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This study investigated the changes in the major etiologic organisms and clinical phenotypes of nontuberculous mycobacterial lung disease (NTM-LD) over a recent 15-year period in Korea. The increase of number of patients with NTM-LD was primarily due to an increase of Mycobacterium avium complex (MAC) lung disease (LD). Among MAC cases, the proportion of M. avium increased compared with M. intracellulare, whereas the incidence of M. abscessus complex and M. kansasii LD remained relatively stable. The proportion of cases of the nodular bronchiectatic form increased compared with the fibrocavitary form of NTM-LD., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2018 The Korean Academy of Medical Sciences.)

The National Health Information Standards Committee was established in 2004 in Korea. The practical subcommittee for laboratory test terminology was placed in charge of standardizing laboratory medicine terminology in Korean. We aimed to establish a standardized Korean laboratory terminology database, Korea-Logical Observation Identifier Names and Codes (K-LOINC) based on former products sponsored by this committee. The primary product was revised based on the opinions of specialists. Next, we mapped the electronic data interchange (EDI) codes that were revised in 2014, to the corresponding K-LOINC. We established a database of synonyms, including the laboratory codes of three reference laboratories and four tertiary hospitals in Korea. Furthermore, we supplemented the clinical microbiology section of K-LOINC using an alternative mapping strategy. We investigated other systems that utilize laboratory codes in order to investigate the compatibility of K-LOINC with statistical standards for a number of tests. A total of 48,990 laboratory codes were adopted (21,539 new and 16,330 revised). All of the LOINC synonyms were translated into Korean, and 39,347 Korean synonyms were added. Moreover, 21,773 synonyms were added from reference laboratories and tertiary hospitals. Alternative strategies were established for mapping within the microbiology domain. When we applied these to a smaller hospital, the mapping rate was successfully increased. Finally, we confirmed K-LOINC compatibility with other statistical standards, including a newly proposed EDI code system. This project successfully established an up-to-date standardized Korean laboratory terminology database, as well as an updated EDI mapping to facilitate the introduction of standard terminology into institutions., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2017 The Korean Academy of Medical Sciences.)

A new CT-based diagnostic method of protrusio acetabuli (PA) was introduced. However, prevalence of PA by this method and correlation between PA and other manifestations of Marfan syndrome (MFS) is unknown in Korean MFS patients. This study aimed to investigate the prevalence of PA diagnosed by a CT-based method in Korean patients with MFS, the association of PA with other manifestations of MFS, and the contribution of PA to MFS diagnosis. We retrospectively reviewed the records of 146 MFS patients with the presence of a causative FBN1 mutation and 146 age- and sex-matched controls from a single tertiary care center. All MFS patients underwent a complete assessment of criteria based on the revised Ghent nosology. PA was assessed quantitatively using a CT-based circle-wall distance (CWD) method. PA was diagnosed in 77.4% of patients in the MFS group and in 11.0% of the control group. CWD was significantly different between the two groups (1.50 mm vs. -0.64 mm, P<0.001). The presence of PA did not correlate with the presence of ectopia lentis, aortic root diameter, or history of aortic dissection. The presence of PA did not have a significant impact on the final diagnosis of MFS. Even though the presence of PA does not related to the cardinal clinical features of MFS or influence MFS diagnosis, its presence may be helpful for the suspicion of MFS when aortic dissection or aneurysm is found on CT angiography of the aorta because of the high frequency of PA in MFS patients.

Mutation or common intronic variants in cardiac ion channel genes have been suggested to be associated with sudden cardiac death caused by idiopathic ventricular tachyarrhythmia. This study aimed to find mutations in cardiac ion channel genes of Korean sudden cardiac arrest patients with structurally normal heart and to verify association between common genetic variation in cardiac ion channel and sudden cardiac arrest by idiopathic ventricular tachyarrhythmia in Koreans. Study participants were Korean survivors of sudden cardiac arrest caused by idiopathic ventricular tachycardia or fibrillation. All coding exons of the SCN5A, KCNQ1, and KCNH2 genes were analyzed by Sanger sequencing. Fifteen survivors of sudden cardiac arrest were included. Three male patients had mutations in SCN5A gene and none in KCNQ1 and KCNH2 genes. Intronic variant (rs2283222) in KCNQ1 gene showed significant association with sudden cardiac arrest (OR 4.05). Four male sudden cardiac arrest survivors had intronic variant (rs11720524) in SCN5A gene. None of female survivors of sudden cardiac arrest had SCN5A gene mutations despite similar frequencies of intronic variants between males and females in 55 normal controls. Common intronic variant in KCNQ1 gene is associated with sudden cardiac arrest caused by idiopathic ventricular tachyarrhythmia in Koreans.

Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders characterized by bone fragility, frequent fractures, and low bone mass. Dominantly inherited COL1A1 or COL1A2 mutations appear to be causative in the majority of OI types, but rare recessively inherited genes have also been reported. Recently, SERPINF1 has been reported as another causative gene in OI type VI. To date, only eight SERPINF1 mutations have been reported and all are homozygous. Our patient showed no abnormalities at birth, frequent fractures, osteopenia, and poor response on pamidronate therapy. At the time of her most recent evaluation, she was 8 yr old, and could not walk independently due to frequent lower-extremity fractures, resulting in severe deformity. No clinical signs were seen of hearing impairment, blue sclera, or dentinogenesis imperfecta. In this study, we describe the clinical and radiological findings of one Korean patient with novel compound heterozygous mutations (c.77dupC and c.421dupC) of SERPINF1.

Since microbial gene sequencing was utilized for etiologic diagnosis of culture-negative endocarditis, cases of Bartonella endocarditis have been reported in various countries. Herein we report the first case of Bartonella quintana endocarditis, which was confirmed for the first time in Korea by 16S rRNA gene sequencing from the excised valve. A 75-yr-old woman was hospitalized due to dyspnea. Echocardiography demonstrated large oscillating vegetation at the aortic valve. Blood culture was negative. She underwent valve replacement and sequencing of the 16S rRNA gene from excised valve identified Bartonella quintana. She was successfully treated with combined use of ceftriaxone and gentamicin.

Rabson-Mendenhall syndrome (RMS) is a rare syndrome manifested by extreme insulin resistance with hyperinsulinemia, acanthosis nigricans, tooth dysplasia and growth retardation. Our patient was first noted at the age of 8 months due to pigmentations on skin-folded areas. Initial laboratory tests showed normal fasting glucose (69 mg/dL). Fasting insulin level was severely elevated, up to 554.6 µIU/mL, and c-peptide level was increased, up to 13.81 ng/mL. However, hemoglobin A1c was within normal range (4.8%). He is now 11 yr old. His growth development followed the 5-10th percentile and oral hypoglycemic agents are being administered. The last laboratory results showed insulin 364.1 µIU/mL, C-peptide 4.30 ng/mL, and hemoglobin A1c 7.6%. The boy was a compound heterozygote for the c.90C > A and c.712G > A mutations of the insulin receptor gene, INSR, which are nonsense and missense mutations. In summary, we report the first Korean case of RMS, which was confirmed by two novel mutations of the INSR.

Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked recessive disorders caused by mutation in dystrophin gene. We analyzed the results of a genetic test in 29 DMD/BMD patients, their six female relatives, and two myopathic female patients in Korea. As the methods developed, we applied different procedures for dystrophin gene analysis; initially, multiplex polymerase chain reaction was used, followed by multiplex ligation-dependent probe amplification (MLPA). Additionally, we used direct DNA sequencing for some patients who had negative results using the above methods. The overall mutation detection rate was 72.4% (21/29) in DMD/BMD patients, identifying deletions in 58.6% (17/29). Most of the deletions were confined to the central hot spot region between exons 44 and 55 (52.9%, 7/19). The percentage of deletions and duplications revealed by MLPA was 45.5% (5/11) and 27.2% (3/11), respectively. Using the MLPA method, we detected mutations confirming their carrier status in all female relatives and symptomatic female patients. In one patient in whom MLPA revealed a single exon deletion of the dystrophin gene, subsequent DNA sequencing analysis identified a novel nonsense mutation (c.4558G > T; Gln1520X). The MLPA assay is a useful quantitative method for detecting mutation in asymptomatic or symptomatic carriers as well as DMD/BMD patients.

