deep tendon reflexes abnormalities, and sensory loss were more frequent compared to CMT2. Electrophysiologic examination revealed motor and sensory conduction velocity (MCV, SCV) slowing below 32 m/s in upper limbs. MCV and SCV were significantly lower than in non‐duplicated CMT1 patients. Amplitudes of upper limb compound muscle action potentials (CMAPs) and of upper and lower limb sensory action potentials (SAPs) were significantly lower than in CMT2, paralleling clinical differences. Clinical severity correlated with CMAP amplitudes and with disease duration. On the other hand, MCV slowing was not correlated with either severity or duration of the disease. We found a direct correlation between age at onset and upper limb MCV slowing. Conclusions: CMT1A is an early‐onset but slowly progressive disorder, on average milder than other CMT1. Axonal loss rather than demyelination per se underlies disease progression.

ALTERED DOSAGE OF PERIPHERAL MYELIN PROTEIN 22 (PMP22) AFFECTS MYELIN PERIODICITY

PMP22 is a 22‐kD glycoprotein expressed by myelinating Schwann cells. PMP22 seems to play a dual role in regulating cell growth and in peripheral myelin compaction. Myelin formation and maintenance are the result of interactions between PMP22 and the peripheral myelin protein zero (P0), which form complexes at the myelin membrane and mutually contribute to stabilize the intraperiod lines and to held together the major dense lines. Both PMP22 and P0 mutations result in specific inherited demyelinating neuropathies, which are neuropathologically characterized by uncompaction of myelin lamellae and splitting of the major dense lines in some myelinated fibers (MF). However, the most common hereditary neuropathies, Charcot‐Marie‐Tooth 1A (CMT1A) and Hereditary Neuropathy with liability to Pressure Palsies (HNPP), are due to a duplication and a deletion respectively, of the PMP22 gene, leading to over‐ and underexpression of the protein. It is unknown how the altered PMP22 dosage impairs peripheral myelination. Using our imaging system for nerve morphometry directly connected to the electron microscope, we evaluated myelin lamellae periodicity in 150 MF from sural nerves of: 3 CMT 1A patients, 3 HNPP patients, and 3 normal controls. Furthermore, we measured myelin period in 50 MF obtained from a CMT1A culture model and in 50 MF from normal DRG cultures. Myelin periodicity was significantly increased in CMT1A patients (9.77 ± 0.9 nm) and in the CMT1A culture model (10.1 ± 0.1 nm) compared respectively to the normal sural nerves (9.1 ± 0.7 nm) and to the control cultures (9.6 ± 0.1 nm). Conversely, myelin periodicity was slightly reduced in HNPP patients (8.9 ± 0.7 nm).In conclusion, PMP22 overexpression induces widening of myelin lamellae, which may be recorded with appropriate morphometric techniques. As this change has been also observed in DRG cultures from a CMT1A rat model, it may be the first stage of the demyelination process going on in this disease. The observation that altered dosage of PMP22 significantly affects myelin periodicity provides further clues in understanding the role of this protein in the process of myelin assembly and maintenance.

Trembler as a Mouse Model of CMT1A?

The Trembler mouse suffers from a dominantly inherited autosomal mutation that results in an abnormal myelination of the peripheral nervous system. Biochemical studies have shown that dysmyelination is the primary event, demyelination being a late-occurring process. The expression of myelin protein genes has been studied. The steady-state levels for PMP22 mRNA represent 10 and 5% of normal values in the nerves of heterozygous and homozygous Trembler, respectively. This is due to a reduced expression of the specific transcript driven by the promoter 1 of the PMP22 gene. Collective results indicate that Trembler dysmyelination is not necessarily the consequence of a large accumulation of the mutated PMP22 protein. Moreover, it appears that the situation in the Trembler is different from that encountered in most CMT1A patients, where an increased PMP22 gene dosage is responsible for the disease. Therefore, the Trembler mutant is perhaps not an ideal model for this human neuropathy.

