Genetic epidemiology of Charcot-Marie-Tooth in the general population.

BACKGROUND AND PURPOSE: the frequency of different Charcot-Marie-Tooth (CMT) genotypes has been estimated in clinic populations, but prevalence data from the general population are lacking. METHODS: our population-based genetic epidemiological survey included persons with CMT residing in eastern Akershus County, Norway. The participants were interviewed and examined by one geneticist/neurologist and classified clinically, neurophysiologically and genetically. RESULTS: two hundred and forty-five persons from 116 families had CMT. This corresponds to 1 per 1214 persons (95% CI 1062-1366) have CMT in the general population. CMT1 (motor conduction velocity (MCV) <38 m/s), CMT2 (MCV >38 m/s) and CMT intermediate (MCV 25-45 m/s) were found in 48.2%, 49.4% and 2.4% of the families. A total of 27.2% of the families and 28.6% of the affected had a mutation in the investigated CMT genes. The prevalence of the peripheral myelin protein 22 (PMP22) duplication and point mutation in the connexin32 (Cx32), myelin protein zero (MPZ) and mitofusin2 (MFN2) genes was found in 13.6%, 6.2%, 1.2%, 6.2% of the families, and in 19.6%, 4.8%, 1.1%, 3.2% of the affected, respectively. None of the families had point mutations in the early growth response 2 (EGR2), PMP22 or small integral membrane protein of lysosome/late endosome (SIMPLE) genes. CONCLUSIONS: CMT is the most common inherited neuropathy. At present, 43 CMT genes are known, and an examination of all known genes would probably only identify mutations in approximately 50% of those with CMT. Thus, it is probable that at least 30-50 CMT genes are yet to be identified.

Symptomatic Charcot-Marie-Tooth? A pair of concordant monozygotic twins.

BACKGROUND: A pair of monozygotic twin brothers were referred due to hereditary peripheral neuropathy resembling late onset Charcot-Marie-Tooth (CMT). AIM OF THE STUDY: Diagnostic classification of the twin pair. METHOD: Clinical, neurological, genetical and neurophysiological examination, and molecular genetic testing. RESULTS: The clinic and neurophysiology was compatible with CMT disease with late onset. Molecular genetic analysis excluded mutations in PMP22, connexin32, MPZ, LITAF and MFNZ genes, as well as duplication and deletion of PMP22. CONCLUSIONS: The twins were employed in PVC production and developed symptoms after 14 years of massive exposure. We think that the heavy exposure to various neurotoxic compounds caused symptoms that mimic late-onset CMT. However, the twins had distal dysesthesia which is unusual in inherited neuropathies. This illustrates the importance of an occupational history even in the molecular genetic era.

Association between polymorphisms of apolipoprotein E, bone mineral density of the lower forearm, quantitative ultrasound of the calcaneus and osteoporotic fractures in postmenopausal women with hip or lower forearm fracture.

A genetic contribution to the development of osteoporosis is well documented. Although the association between the common allelic variation of apolipoprotein E (APOE), fracture risk, bone loss and bone mineral density (BMD) has been examined in several studies, the results of these investigations are contradictory. The aim of this study was to examine the association between polymorphisms of APOE, BMD of the lower forearm, quantitative ultrasound of the calcaneus and osteoporotic fractures in a population of postmenopausal women with hip or lower forearm fractures admitted to a department of orthopaedic surgery and age-matched controls from the population register. The APOE genotypes of 327 women were studied: 73 with lower forearm fractures, 43 with hip fractures and 211 age-matched controls. The participants were not receiving antiosteoporotic treatment. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used to detect the APOE genotypes. Quantitative ultrasound was measured at the calcaneus. Bone mineral density (BMD) of the lower forearm was measured with dual-energy X-ray absorptiometry. The distributions of genotype frequencies in this study were: E2/E2: 0.3%; E2/E3: 16.5%; E2/E4: 2.5%; E3/E3: 54.7%; E3/E4: 24.2%; E4/E4: 1.8%. All subpopulations were in Hardy-Weinburg equilibrium. There was no association between bone mass parameters and the APOE allele groups. Logistic regression analysis did not show any association between fractures and APOE allele groups. In conclusion, this study showed no association between bone mass parameters (BMD, speed of sound (SOS), broadband ultrasound attenuation (BUA)), hip or lower forearm fracture and APOE genotypes in a population of postmenopausal women and age-matched controls.

