Genetics of the Charcot‐Marie‐Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy‐Russe in depth

Four private mutations responsible for three forms demyelinating of Charcot‐Marie‐Tooth (CMT) or hereditary motor and sensory neuropathy (HMSN) have been associated with the Gypsy population: the NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN‐Lom); p.C737_P738delinsX and p.R1109X mutations in the SH3TC2 gene (CMT4C); and a G>C change in a novel alternative untranslated exon in the HK1 gene causative of CMT4G (CMT4G/HMSN‐Russe). Here we address the findings of a genetic study of 29 Gypsy Spanish families with autosomal recessive demyelinating CMT. The most frequent form is CMT4C (57.14%), followed by HMSN‐Russe (25%) and HMSN‐Lom (17.86%). The relevant frequency of HMSN‐Russe has allowed us to investigate in depth the genetics and the associated clinical symptoms of this CMT form. HMSN‐Russe probands share the same haplotype confirming that the HK1 g.9712G>C is a founder mutation, which arrived in Spain around the end of the 18th century. The clinical picture of HMSN‐Russe is a progressive CMT disorder leading to severe weakness of the lower limbs and prominent distal sensory loss. Motor nerve conduction velocity was in the demyelinating or intermediate range.     

Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) and genetic heterogeneity

Hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) is an adult-onset peripheral neurodegenerative disorder which has been reported only in the Okinawa Islands, Japan. The disease locus of "Okinawa-type" HMSN-P has been previously mapped to 3q13.1, with all affected individuals sharing an identical haplotype around the locus, suggesting that the undiscovered causative mutation in HMSN-P originated from a single founder. We have newly found two large families from the western part of Japan within which multiple members developed symptoms similar to those exhibited by HMSN-P patients from Okinawa, with no record of affinal connection between the islands. Using these pedigrees with "Kansai-type" HMSN-P, we carried out a linkage study utilizing eight microsatellite markers and identified a candidate region on 3q13.1 cosegregating with the disease (maximum two-point LOD score of 8.44 at theta=0.0) overlapping with the Okinawa-type HMSN-P locus. However, the disease haplotype shared among all affected members in these families was different from that in the Okinawa kindred, suggesting allelic heterogeneity. Such allelic variation should aid in the identification of the disease-causative gene. Moreover, the allelic heterogeneity of HMSN-P in the Japanese population suggests that HMSN-P may be more common across other ethnic groups, but classified into other disease categories.     

Charcot‐Marie‐Tooth disease type I and related demyelinating neuropathies: Mutation analysis in a large cohort of Italian families

Charcot‐Marie‐Tooth neuropathy type 1 (CMT1), the most common hereditary neurological disorder in humans, is characterized by clinical and genetic heterogeneity. It is caused mainly by a 1.5 Mb duplication in 17p11.2, but also by mutations in the myelin genes PMP22 (peripheral myelin protein 22), MPZ (myelin protein zero), Cx32 (connexin 32; also called GJB1), and EGR2 (early growth response 2). In this study, we have screened 172 index cases of Italian families in which there was at least one subject with a CMT1 diagnosis for the duplication on 17p11.2 and mutations in these genes. Among 170 informative unrelated patients, the overall duplication frequency was 57.6%. A difference could be observed between the duplication frequency in familial cases (71.6%) and that observed in non‐familial cases (36.8%). Among the non‐duplicated patients, 12 were mutated in Cx32, four in MPZ, two in PMP22, and none in the EGR2. In the non‐duplicated cases, the overall point mutation frequency for these genes was 25.0%. We describe the mutations identified, and consider possible genotype–phenotype correlation. Hum Mutat 18:32–41, 2001. © 2001 Wiley‐Liss, Inc.     

A prevalent founder mutation and genotype–phenotype correlations of OTOF in Japanese patients with auditory neuropathy

Matsunaga T, Mutai H, Kunishima S, Namba K, Morimoto N, Shinjo Y, Arimoto Y, Kataoka Y, Shintani T, Morita N, Sugiuchi T, Masuda S, Nakano A, Taiji H, Kaga K. A prevalent founder mutation and genotype–phenotype correlations of OTOF in Japanese patients with auditory neuropathy. Auditory neuropathy is a hearing disorder characterized by normal outer hair cell function and abnormal neural conduction of the auditory pathway. Aetiology and clinical presentation of congenital or early‐onset auditory neuropathy are heterogeneous, and their correlations are not well understood. Genetic backgrounds and associated phenotypes of congenital or early‐onset auditory neuropathy were investigated by systematically screening a cohort of 23 patients from unrelated Japanese families. Of the 23 patients, 13 (56.5%) had biallelic mutations in OTOF, whereas little or no association was detected with GJB2 or PJVK, respectively. Nine different mutations of OTOF were detected, and seven of them were novel. p.R1939Q, which was previously reported in one family in the United States, was found in 13 of the 23 patients (56.5%), and a founder effect was determined for this mutation. p.R1939Q homozygotes and compound heterozygotes of p.R1939Q and truncating mutations or a putative splice site mutation presented with stable, and severe‐to‐profound hearing loss with a flat or gently sloping audiogram, whereas patients who had non‐truncating mutations except for p.R1939Q presented with moderate hearing loss with a steeply sloping, gently sloping or flat audiogram, or temperature‐sensitive auditory neuropathy. These results support the clinical significance of comprehensive mutation screening for auditory neuropathy.