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic response to relatively low doses of levodopa. However, patients with DRD can be misdiagnosed as cerebral palsy or spastic diplegia due to phenotypic variation. Here we report a young woman with DRD who were severely disabled and misdiagnosed as cerebral palsy for over 10 yr. A small dose of levodopa restored wheelchair-bound state to normality. However, thoracolumbar scoliosis has remained as a sequel due to late detection of DRD. Genetic analysis by using PCR-direct sequencing revealed a novel initiation codon mutation (c.1A>T; p.Met1Leu) in GTP cyclohydrolase 1 (GCH1) gene. Although it is known that DRD can be misdiagnosed as cerebral palsy, this case reinforces the importance of differential diagnosis of DRD from cerebral palsy.

Carrier woman of Duchenne muscular dystrophy (DMD) can mimic the inflammatory myositis in presenting symptoms. Two diseases should be differentiated by the clinical history, muscle biopsy and genetic study. There are few reports in which both histochemical and genetic study showed the possible link of overlapping inflammatory pathophysiology with dystrophinopathy. We report a 40-yr-old woman who presented with subacute proximal muscle weakness and high serum level of creatine kinase. She had a history of Graves' disease and fluctuation of serum liver aminotransferase without definite cause. MRI, EMG and NCV were compatible with proximal muscle myopathy. Muscle biopsy on vastus lateralis showed suspicious perifascicular atrophy and infiltration of mono-macrophage lineage cells complicating the diagnosis. Dystrophin staining showed heterogeneous diverse findings from normal to interrupted mosaic pattern. Multiple ligation probe amplification and X chromosome inactivation test confirmed DMD gene deletion mutation in exon 44 and highly skewed X inactivation.

Cornelia de Lange Syndrome (CdLS) is a multiple congenital anomaly characterized by distinctive facial features, upper limb malformations, growth and cognitive retardation. The diagnosis of the syndrome is based on the distinctive clinical features. The etiology is still not clear. Mutations in the sister chromatid cohesion factor genes NIPBL, SMC1A (also called SMC1L1) and SMC3 have been suggested as probable cause of this syndrome. We experienced a case of newborn with CdLS showing bushy eyebrows and synophrys, long curly eyelashes, long philtrum, downturned angles of the mouth and thin upper lips, cleft palate, micrognathia, excessive body hair, micromelia of both hands, flexion contracture of elbows and hypertonicity. We detected a NIPBL gene mutation in a present neonate with CdLS, the first report in Korea.

Incontinentia pigmenti (IP) is a rare X-linked dominant disorder characterized by highly variable abnormalities of the skin, eyes and central nervous system. A mutation of the nuclear factor-κB essential modulator (NEMO) located at Xq28 is believed to play a role in pathogenesis and the mutation occurs mostly in female patients due to fatal consequence of the mutation in males in utero. This study was designed to identify the common NEMO rearrangement in four Korean patients with IP. Deletion of exons 4 to 10 in the NEMO, the most common mutation in IP patients, was detected in all of the patients by the use of long-range PCR analysis. This method enabled us to discriminate between NEMO and pseudogene rearrangements. Furthermore, all of the patients showed skewed XCI patterns, indicating pathogenicity of IP was due to cells carrying the mutant X chromosome. This is the first report of genetically confirmed cases of IP in Korea.

Hypoparathyroidism is an abnormality of calcium metabolism characterized by low serum levels of parathyroid hormone in spite of hypocalcemia. The causes of hypoparathyroidism are numerous. Activating mutations in the calcium-sensing receptor (CaSR) gene are well-known causes of familial isolated hypoparathyroidism, also known as autosomal dominant hypocalcemia (ADH). Here we describe members of a Korean family with a heterozygous Pro221Leu mutation causing ADH. This case is the first report in Korea.

