Two novel insulin receptor gene mutations in a patient with Rabson-Mendenhall syndrome: the first Korean case confirmed by biochemical, and molecular evidence.

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.

A Korean patient with Morquio B disease with a novel c.13_14insA mutation in the GLB1 gene.

Mutations in the GLB1 gene, which encodes acid ß-galactosidase, can result in two disease phenotypes: GM1-gangliosidosis (MIM #230500) and Morquio B disease (Mucopolysaccharidosis type IVB, MIM #253010). Morquio B disease occurs much more infrequently than GM1-gangliodosis and is characterized by severe skeletal manifestations (dysostosis multiplex) without central nervous system involvement. Here, we report the first known Korean patient with Morquio B disease. A 7-year-old boy presented with severe progressive skeletal dysplasia including scoliosis, contractures of the elbows, xenu valgum, funnel chest, and trigger thumb requiring surgical intervention. The patient had normal neurological functions and mental status when evaluated by pediatric neurologists. The patient's urinary glycosaminoglycans, measured by the cetylpyridinium chloride (CPC) precipitation test, were 252.8 CPC unit/g creatinine (reference range < 175). Thin layer chromatography of urine showed a keratan sulfate band. Enzyme activity of ß-galactosidase in leukocytes was 1.15 nmol/hr/mg protein (reference range 78.1-117.7; 1-1.5% of normal). The patient had compound heterozygous mutations of the GLB1 gene: c.13_14insA (p.L5HfsX29), which was reported in a patient with infantile GM1 gangliosidosis with the near-complete absence of enzyme activity, and c.367G>A (p.G123R), which is a novel frame-shift mutation. In summary, we report the first known Korean patient with Morquio B disease and a novel mutation (c.13_14insA of GLB1).

A polymorphism in the growth hormone receptor is associated with height in children with Prader-Willi syndrome.

The exon-3 deletion polymorphism (d3, Database of Genomic Variants ID: Variation_64191) in the growth hormone receptor (GHR) gene is associated with increased growth response to growth hormone (GH) therapy in GH-deficient patients. However, an association of the GHR genotype with height has not yet been reported in Prader-Willi syndrome (PWS). The aim of this study was to assess the association of GHR alleles with height before starting GH therapy in patients with PWS. Seventy-four patients with PWS were genotyped and their medical records were retrospectively reviewed (45 males and 29 females, median age 8.7 years). One hundred normal controls, with known final height, were also genotyped. The GH-exon 3 locus was genotyped using a PCR multiplex assay. The distribution of alleles in the patients with PWS was not different from controls [(fl/fl n = 53 (72%), fl/d3 n = 21 (28%)) in PWS vs. (fl/fl n = 72(72%), fl/d3 n = 26(26%), and d3/d3 n = 2(2%)]. However, patients with PWS carrying a d3 allele had significantly greater height standard deviation scores (SDS) (P = 0.025) and higher insulin-like growth factor I (IGF-I) level (P = 0.041), although the age at the start of GH therapy, weight, BMI, and body fat were not different. The d3 allele was associated with height and IGF-I levels before GH therapy and suggests that even before GH therapy, d3 allele may influence height through GH secretion.

Mutations of ACADS gene associated with short-chain acyl-coenzyme A dehydrogenase deficiency.

Short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD) is an autosomal recessive disorder of mitochondrial fatty acid oxidation associated with mutations in the ACADS gene (Acyl-CoA Dehydrogenase, Short-chain, OMIM #606885). SCADD is a heterogeneous condition that has been associated with various clinical phenotypes ranging from fetal metabolic decompensation in infancy to asymptomatic individuals. Here, the first Korean neonate diagnosed with SCADD by biochemical and genetic findings is reported. The patient has remained asymptomatic by avoiding hypoglycemia. An increased concentration of butylcarnitine was detected on newborn screening. Subsequent urine organic acid analysis showed increased urinary excretion of ethylmalonic acid. To confirm the presence of the genetic abnormality, all the coding exons of the ACADS gene and flanking introns were amplified by the polymerase chain reaction (PCR). Sequence analysis of the ACADS gene revealed novel homozygous missence mutations, c. 1031A>G (p.E344G) in exon 9. In summary, the first Korean patient with confirmed SCADD by genetic analysis is reported with novel mutation.

A mother and daughter with the p.R443X mutation of mucopolysaccharidosis type II: Genotype and phenotype analysis.

Mucopolysaccharidosis type II (Hunter syndrome) is a lysosomal storage disease caused by a deficiency of iduronate-2-sulfatase. Most reported patients are males because of X-linked recessive inheritance pattern. Only a few female patients with Hunter syndrome have been reported, and there is no prior report of offspring from a patient with Hunter syndrome. In this report, we describe a woman with mild manifestations of Hunter syndrome who gave birth to a daughter. Both the mother and daughter carried the p.R443X mutation in exon 9 of the ID2S gene. Iduronate-2-sulfatase activity in the mother was as low as that found in male Hunter syndrome patients, but it was in the low-normal range in her daughter. Unlike her mother, the daughter did not show any physical signs of Hunter syndrome, and urinary excretion of glycosaminoglycan was within normal range. However, she had severe pulmonary vein stenosis with pulmonary hypertension and a large atrial septal defect and died at 11 months of age.

Molecular evidence for the taxonomic identity of Korean Adonis (Ranunculaceae).

Although Korean Adonis has been traditionally recognized as Adonis amurensis Regel and Radde with various infraspecific taxa described, its taxonomic identity is still in dispute. We investigated the genetic variation in 60 individuals from 12 populations in Korea to elucidate the taxonomic identity of the Korean Adonis complex. Random amplified polymorphic DNA (RAPD) analysis revealed that Korean Adonis comprises three species: A. amurensis, A. pseudoamurensis, and A. multiflora. Adonis amurensis is distributed in northern central inland regions of Korea and A. pseudoamurensis is found in southern parts of the Korean peninsula. Adonis multiflora grows only on Cheju Island, which is the southernmost part of Korea. Phylogenetic analysis of nuclear ribosomal internal transcribed spacer (ITS) sequences partially supported the presence of three Adonis taxa in Korea as detected by RAPD analysis. The Adonis population on Jangbong Island located in the West Sea, which was referred to as A. pseudoamurensison the basis of morphological examination, was separated from the other populations of A. pseudoamurensis. Otherwise, the molecular evidence is well congruent with the recent morphological study that proposes that Korean Adonis consists of these three species.