ABSTRACT
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. RESULTS: Sixty-one persons from 18 families were affected. Ninety percent of patients were able to walk with or without the help of aids. Proximal leg muscle weakness was present in 13%. Asymmetrical features were present in 15%. Normal or brisk knee reflexes were present in 36%. Extensor plantar responses without associated spasticity occurred in 10 patients from eight families. Only three causative mutations were identified in the MFN2, BSCL2, and RAB7 genes. No mutations were found in the NEFL, HSPB1, HSPB8, GARS, DNM2, and GDAP1 genes. CONCLUSIONS: At group level, the clinical phenotype of Charcot-Marie-Tooth disease (CMT) Type 2 is uniform, with symmetric, distal weakness, atrophy and sensory disturbances, more pronounced in the legs than in the arms, notwithstanding the genetic heterogeneity. Brisk reflexes, extensor plantar responses, and asymmetrical muscle involvement can be considered part of the CMT Type 2 phenotype. The causative gene mutation was found in only 17% of the families we studied.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , GTP-Binding Protein gamma Subunits/genetics , Genetic Heterogeneity , Membrane Proteins/genetics , Mitochondrial Proteins/genetics , Nerve Tissue Proteins/genetics , Neural Conduction , rab GTP-Binding Proteins/genetics , Action Potentials , Adolescent , Adult , Age of Onset , Aged , Axons/physiology , Charcot-Marie-Tooth Disease/classification , Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/epidemiology , Charcot-Marie-Tooth Disease/physiopathology , Child , Child, Preschool , DNA Mutational Analysis , Demyelinating Diseases , Electromyography , Female , GTP Phosphohydrolases , GTP-Binding Protein gamma Subunits/physiology , Genotype , Humans , Hypesthesia/etiology , Infant , Male , Membrane Proteins/physiology , Middle Aged , Mitochondrial Proteins/physiology , Muscle Weakness/etiology , Muscular Atrophy/etiology , Mutation , Nerve Tissue Proteins/physiology , Netherlands/epidemiology , Neurologic Examination , Peripheral Nerves/physiopathology , Phenotype , Reflex, Abnormal , Retrospective Studies , Severity of Illness Index , Walking , rab GTP-Binding Proteins/physiology , rab7 GTP-Binding ProteinsABSTRACT
We report a 32-year-old patient with Charcot-Marie-Tooth (CMT2B) including foot ulcerations. Genetic analysis identified a de novo mutation in the small GTP-ase late endosomal RAB7 gene, consisting of a c.471G>C, p.Lys157Asn missense mutation. This observation strongly supports the hypothesis that RAB7 mutations are responsible for CMT2B.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , Mutation, Missense , rab GTP-Binding Proteins/genetics , Acyltransferases/genetics , Adult , Asparagine , Charcot-Marie-Tooth Disease/complications , Cytosine , Foot Ulcer/etiology , Genetic Variation , Guanine , Heterozygote , Humans , Lysine , Male , Pedigree , Serine C-Palmitoyltransferase , rab7 GTP-Binding ProteinsABSTRACT
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.
Subject(s)
Axons/pathology , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/pathology , Intracellular Signaling Peptides and Proteins/genetics , Myelin P0 Protein/genetics , Phosphoproteins/genetics , Adult , Age of Onset , Aged , Biopsy , Charcot-Marie-Tooth Disease/epidemiology , Cohort Studies , Connexins/genetics , DNA Mutational Analysis , Demyelinating Diseases/pathology , Female , Humans , Male , Median Nerve/physiopathology , Middle Aged , Myelin Proteins/genetics , Neural Conduction/physiology , Pedigree , Phenotype , Point Mutation , Polymorphism, Single-Stranded Conformational , Sural Nerve/pathology , Sural Nerve/physiopathology , Ulnar Nerve/physiopathology , Gap Junction beta-1 ProteinABSTRACT
OBJECTIVES: To assess the reliability of quantitative assessment of vibration sense with a Vibrameter type III. MATERIAL AND METHODS: We examined 111 healthy subjects (21-69 years). For intraobserver reliability, short-term (15 min between measurements) (n=11) and 24-h (n=28) reliability was tested. For interobserver reliability, a second tester performed the second measurement 15 min after the initial test (n=39). We also assessed the independent impact of effects of age, gender and height on vibration thresholds. RESULTS: In our study the intraobserver reliability is good [intraclass correlation coefficients (ICC) ranging from 0.55 to 0.99], whereas the interobserver reliability is moderate (ICC ranging from 0.32 to 0.88). Multiple linear regression analysis showed that age and--to a lesser extent--height was independently associated with the threshold values of the feet, but not with the thresholds of the hands. CONCLUSION: The use of a Vibrameter for measuring vibration thresholds in clinical practice and in multicentre studies is restricted because of the moderate interobserver reliability.
Subject(s)
Touch , Vibration , Adult , Aged , Diagnostic Tests, Routine/instrumentation , Female , Humans , Male , Middle Aged , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/physiopathology , Reference Values , Reproducibility of Results , Sensation/physiology , Sensory Thresholds/physiology , Touch/physiologyABSTRACT
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. Our patient shows a less severe phenotype than previously described patients with a His81Arg mutation. Multiple mutations in the myelin protein zero gene, as well as Charcot-Marie-Tooth with pupillary abnormalities have previously been described in rare instances. However, concurrent occurrence of both phenomena is a novel finding.
