Jin-Hong Shin

Phenotypic variability in Kennedy's disease: implication of the early diagnostic features

Objectives –  The clinical diagnosis of Kennedys disease (KD) is not easy when the typical manifestations are lacking, especially in early stage of the disease. In our study, we tried to identify the relative frequency of common clinical features and early symptoms in KD.

Limb-girdle phenotype is frequent in patients with myopathy associated with GNE mutations

The gene GNE encodes a bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. Its mutations are found in distal myopathy with rimmed vacuoles (DMRV) and hereditary inclusion body myopathy (HIBM). Those disorders are characterized clinically by predominant anterior tibial muscle weakness and atrophy, and pathologically by rimmed vacuoles on muscle biopsy. We analyzed 11 Korean patients with GNE mutations. The mutations showed ethnic similarity to those of Japanese patients, showing the highest frequency with V572L. Another mutation of C13S was also found recurring in our patient group. Interestingly, about half of the patients showed limb-girdle myopathy rather than distal myopathy. This was further represented by limb muscle CT scans revealing atrophic hamstring and relatively spared anterior tibial muscle. However, quadriceps muscles were consistently spared both in distal and limb-girdle phenotypes. In conclusion, this study demonstrates a phenotypic diversity associated with GNE mutations. Recognizing a wider clinical spectrum of GNE mutations will help benefit more patients with imminent new therapy.

NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn's disease.

Purpose Thiopurine-induced leukopenia is a relatively common adverse event related to thiopurine medication in Korean pediatric Crohn’s disease. In addition to the mutations of TPMT gene, the NUDT15 c.415C>T variant was recently identified to have a strong association with thiopurine-induced early leukopenia. We conducted this study to define the incidence of azathioprine (AZA)-related leukopenia and to determine the incidence and characteristics of their genetic variants in Korean pediatric Crohn’s disease patients. Patients and methods Patients diagnosed with pediatric Crohn’s disease who had used AZA for more than 3 months were recruited. The dose and duration of medication and data regarding adverse events including leukopenia were collected. TPMT and NUDT15 gene sequencing was performed for patients who had experienced AZA-induced leukopenia. Results A total of 81 patients had used AZA as a maintenance therapy of Crohn’s disease. The mean dose of AZA was 1.88±0.39 mg/kg/day. Nine patients (11.1%) experienced AZA-induced leukopenia, and eight patients (9.9%) experienced AZA-induced early leukopenia. Among the eight early leukopenia patients, six patients (75.0%) harbored the NUDT15 c.415C>T variant and one patient (12.5%) had the TPMT c.719A>G (TPMT*3C) variant. All the three patients with NUDT15 c.415C>T homozygous variant suffered from alopecia totalis, and two of them experienced severe systemic infection. Three patients with the NUDT15 heterozygous variant are currently treated with AZA at a dose of 0.76 mg/kg/day. Conclusion Mutations of the NUDT15 and TPMT gene accounted for ∼88% of cases with thiopurine-induced early leukopenia. Extensive hair loss was a recognizable early symptom in patients with the homozygous NUDT15 c.415C>T variant. Sequencing of the NUDT15 genes can guide the clinicians before thiopurine medication. An alternative immunosuppressive medication is recommended for patients with homozygous NUDT15 c.415C>T variant. For those with the heterozygous variant, half the usual dose of AZA can achieve efficacy comparable to that for wild-type patients.

Novel CLCN1 mutations and clinical features of Korean patients with myotonia congenita.

Myotonia congenita (MC) is a form of nondystrophic myotonia caused by a mutation of CLCN1, which encodes human skeletal muscle chloride channel (CLC-1). We performed sequence analysis of all coding regions of CLCN1 in patients clinically diagnosed with MC, and identified 10 unrelated Korean patients harboring mutations. Detailed clinical analysis was performed in these patients to identify their clinical characteristics in relation to their genotypes. The CLCN1 mutational analyses revealed nine different point mutations. Of these, six (p.M128I, p.S189C, p.M373L, p.P480S, p.G523D, and p.M609K) were novel and could be unique among Koreans. While some features including predominant lower extremity involvement and normal to slightly elevated creatine kinase levels were consistently observed, general clinical features were highly variable in terms of age of onset, clinical severity, aggravating factors, and response to treatment. Our study is the first systematic study of MC in Korea, and shows its expanding clinical and genetic spectrums.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia linked CSF1R mutation: Report of four Korean cases.

We describe detailed clinical, biochemical, neuroimaging and neuropathological features in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), linked to colony-stimulating factor 1 receptor (CSF1R) mutations in four Korean cases. Clinical, biochemical, neuroimaging and neuropathological findings were obtained by direct evaluation and from previous medical records. The genetic analysis of the CSF1R gene was done in two autopsy-confirmed ALSP cases and two cases where ALSP was suspected based on the clinical and neuroimaging characteristics. We identified two known mutations: c.2342C>T (p.A781V) in one autopsy-proven HDLS and clinically ALSP-suspected case and c.2345G>A (p.R782H) in another autopsy-proven POLD case. We also found a novel mutation (c.2296A>G; p.M766V) in a patient presenting with hand tremor, stuttering and hesitant speech, and abnormal behavior whose father died from a possible diagnosis of spinocerebellar ataxia. To the best of our knowledge, this is the first documented ALSP-linked CSF1R mutation in Korea and supports the suggestion that HDLS and POLD, with pathological characteristics that are somewhat different but which are caused by CSF1R mutations, are the same spectrum of disease, ALSP.