We describe a Korean family presenting with pediatric-onset, progressive, generalized dystonia with bilateral striatal necrosis and the homoplasmic G14459A mutation in the mitochondrial ND6 gene. The G14459A mutation has been reported in families presenting with Leber hereditary optic neuropathy (LHON) alone, LHON plus dystonia, or pediatric-onset dystonia. The proband had shown dysarthria, progressive generalized dystonia, and spasticity at 5 yr. Brain MRI demonstrated bilateral striatal necrosis. Additional investigation of family members revealed the presence of homoplasmic G14459A mutation in asymptomatic individuals. The clinical manifestation of the homoplasmic G14459A mtDNA mutation within the same family showed asymptomatic or pediatric-onset dystonia, without optic neuropathy. This study reemphasizes that the G14459A mutation is a candidate mutation for maternally inherited dystonia, regardless of optic neuropathy, and supports the hypothesis that nuclear genes may play a role in modifying the clinical expression of mitochondrial disease.

Cystic fibrosis (CF) is an autosomal recessive disease that is very rare in Asians: only a few cases have been reported in Korea. We treated a female infant with CF who had steatorrhea and failure to thrive. Her sweat chloride concentration was 102.0 mM/L. Genetic analysis identified two novel mutations including a splice site mutation (c.1766+2T >C) and a frameshift mutation (c.3908dupA; Asn1303LysfsX6). Pancreatic enzyme replacement and fat-soluble vitamin supplementation enabled the patient to get a catch-up growth. This is the first report of a Korean patient with CF demonstrating pancreatic insufficiency. CF should therefore be considered in the differential diagnosis of infants with steatorrhea and failure to thrive.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive malformation syndrome caused by a defect in cholesterol biosynthesis. The incidence is very low in Asians and only one case has been reported in Korea thus far. Recently, we found an infant with neonatal cholestasis. He had microcephaly, ambiguous genitalia, cleft palate, syndactyly of toes, patent ductus arteriosus and hypertrophic pyloric stenosis. The serum cholesterol was decreased and serum 7-dehydrocholesterol was markedly elevated. Genetic analysis of the DHCR7 gene identified a novel missense mutation (Pro227Ser) as well as a known mutation (Gly303Arg) previously identified in a Japanese patient with SLOS. Although rare in Korea, SLOS should be considered in the differential diagnosis of neonatal cholestasis, especially in patients with multiple congenital anomalies and low serum cholesterol levels.

von Hippel-Lindau (VHL) disease is an autosomal dominant inherited tumor syndrome characterized by the development of tumors in the eye, brain, spinal cord, inner ear, adrenal gland, pancreas, kidney, and epididymis, associated with germline mutations in the VHL gene. We used sequentially sequencing method and multiple ligation-dependent probe amplification (MLPA) analysis and detected germline mutations in the VHL in 15/15 (100%) of VHL patients fulfilling the clinical criteria. Of the 15 distinct mutations detected, large deletions were detected in 5/15 (33.3%) patients, including 4/15 (26.7%) partial deletions and 1/15 (6.6%) deletion of the entire VHL gene by MLPA and the remainder were point mutations detected by sequencing method, of which five mutations were novel. Using MLPA analysis, we detected large deletions including both partial deletions and complete gene deletion, which has not been reported in Korean VHL patients. In conclusion, sequential application of sequencing method and MLPA analysis might make possible to identify germline mutations in most patients with VHL.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that is characterized by abnormal communication between the arteries and veins in the skin, mucosa, and various organs. HHT has been reported to show significant phenotypic variability and genetic heterogeneity with wide ethnic and geographic variations. Although mutations in the endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes have been known to cause HHT for more than 10 yr, little is known about the clinical features or genetic background of Korean patients with HHT. In addition, mutations in mothers against decapentaplegic homolog 4 (SMAD4) are also seen in patients with the combined syndrome of juvenile polyposis and HHT. This study examined five Korean patients with the typical manifestations of HHT such as frequent epistaxis and pulmonary arteriovenous malformations. Direct sequencing of the ENG and ACVRL1 genes revealed one known mutation, ENG c.277C>T, in one patient and two novel mutations, ENG c.992-1G>C and ACVRL1 c.81dupT in two patients, respectively. The remaining two patients with negative results were screened for SMAD4 mutations as well as gross deletions of ENG and ACVRL1 using multiple ligation-dependent probe amplification, but none was detected. Despite the small number of patients investigated, we firstly report Korean patients with genetically confirmed HHT, and show the genetic and allelic heterogeneity underlying HHT.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominantly inherited muscular disorder, which is characterized by weakness of facial, shoulder and hip girdle, humeral, and anterior distal leg muscles. The FSHD gene has been mapped to 4q35 and a deletion of integral copies of a 3.3-kb DNA repeat motif named D4Z4 was known to be the genetic background of the disorder. Although FSHD is the second most common muscular dystrophy in adulthood, there were few reports on the genetically confirmed patients in Korea. Recently, we experienced four Korean patients with clinical features resembling FSHD. In order to confirm the diagnosis, conventional Southern blot (SB) analysis by using double digestion with EcoRI and BlnI and hybridization with p13E-11 probe was performed in three patients and newly developed long polymerase chain reaction (PCR) method was used for one patient because genomic DNA was not enough for conventional SB for this patient. All patients were demonstrated to have shortened D4Z4 repeats that were consistent with FSHD. Therefore, we could confirm the diagnosis of FSHD in four Korean patients and appropriate genetic counseling was done for the patients and their families. It is of note that long-PCR method could be a good alternative for conventional SB when D4Z4 repeats were less than 5.

