Byoung-Joon Kim

Mutations in PRPS1, Which Encodes the Phosphoribosyl Pyrophosphate Synthetase Enzyme Critical for Nucleotide Biosynthesis, Cause Hereditary Peripheral Neuropathy with Hearing Loss and Optic Neuropathy (CMTX5)

We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss. The family of European descent was reported in 1967 as having Rosenberg-Chutorian syndrome, and recently a Korean family with the same symptom triad was identified with a novel disease locus CMTX5 on the chromosome band Xq21.32-q24. PRPS1 (phosphoribosyl pyrophosphate synthetase 1) is an isoform of the PRPS gene family and is ubiquitously expressed in human tissues, including cochlea. The enzyme mediates the biochemical step critical for purine metabolism and nucleotide biosynthesis. The mutations identified were E43D, in patients with Rosenberg-Chutorian syndrome, and M115T, in the Korean patients with CMTX5. We also showed decreased enzyme activity in patients with M115T. PRPS1 is the first CMT gene that encodes a metabolic enzyme, shedding a new light on the understanding of peripheral nerve-specific metabolism and also suggesting the potential of PRPS1 as a target for drugs in prevention and treatment of peripheral neuropathy by antimetabolite therapy.

A novel locus for X-linked recessive CMT with deafness and optic neuropathy maps to Xq21.32-q24.

The authors describe a Korean family with X-linked recessive Charcot–Marie–Tooth disease (CMT) having deafness and optic neuropathy. An X chromosome-wide linkage analysis identified a 15.2-cM candidate region flanked by DXS990 and DXS8067 on Xq21.32-q24 with the maximum lod score at DXS8077 (3.62, θ = 0.00). This locus does not overlap previously identified four loci for X-linked CMT, and the authors propose it as CMTX5.

Prevalence of multiple sclerosis in Korea

Objective: The aim of this study was to estimate the prevalence of multiple sclerosis (MS) in Korea through a nationwide survey. Methods: We estimated the prevalence of MS in Korea using several sources collected between 2000 and 2005: verified cases from 38 major referral hospitals across the nation, the National Health Insurance (NHI) payment request data from NHI Corporation of Korea, and the national mortality dataset from Statistics Korea. We established a network of neurologists from 38 major referral hospitals and performed a nationwide hospital survey for MS cases. The diagnoses of MS were validated according to the McDonald criteria. The diagnostic validity of each hospital was evaluated from hospital survey data to reduce the uncertainty of NHI data and was applied to estimate the prevalence using novel statistical methods. Results: The estimated numbers of MS cases in Korea through 2 different statistical methods which adjust NHI data by the diagnostic validity of each hospital were very similar: 1,681 (95% confidence interval [CI] 1,490–1,902) by the stratification method and 1,640 (95% CI 1,402–1,789) by the linear regression method. The crude MS prevalence was 3.5–3.6 cases per 100,000 individuals. The estimated female-to-male ratio was 1.26. Conclusion: This study is the first nationwide survey for the prevalence of MS in Korea utilizing a national database in complementary way. We found an increase in the prevalence of MS that is consistent with reports from neighboring Asian countries.

Mitochondrial GTPase mitofusin 2 mutations in Korean patients with Charcot-Marie-Tooth neuropathy type 2.

Charcot‐Marie‐Tooth disease (CMT) is classified into two types, the demyelinating (CMT1) and axonal forms (CMT2). CMT2 is further subdivided by linkage analysis into eight subgroups. Recently, mutations in the MFN2 gene, which encodes the mitochondrial GTPase mitofusin 2 (Mfn2) that regulates the mitochondrial network architecture by fusing the mitochondria, were identified in CMT2A patients. This study carried out mutation analysis of the MFN2 gene in 12 unrelated Korean patients suspected of having CMT2 and identified four mutations (Arg94Trp, His165Arg, Ser263Pro, and Ser350Pro). Three mutations were found within the highly conserved GTPase domain that is essential for the function of Mfn2, and one mutation (Ser350Pro) was observed between the GTPase domain and the downstream coiled‐coil domain. This suggests that mutations in the MFN2 gene are an important causative gene underlying Korean patients with CMT2, and screening for a mutation in the MFN2 gene is strongly recommended for making a molecular diagnosis of CMT2.