Charcot-marie-tooth disease type 1A duplication by PCR analysis

By generating new junctional fragments from the recombinant Charcot-Marie-Tooth (CMT) 1A-REPs in CMT1A patients, a 3.2-kb recombination hot spot is observed in three quarters of CMT1A patients. By a polymerase chain reaction (PCR) method the authors analyzed eight patients CMT1A duplication, confirmed by Southern blot, to detect a recombination hot spot. Four patients had a novel 3.2-kb junctional fragment by PCR analysis. These four patients with a novel 3.2-kb junctional fragment had an abnormal 1789-bp fragment in addition to 1986-bp fragment after NsiI digestion (type 1). One patient who demonstrated no novel 3.2-kb junctional fragment had an abnormal 336-bp fragment in addition to 265 bp (type 2). Three patients with CMT1A duplication were not diagnosed as having CMT1A on the basis of PCR analysis. The PCR-based DNA test is valuable for screening to detect CMT1A duplication.

Improved culture methods to expand Schwann cells with altered growth behaviour from CMT1A patients.

A duplication of the gene for myelin protein PMP22 is by far the most common cause of the hereditary demyelinating neuropathy CMT1A. A role for PMP22 in cell growth in addition to its function as a myelin protein has been suggested because PMP22 is homologous to a gene specifically upregulated during growth arrest. Furthermore, transfected rat Schwann cells overexpressing PMP22 show reduced growth. In addition, abnormal Schwann cell differentiation has been described in nerve biopsies from CMT1A patients. To analyse whether the duplication of the PMP22 gene in CMT1A neuropathy primarily alters Schwann cell differentiation and to exclude nonspecific secondary responses, we improved human Schwann cell culturing. This allowed us long-term passaging of human Schwann cells with unchanged phenotype, assessed by expression of different Schwann cell markers. Subsequently we established Schwann cell cultures from CMT1A nerve biopsies. We find decreased proliferation of Schwann cells from different CMT1A patients in all passages. We also demonstrate PMP22 mRNA overexpression in cultured CMT1A Schwann cells. We conclude that decreased proliferation in cultured Schwann cells that carry the CMT1A duplication indicates abnormal differentiation of CMT1A Schwann cells. The identification of an abnormal phenotype of CMT1A Schwann cells in culture could possibly lead to an in vitro disease model.

Charcot-Marie-Tooth disease: histopathological features of the peripheral myelin protein (PMP22) duplication (CMT1A) and connexin32 mutations (CMTX1).

The two most common subtypes of Charcot-Marie-Tooth (CMT) disease are CMT1A and CMTX1. To determine whether these different genetic entities display different morphological phenotypes we compared sural nerve biopsies of CMT1A patients due to PMP22 duplication with biopsies of CMTX1 patients with proven Connexin32 mutations. In CMT1A nerve biopsies we found a severe reduction in myelinated fiber density, hypermyelination as well as demyelination, and a high percentage of onion bulb formations. CMTX1 nerve biopsies showed significant differences: a higher myelinated fiber density, thinner myelin sheaths, more cluster formations, and only few onion bulb formations. Teased fibers studies in CMT1A patients showed features of demyelination and/or remyelination in almost all fibers. In contrast, teased fibers of CMTX1 patients were uniformly thinly myelinated with 5-10% active axonal degeneration and 15% segmental demyelination. Median nerve motor conduction velocities were significantly faster in CMTX1 patients (31.6+/-5.5 m/s) than in CMT1A patients (18.2+/-6.9 m/s). The possible roles of PMP22 and Connexin32 in the pathogenesis of CMT are discussed.

Autosomal dominant Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies: detection of the recombination in Slovene patients and exclusion of the potentially recessive Thr118Met PMP22 point mutation.

Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy with liability to pressure palsies (HNPP) are the most frequent autosomal dominantly inherited disorders of the peripheral nervous system. The recessive inheritance is observed only exceptionally. Unequal crossing-over of misaligned flanking CMT1A-REP elements on chromosome 17p11.2 is the most frequent cause of the CMT1A duplication and of the reciprocal deletion in HNPP patients. Recently a recombination was noted. In our study 71 Slovene CMT1 patients from 36 families, 12 HNPP patients from 6 families and their 31 healthy relatives were analysed for the presence of these recombination mutations. In 29 of 36 unrelated CMT1 (81%) and in all 6 unrelated HNPP patients the duplication or the deletion, on chromosome 17p11.2-12 was detected. In 26 out of 29 duplication patients (CMT1A) (90%) a 3.2 kb EcoRI/SacI duplication junction fragment was observed. The analogous 7.8 kb EcoRI/EcoRI deletion junction fragment was found in 4 out of 6 unrelated HNPP deletion patients (67%). Overall we found a recombination mutation inside the in 86% of unrelated Slovene CMT1A and HNPP patients. One hundred and thirty-six DNA samples of the CMT1 and HNPP patients and of the healthy controls were negative for the potentially recessive Thr118Met PMP22 amino acid substitution. Dominantly inherited CMT1A duplications and HNPP deletions on chromosome 17p11.2 are thus, as in most other European countries, the most common mutations in Slovene CMT1 and HNPP patients. No signs of polymorphism or of potentially recessive mutation were found at the specific Thr118Met PMP22 site.

Overloaded Endoplasmic Reticulum–Golgi Compartments, a Possible Pathomechanism of Peripheral Neuropathies Caused by Mutations of the Peripheral Myelin Protein PMP22

Nonconservative point mutations of the peripheral myelin protein 22 (PMP22) are associated with Charcot-Marie-Tooth type 1A disease, the most common inherited peripheral neuropathy in humans, and with the Trembler J (TrJ) and Trembler (Tr) alleles in mice. We investigated the intracellular transport of wild-type PMP22 and its TrJ and Tr mutant forms in Schwann cells and in a non-neuronal cell line. In contrast to wild type, mutant proteins were not inserted into the plasma membrane and accumulated in the endoplasmic reticulum and Golgi compartments. Coexpression of each mutant with wild-type PMP22 confirmed the different intracellular distribution of the mutant forms, indicating that neither the TrJ nor Tr protein has a dominant-negative effect on the cellular distribution of wild-type PMP22. Accumulation of PMP22 immunoreactivity in the cell body of myelinating Schwann cells was also observed in nerve biopsies obtained from CMT1A patients carrying the TrJ point mutation. We propose that impaired trafficking of mutated PMP22 affects Schwann cell physiology leading to myelin instability and loss.

Animal models for inherited peripheral neuropathies.

Recent progress in human genetics and neurobiology has led to the identification of various mutations in particular myelin genes as the cause for many of the known inherited demyelinating peripheral neuropathies. Mutations in 3 distinct myelin genes, PMP22, P0, and connexin 32 cause the 3 major demyelinating subtypes of Charcot-Marie-Tooth (CMT) disease, CMT1A, CMT1B and CMTX, respectively. In addition, a reduction in the gene dosage of PMP22 causes hereditary neuropathy with liability to pressure palsies (HNPP), while particular point mutations in PMP22 and P0 cause the severe Dejerine-Sottas (DS) neuropathy. A series of spontaneous and genetically engineered rodent mutants for genes for the above-mentioned myelin constituents are now available and their suitability to serve as models for these still untreatable diseases is an issue of particular interest. The spontaneous mutants Trembler-J and Trembler, with point mutations in PMP22, reflect some of the pathological alterations seen in CMT1A and DS patients, respectively. Furthermore, engineered mutants that either over or underexpress particular myelin genes are suitable models for patients who are similarly compromised in the gene dosage of the corresponding genes. In addition, engineered mutants heterozygously or homozygously deficient in the myelin component P0 show the pathology of distinct CMT1B and DS patients, respectively, while Cx32 deficient mice develop pathological abnormalities similar to those of CMTX patients. Mutants that mimic human peripheral neuropathies might allow the development of strategies to alleviate the symptoms of the diseases, and help to define environmental risk factors for aggravation of the disease. In addition, such mutants might be instrumental in the development of strategies to cure the diseases by gene therapy.