Erratum: Mutation Analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia

aDepartment of Neurology, Pusan National University School of Medicine, Yangsan, Korea bResearch Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea cDepartment of Neurology, Chonnam National University Hospital, Gwangju, Korea dDepartment of Neurology, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea J Clin Neurol 2014;10(3):257-261 http://dx.doi.org/10.3988/jcn.2014.10.3.257 Print ISSN 1738-6586 / On-line ISSN 2005-5013 http://dx.doi.org/10.3988/jcn.2014.10.4.376 ERRATUM J Clin Neurol 2014;10(4):376-376

A Case of Lambert-Eaton Myasthenic Syndrome Associated with Atypical Bronchopulmonary Carcinoid Tumor

The Lambert-Eaton myasthenic syndrome (LEMS) is typically recognized as a paraneoplastic syndrome associated with a small cell lung carcinoma (SCLC), whereas LEMS with other neuroendocrine lung tumors, including carcinoids or large cell lung carcinoma, are highly unusual. Here, we report a rare case of LEMS with atypical bronchopulmonary carcinoid tumor: A 65-yr-old man presented with progressive leg weakness and a diagnosis of LEMS was made by serial repetitive nerve stimulation test. Chest CT revealed a lung nodule with enlargement of paratracheal lymph nodes, and surgically resected lesion showed pathological features of atypical carcinoid tumor. We concluded that LEMS could be associated with rare pulmonary neuroendocrine tumor other than SCLC, which necessitates pathologic confirmation followed by aggressive treatment for optimal management in these rare cases.

Late-onset episodic ataxia associated with SLC1A3 mutation

Episodic ataxia type 6 (EA6) is caused by mutations in SLC1A3 that encodes excitatory amino acid transporter 1 (EAAT1), a glial glutamate transporter. EAAT1 regulates the extent and durations of glutamate-mediated signal by the clearance of glutamate after synaptic release. In addition, EAAT1 also has an anion channel activity that prevents additional glutamate release. We identified a missense mutation in SLC1A3 in a family with EA. The proband exhibited typical EA2-like symptoms such as recurrent ataxia, slurred speech with a duration of several hours, interictal nystagmus and response to acetazolamide, but had late-onset age of sixth decade. Whole-exome sequencing detected a heterozygous c.1177G>A mutation in SLC1A3. This mutation predicted a substitution of isoleucine for a highly conserved valine residue in the seventh transmembrane domain of EAAT1. The mutation was not present in 100 controls, a large panel of in-house genome data and various mutation databases. Most functional prediction scores revealed to be deleterious. Same heterozygous mutation was identified in one clinically affected family member and two asymptomatic members. Our data expand the mutation spectrum of SLC1A3 and the clinical phenotype of EA6.

Electrophysiological Characteristics of Six Mutations in hClC-1 of Korean Patients with Myotonia Congenita

ClC-1 is a member of a large family of voltage-gated chloride channels, abundantly expressed in human skeletal muscle. Mutations in ClC-1 are associated with myotonia congenita (MC) and result in loss of regulation of membrane excitability in skeletal muscle. We studied the electrophysiological characteristics of six mutants found among Korean MC patients, using patch clamp methods in HEK293 cells. Here, we found that the autosomal dominant mutants S189C and P480S displayed reduced chloride conductances compared to WT. Autosomal recessive mutant M128I did not show a typical rapid deactivation of Cl− currents. While sporadic mutant G523D displayed sustained activation of Cl− currents in the whole cell traces, the other sporadic mutants, M373L and M609K, demonstrated rapid deactivations. V1/2 of these mutants was shifted to more depolarizing potentials. In order to identify potential effects on gating processes, slow and fast gating was analyzed for each mutant. We show that slow gating of the mutants tends to be shifted toward more positive potentials in comparison to WT. Collectively, these six mutants found among Korean patients demonstrated modifications of channel gating behaviors and reduced chloride conductances that likely contribute to the physiologic changes of MC.

Possible anticipation associated with a novel splice site mutation in episodic ataxia type 2

Anticipation is a phenomenon characterized by decreasing age at onset and increasing severity of symptoms of a disease in successive generations within a pedigree. Anticipation mostly occurs in neurodegenerative diseases with expansion of unstable trinucleotide repeats. However, it has not been previously pointed out in episodic ataxia type 2 (EA2). Clinical and genetic analyses were performed in nine members from three consecutive generations of a Korean family with EA2. We performed a polymerase chain reaction (PCR)-based direct sequence analysis of all coding regions of CACNA1A using genomic DNA. The clinically affected family members showed recurrent vertigo, interictal nystagmus, and childhood epilepsy. There is a decrease in the age onset (possible genetic anticipation) in three succeeding generations of the family. Genetic analysis identified a splice site mutation (p.Val1465Glyfs13X) and normal trinucleotide repeats in CACNA1A in all clinically affected and one unaffected members. Recognizing anticipation would aid in genetic counseling in EA2.