Mutation analysis of the PMP22, MPZ, EGR2, LITAF, and GJB1 genes in Korean patients with Charcot-Marie-Tooth neuropathy type 1

To the Editor: Charcot-Marie-Tooth disease (CMT) is one of the most common hereditary neurological disorders in humans, which is characterized by its clinical and genetic heterogeneity (1, 2). Approximately 60% of CMT patients have CMT1, which is the demyelinating type. Most CMT1 patients have a duplication of 17p11.2–p12 (CMT1A duplication) containing the peripheral myelin protein 22 gene (PMP22) (3, 4), and mutations in several other genes including PMP22 (5), myelin protein zero (MPZ) (6), connexin 32 (GJB1) (7), early growth response 2 (EGR2) (8), and lipopolysaccharide-induced tumor necrosis factor-alpha factor (LITAF ) genes (9) have also been identified in patients without the CMT1A duplication. This study investigated the genetic background of Korean patients with CMT1 using pulsed-field gel electrophoresis–Southern blotting to detect the CMT1A duplication (10), and bidirectional sequencing analysis of the MPZ, LITAF, EGR2, PMP22 and GJB1 genes. From November 1997 to March 2004, 80 patients were referred to our hospital for the CMT1 gene study. The clinical and neurological data of the patients were reviewed and 31 of 80 patients were excluded based on the nerve conduction study as follows: axonal type, 15; equivocal, 10; mixed features of demyelinating and axonal types, 3; and normal, 3. In addition, another 13 patients were also excluded for the following: family members of known CMT1 patients, 4; lack of clinical and/or neurological information, 7; and insufficient specimens, 2. Finally, 36 patients, who were diagnosed with CMT1 by the findings of a decreased ulnar nerve conduction velocity (NCV , 38 m/s), as described by Harding and Thomas (11), were examined. Twenty-seven of the 36 patients (75%) had the CMT1A duplication. The duplication frequency was higher than those reported in previous studies: 70.7% in a European collaborative study (12), 57.6% in an Italian study (13), and 53.6% in another study of Korean CMT1 patients (14). The subjects in the present study were not actively recruited but were referred to our hospital for a CMT1 gene test. Therefore, the proportion of typical CMT1 patients might be higher than those in previous studies. However, the CMT1A duplication frequency decreased to 60% when the seven patients with the lack of clinical and/or neurological information and the two patients with insufficient specimens were included. Moreover, the proportion would become much lower (46.5%) if the 10 patients with the equivocal phenotypes and three patients with mixed features of the demyelinating and axonal types were also included. Among the nine patients without the duplication, one and four patients had mutations in the PMP22 (c.179-2A.G) and GJB1 (D46G, V95M, T151H, and F180L) genes, respectively (Fig. 1, Table 1). Since two novel variations, c.1792A.G in PMP22 and the D46G in GJB1, have not been found in 100 normal chromosomes and the c.179-2A.G variation modifies the consensus acceptor sequence of intron 4, these variations might be disease-causing mutations in each CMT patient. It should be noted that patient 5 was included in this study because of a decreased NCV. However, a nerve biopsy showed a marked loss of myelinated nerve fibers, suggesting chronic axonal neuropathy. A GJB1 gene mutation was identified in this patient. No mutations were found in the remaining four patients. There were no mutations found in the MPZ, EGR2, and LITAF genes, which have been associated

Reduced serum uric acid levels in neuromyelitis optica: serum uric acid levels are reduced during relapses in NMO.

Uric acid (UA), a product of purine metabolism, is known to be reduced in patients with various neurological disorders including multiple sclerosis (MS). However, it has still remained unclear whether there is a close relationship between UA and neuromyelitis optica (NMO). The aim of this study was to investigate the association between serum UA levels and disease activity in NMO.

Characteristics of South Korean Patients with Hereditary Transthyretin Amyloidosis

Background and Purpose This retrospective cross-sectional study included 18 patients from unrelated families harboring mutations of the transthyretin gene (TTR), and analyzed their characteristics and geographical distribution in South Korea. Methods The included patients had a diagnosis of systemic amyloidosis, clinical symptoms, such as amyloid neuropathy or cardiomyopathy, and confirmation of a TTR gene mutation using genetic analysis recorded between April 1995 and November 2014. Results The mean age at disease onset was 49.6 years, and the mean disease duration from symptom onset to diagnosis was 3.67 years. Fifteen of the 18 patients were classified as mixed phenotype, 2 as the neurological phenotype, and only 1 patient as the cardiac phenotype. The most-common mutation pattern in South Korea was Asp38Ala, which was detected in eight patients. Thirteen patients reported their family hometowns, and five of the eight harboring the Asp38Ala mutation were from the Gyeongsang province in southeast Korea. The other eight patients exhibited a widespread geographical distribution. A particularly noteworthy finding was that the valine at position 30 (Val30Met) mutation, which was previously reported as the most-common TTR mutation worldwide and also the most common in the Japanese population, was not detected in the present South Korean patients. Conclusions South Korean patients with hereditary TTR amyloidosis exhibited heterogeneous TTR genotypes and clinical phenotypes. The findings of this study suggest that the distribution of TTR amyloidosis in South Korea is due to de novo mutations and/or related to the other countries in East Asia.