[Relation between common allelic variation in a cross-sectional longitudinal population study. Vitamin D receptor locus, bone mineral density and postmenopausal bone loss]. / Relation mellem simpel allelisk variation i et tvaersnits- og longitudinelt befolkningsstudie. Vitamin D-receptorlocus, knoglemineraldensitet og postmenopausalt knogletab.

The aim of this study was to determine whether common allelic variation at the vitamin D receptor locus is related to bone mineral density and postmenopausal bone loss. Five hundred and ninety-nine healthy women aged 27 to 72 and 125 women with low bone mass aged 55-77 were measured once in a cross-sectional design. Furthermore, 136 women aged 45-54 were followed longitudinally for 18 years. The vitamin D receptor genotypes were determined using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism analysis for three different polymorphic restriction sites (BsmI, ApaI and TaqI). Bone mineral density was measured by photon and X-ray absorptiometry. The cross-sectional study showed no significant relationship between vitamin D receptor genotype and bone mineral density. The maximum difference between homozygotes was 1.3%, P = 0.33, N = 723. The low bone mineral density group had virtually the same genotype frequencies as the normal bone mineral density group. The results of the longitudinal study showed that vitamin D receptor genotype was neither related to early postmenopausal bone loss: age 51-53 (total bone loss at the lower forearm: -3.6% [3.6%], mean [standard deviation]), late postmenopausal bone loss: age 63-69 (total bone loss at the hip: -6.2% [8.7%]) nor to long term postmenopausal bone loss: age 51-69 (total bone loss at the lower forearm: -24.5% [11.4%]). Using analysis of variance to test for differences in the rates of bone loss between the vitamin D receptor genotypes, P values ranged from 0.07 to 0.79. We conclude that common allelic variation at the vitamin D receptor locus as defined by the endonucleases ApaI, BsmI and TaqI is neither related to bone mineral density nor to the rate of bone loss in healthy postmenopausal Danish women.

Relation of common allelic variation at vitamin D receptor locus to bone mineral density and postmenopausal bone loss: cross sectional and longitudinal population study.

OBJECTIVE: To determine whether common allelic variation at the vitamin D receptor locus is related to bone mineral density and postmenopausal bone loss. DESIGN: Cross sectional and longitudinal population study. SETTING: Outpatient clinic in research centre. SUBJECTS: 599 healthy women aged 27 to 72 and 125 women with low bone mass aged 55-77 had bone mineral density measured once in the cross sectional study. 136 women aged 45-54 were followed up for 18 years in the longitudinal study. MAIN OUTCOME MEASURES: Bone mineral density measured at the lumbar spine, hip, and forearm and rate of bone loss at different times over 18 years in relation to vitamin D receptor genotype as defined by the endonucleases ApaI, EsmI, and TaqI. RESULTS: Vitamin D receptor genotype was not related to bone mineral density at any site. The maximum difference between homozygotes was 1.3% (P = 0.33, n = 723). Women with low bone mineral density had almost the same genotype frequencies as the women with normal bone mineral densities. Vitamin D receptor genotype was not related to early postmenopausal bone loss from age 51 to 53 (mean (SD) total loss at the lower forearm -3.6% (3.6%)), late postmenopausal bone loss from age 63 to 69 (at the hip-6.2% (8.7%)), or to long term postmenopausal loss from age 51 to 69 (at the lower forearm-24.5% (11.4%)). CONCLUSION: Common allelic variation at the vitamin D receptor locus as defined by the endonucleases ApaI, EsmI, and TaqI is related neither to bone mineral density nor to the rate of bone loss in healthy postmenopausal Danish women.