Although acquired mutations in the GATA1 gene have been reported for Down syndrome-related acute megakaryoblastic leukemia (DS-AMKL) in Caucasians, this is the first report of a Korean Down syndrome patient with AMKL carrying a novel mutation of the GATA1 gene. A 3-yr-old Korean girl with Down syndrome was admitted to our hospital complaining of pallor and fever. The findings of a peripheral blood smear and bone marrow study were compatible with the presence of AMKL. A chromosome study showed 48,XX,-7,+21c,+21,+r[3]/47,XX,+21c[17]. Following GATA1 gene mutation analysis, a novel mutation, c.145dupG (p.Ala49GlyfsX18), was identified in the N-terminal activation domain of the GATA1 gene. This mutation caused a premature termination at codon 67 and expression of an abnormal GATA-1 protein with a defective N-terminal activation domain, and the absence of full-length GATA-1 protein. This case demonstrates that a leukemogenic mechanism for DS-AMKL is contributed by a unique collaboration between overexpressed genes from trisomy 21 and an acquired GATA1 mutation previously seen in Caucasians and now in a Korean patient.

Standardization of medical terminology is essential in data transmission between health care institutes and in maximizing the benefits of information technology. The purpose of this study was to standardize medical terms for laboratory observations. During the second year of the study, a standard database of concept names for laboratory terms that covered those used in tertiary health care institutes and reference laboratories was developed. The laboratory terms in the Logical Observation Identifier Names and Codes (LOINC) database were adopted and matched with the electronic data interchange (EDI) codes in Korea. A public hearing and a workshop for clinical pathologists were held to collect the opinions of experts. The Korean standard laboratory terminology database containing six axial concept names, components, property, time aspect, system (specimen), scale type, and method type, was established for 29,340 test observations. Short names and mapping tables for EDI codes and UMLS were added. Synonym tables were prepared to help match concept names to common terms used in the fields. We herein described the Korean standard laboratory terminology database for test names, result description terms, and result units encompassing most of the laboratory tests in Korea.

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive disorder with a prototype of a dysmyelinating leukodystrophy that is caused by a mutation in the proteolipid protein 1 (PLP1) gene on the long arm of the X chromosome in band Xq22. This mutation results in abnormal expression or production of PLP. We here present a Korean boy with spastic quadriplegia, horizontal nystagmus, saccadic gaze, intentional tremor, head titubation, ataxia, and developmental delay. The brain magnetic resonance imaging (MRI) showed abnormally high signal intensities in the white matter tract, including a subcortical U fiber on the T2-weighted and fluid attenuated inversion recovery (FLAIR) image. The chromosomal analysis was normal; however, duplication of the PLP1 gene in chromosome Xq22 was detected when the multiplex ligation-dependent probe amplification (MLPA) method was used. We also investigated the pedigree for a genetic study related to PMD. This case suggests that the duplication mutation of the PLP1 gene in patients with PMD results in a mild clinical form of the disorder that mimics the spastic quadriplegia of cerebral palsy.