INHERITED PERIPHERAL NEUROPATHIES

BACKGROUND– Peripheral neuropathy may result from diverse genetic causes. In recent years molecular diagnostic methods have clarified the relationships between many of these different causes and their resultant clinical phenotypes. REVIEW SUMMARY– Charcot-Marie-Tooth neuropathy type 1 (CMT 1) (demyelinating CMT) is most commonly associated with a duplication on chromosome 17 (CMT 1 A) and, less frequently, with point mutations within the myelin gene PMP22 (on chromosome 17) or in the myelin protein zero (Po) (on chromosome 1; CMT 1B). Hereditary neuropathy with liability to pressure palsies results from a deletion on chromosome 17p, which is reciprocal to the duplication seen in CMT 1A patients. Dejerine-Sottas disease is a less common, severe, demyelinating neuropathy that has been associated with mutations in either PMP22 or Po. X-linked CMT is associated with mutations in the connexin 32 gene. No candidate genes have been identified in CMT 2, but at least three different forms have been identified by genetic linkage analysis. These forms map to chromosomes 1p, 3, and 7. Refsum's disease, resulting from abnormalities of phytanic acid metabolism, is an autosomal recessive cause of demyelinating neuropathy. Familial amyloid neuropathy (FAP) is a less frequently diagnosed cause of hereditary neuropathy. In many cases, FAP arises from mutations in the transthyretin protein and may be treatable with liver transplantation. Mitochondria) DNA mutations may also lead to peripheral neuropathy, but usually in the context of more generalized mitochondrial illness. CONCLUSIONS– Understanding of the molecular genetics of neuropathies has facilitated patient care by providing direct methods for confirming the diagnosis. This should eventually lead to improved therapy for each particular disorder.

Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases

A clinical and electrophysiological study was performed in 119 Type 1A Charcot-Marie-Tooth disease (CMT1A) patients with proven 17p11.2 duplication. Onset of the first functional manifestations was in the first decade in 50% of cases and before the age of 20 years in 70% of cases. The predominant clinical signs were muscle weakness and wasting in the lower limbs. None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia. Motor nerve conduction velocity (MNCV) was uniformly reduced in all nerves, and was < or = 33 m/s in the median nerve for all patients. Sensory potentials were abnormal in all cases, even where there was no clinical sensory loss. Needle electromyography recruitment was reduced in distal muscles for all patients. MNCV slowing was fully consistent with the presence of duplication even in clinically asymptomatic individuals or in children, confirming the complete electrophysiological penetrance of 17p11.2 duplication and making median nerve MNCV a reliable tool for screening affected at-risk individuals. Functional disability was mild. Ninety-six percent of patients were autonomous; 25% were asymptomatic and diagnosed by systematic family investigation especially on the basis of median nerve MNCV reduction. Early age at onset and greatly reduced median nerve MNCV were predictive of a more severe disease course; the earlier the onset the more reduced the median nerve MNCV and the higher the functional disability tended to be after an equivalent disease duration. Cross-sectional analysis of neurological deficit, functional deficit and MNCV according to disease duration showed that, regardless of age at onset, CMT1A disease with 17p11.2 duplication is a clinically progressive disorder. Neurological deficit and functional disability increased, whereas median nerve MNCV and compound muscle action potential (CMAP) amplitude did not change with disease course. Intrafamilial phenotype variation between parents and children and between siblings was studied in large families. Functional disability and neurological deficit differed widely and the highest range of median nerve MNCV within a family reached 23 m/s. Clinical and electrophysiological data were compared with those of CMT1B patients with peripheral myelin P0 protein point mutation. CMT1A patients were found to be more severely affected with more prolonged distal motor latency and more reduced CMAP amplitude, whereas MNCV did not significantly differ, indicating that peripheral myelin P0 protein point mutation is not always associated with a severe phenotype. The same genetic defect (17p11.2 duplication) results in variable expression within the phenotype, even in siblings with variations in age at onset, clinical severity and MNCV slowing. This phenotypic variation could be due to additional genetic factors related to peripheral myelin protein 22 expression as well as to other endogenous or environmental factors.

Detection of the CMT1A/HNPP recombination hotspot in unrelated patients of European descent.

Charcot-Marie-Tooth type 1 disease (CMT1) and hereditary neuropathy with liability to pressure palsies (HNPP) are common inherited disorders of the peripheral nervous system. The majority of CMT1 patients have a...