Although mutations in three genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as genetic causes of early-onset Alzheimer s disease (EOAD), there has been a single report on a PSEN1 mutation in Koreans. In the present study, we performed a genetic analysis of six Korean patients with EOAD. Direct sequencing analysis of the APP, PSEN1 and PSEN2 genes revealed two different mutations of the PSEN1 gene (G206S and M233T) and one mutation of the APP gene (V715M) in three patients with age-at-onset of 34, 35, and 42 yr, respectively. In addition, two patients with age-at-onset of 55 and 62 yr, respectively, were homozygous for APOE epsilon 4 allele. One woman had no genetic alterations. These findings suggest that PSEN1 and APP gene mutations may not be uncommon in Korean patients with EOAD and that genetic analysis should be provided to EOAD patients not only for the identification of their genetic causes but also for the appropriate genetic counseling.

Ehlers-Danlos syndrome (EDS) is a hereditary disorder of the connective tissue. EDS type IV (EDS IV), the vascular type of the disease, is characterized by easy bruising, thin skin with visible veins, and spontaneous rupture of the large arteries, uterus, or bowel. EDS IV is caused by mutations in the gene for type III procollagen (COL3A1). However, recent studies suggest that the causative mutation of EDS IV is not homogeneous. We report our experience with three patients presenting with clinical features of type IV EDS. A 48-yr-old woman presented with acute aortic dissection (patient 1) and 36-yr-old and 21-yr-old women presented with carotidcavernous fistula (patients 2 and 3, respectively). All three patients bruised easily. Two patients (patients 1 and 3) had thin transparent skin with visible veins. Genetic analysis of COL3A1 revealed a Gly732Val (c.2195G>T) mutation in patient 1 and a duplication of 15 base pairs (c.3221&#95;3235dup) which resulted in an interposition of five amino acids (p.Gly1074&#95;Pro1078dup) in patient 2. However, no mutations were observed in COL3A1 or transforming growth factor beta receptors 1 and 2 in patients 3, which might be either due to a deletion of single or multiple exons in the COL3A1 gene or due to a genetic heterogeneity. This is the first report of genetically confirmed cases of EDS IV in Korea.

Alexander disease (AD) is a rare leukodystrophy of the central nervous system of unknown etiology. AD is characterized by progressive failure of central myelination and the accumulation of Rosenthal fibers in astrocytes, and is inevitably lethal in nature. Symptomatically, AD is associated with leukoencephalopathy with macrocephaly, seizures, and psychomotor retardation in infants, and usually leads to death within the first decade. Its characteristic magnetic resonance imaging (MRI) findings have been described as demyelination predominantly in the frontal lobe. Moreover, dominant mutations in the GFAP gene, coding for glial fibrillary acidic protein (GFAP), a principal astrocytic intermediate filament protein, have been shown to lead to AD. The disease can now be detected by genetic diagnosis. We report the Korean case of an 8-month-old male patient with AD. He was clinically characterized due to the presence of psychomotor retardation, megalencephaly, spasticity, and recurrent seizures including infantile spasms which is a remarkable presentation. Demyelination in the frontal lobe and in a portion of the temporal lobe was demonstrated by brain MRI. Moreover, DNA analysis of peripheral blood showed the presence of a R239L mutation in the GFAP gene, involving the replacement of guanine with thymine.

X-linked Opitz G/BBB syndrome (XLOS; MIM 300000) is a rare multiple congenital anomaly disorder that is characterized by facial anomalies, laryngeal/tracheal/esophageal defects and genitourinary abnormalities. XLOS is caused by mutations in the MID1 gene which encodes a microtubule-associated RING-Bbox-Coiled-coil (RBCC) protein. We recently found a four-year Korean male patient who was suspected of having XLOS. Mutation analysis of the MID1 gene in the patient and his mother demonstrated that the patient had a novel insertion mutation (c.1798&#95;1799-insC), and his mother was a heterozygous carrier of the mutation. After identification of the causative mutation in this family, prenatal diagnosis of two consecutive fetuses were successfully undertaken. This is the first report on a genetically confirmed case of XLOS in Korea.

Miyoshi myopathy (MM) is an autosomal recessive distal muscular dystrophy caused by mutations in the dysferlin gene (DYSF) on chromosome 2p13. Although MM patients and their mutations in the DYSF gene have been found from all over the world, there is only one report of genetically confirmed case of MM in Korea. Recently, we encountered three unrelated Korean patients with MM and two of them have previously been considered as having a type of inflammatory myopathy. The clinical and laboratory evaluation showed typical features of muscle involvement in MM in all patients but one patient initially had moderate proximal muscle involvement and another showed incomplete quadriparesis with rapid progression. Direct sequencing analysis of the DYSF gene revealed that each patient had compound heterozygous mutations (Gln832X and Trp992Arg, Gln832X and Trp999Cys, and Lys1103X and Ile1401HisfsX8, respectively) among which three were novel. Although MM has been thought to be quite rare in Korea, it should be considered in a differential diagnosis of patients exhibiting distal myopathy.

Although cystic fibrosis (CF) is one of the most frequently seen autosomal-recessive disorders in Caucasians, it is extremely rare in the Korean population. Recently, a 15-yr-old Korean boy was admitted to our hospital complaining of coughing, sputum, and exertional dyspnea. Chest radiographs and computed tomographic chest and paranasal sinus scans revealed diffuse bronchiectasis and pansinusitis. Pulmonary function tests revealed severe obstructive impairment. The average sweat chloride concentrations on both of the patients' forearms were 63.0 mM/L (reference limit: < 40 mM/L). Upon mutation analysis, two different mutations (Q98R and Q220X) were identified in the cystic fibrosis transmembrane conductance regulator gene, both of which had been previously detected in CF patients, one from France and the other from England. As CF is quite rare in Korea, the diagnosis of CF in this patient might be delayed. Therefore, we recommend that a diagnosis of CF should be suspected in patients exhibiting unexplained chronic respiratory symptoms.

Many risk factors for atherosclerosis have been proposed to identify high risk individuals. We conducted a retrospective study to determine the risk factors for development of carotid stenosis (CS) in Koreans. Database of 2,805 subjects who underwent a check up of carotid artery for health examination were analyzed. Stenosis (%) of common carotid artery or proximal internal carotid artery was examined with ultrasonography. Subjects were divided into 2 groups (Group I; CS <10%, Group II; CS >or= 30%). We compared demographic, laboratory and clinical data between 2 groups to determine the risk factors of CS. One hundred ninety seven subjects (7.0%) were categorized as Group II. At age- and sex-adjusted multivariate analysis, diabetes mellitus, hypertension, cerebrovascular disease, ischemic heart disease, hyperlipidemia, aspirin medication, current smoking, fasting glucose, total cholesterol, low density lipoprotein-cholesterol (LDL-C) and leukocyte count were significant risk factors of CS. At stepwise logistic regression analysis, age, hypertension, hyperlipidemia, LDL-C and leukocyte count were independent risk factors. At subgroup analysis by smoking, age and leukocyte count were independent risk factors in smoker and age and hypertension in nonsmoker.

The isoenzymes of the glutathione s transferase (GST) family play a vital role in phase II of biotransformation of many substances. Using a multiplex polymerase chain reaction and a direct sequencing analysis, the frequencies of GSTM1, GSTT1, and GSTP1 polymorphisms were evaluated in 1,051 Korean male subjects. We found that 53.8% of the individuals had the GSTM1 null genotype and 54.3% had the GSTT 1 null genotype. The genotypic distribution of GSTP1 was Ile105/Ile105 in 68.4%, Ile105/Val105 in 29.1% and Val105/Va105 in 2.5%. The most frequently observed combination of GSTM1, GSTP1 and GSTT1 genotypes was Null type/Ile105/Ile105/Null type, while the combination of Non-null type/Val105/Val105/Non-Null type was not observed. We found that the genotype distributions of three GST isoenzymes in the Koreans are similar to those reported in Asians and previously reported Koreans. We believe our results, which are represented by a large population, are reliable estimates of the frequencies of the polymorphic GST alleles in the Koreans and will help future researches on GST polymorphisms.

We report a Korean patient with glycogen storage disease type 1b (GSD-1b) whose diagnosis was confirmed by liver biopsy and laboratory results. The patient presented with delay of puberty and short stature on admission and had typical clinical symptoms of GSD as well as chronic neutropenia and inflammatory bowel disease. Mutation analysis of the glucose 6-phosphate translocase 6-phosphate translocase (SLC37A4) gene revealed that the patient was a compound heterozygote of two different mutations including a deletion mutation (c.1042&#95;1043delCT; L348fs) and a missense mutation (A148V). The L348fs mutation was inherited from the patient's father and has been reported in an Italian family with GSD-1b, while the A148V mutation was transmitted from the patient's mother and was a novel mutation. To the best of our knowledge, this is the first report of genetically confirmed case of GSD-1b in Korean.

Complement C7 deficiency is an autosomal recessive disorder well known to be associated with increased susceptibility to meningococcal infection and has mostly been reported in Caucasians. In the Korean population, no case of C7 deficiency has been reported to date. Recently we experienced an 11-yr-old girl with meningococcal meningitis who was diagnosed as having C7 deficiency based upon the undetectable serum C7 protein on radial immunodiffusion and the undetectable serum total and C7 hemolytic activities. To identify the genetic basis of the C7 deficiency of the patient, we performed a mutation analysis for the C7 gene and found two novel mutations; a point mutation at the 3' splice acceptor site of intron 4 (c.281-1G>T) and a large deletion mutation encompassing almost the whole C7 gene from exon 1 to exon 17 (c.1-?&#95;2350+?del). A haplotype analysis showed that the large deletion mutation was inherited from the patient's father. To the best of our knowledge, this is the first confirmed case of C7 deficiency in Korea.

Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy type 1B (LGMD1B) are characterized by cardiac dysrhythmias, late-onset cardiomyopathy, slowly progressive skeletal myopathy and contractures of the neck, elbows and ankles. The causative mutation is either in the emerin gene (X-linked recessive EDMD) or lamin A/C gene (autosomal dominant EDMD2 or LGMD1B). We report three cases of EDMD, EDMD2 and LGMD1B. A 14-yr-old boy showed limitation of cervical flexion and contractures of both elbows and ankles. Sinus arrest with junctional escape beats was noted. He was diagnosed as X-linked recessive EDMD (MIM 310300). A 28-yr-old female showed severe wasting and weakness of humeroperoneal muscles. Marked limitation of cervical flexion and contractures of both elbows and ankles were noted. Varying degrees of AV block were noted. She was diagnosed as autosomal dominant EDMD2 (MIM 181350). A 41-yr-old female had contractures of both ankles and limb-girdle type muscular dystrophy. ECG revealed atrial tachycardia with high grade AV block. She was diagnosed as autosomal dominant LGMD1B (MIM 159001). Cardiac dysrhythmias in EDMD and LGMD1B include AV block, bradycardia, atrial tachycardia, atrial fibrillation, and atrial standstill, causing sudden death necessitating pacemaker implantation. Cardiologists should know about these unusual genetic diseases with conduction defects, especially in young adults.

We present a case with decreased metabolic activity of CYP2D6, a cytochrome P450 enzyme catalyzing the metabolism of nortriptyline (NT). Conventional dosage regimen led to toxic plasma concentration of NT and adverse effects such as dry mouth, constipation, and dizziness in this case with genotype CYP2D6*5/*10B. This case suggests the clinical usefulness of pharmacogenetic testing in individualized dosage adjustments of NT.

We report a 52-yr-old Korean woman with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) whose diagnosis was confirmed by skin biopsy and the presence of a novel mutation in the NOTCH3 gene. The patient's clinical features were rather unusual in that 1) clinical presentations were only two episodes of stroke and mild dementia unaccompanied by mood disturbances or migraine, and 2) there was no family history. Brain MRI showed T2 hyperintensities in both temporal pole areas in line with the recent suggestion by O'Sullivan et al. that the abnormality could be a radiologic marker of CADASIL. FDG-PET also showed a hypometabolism in the temporal pole areas with an abnormal finding on MRI in addition to the hypometabolism in cortical and subcortical regions. We could learn from this case that CADASIL may be included in the differential diagnoses in patients with vascular dementia associated with a small vessel disease, even in the absence of a family history, especially when there are no known stroke risk factors and when the MRI shows T2 hyperintensity in the temporal pole regions.