Si Houn Hahn
Mayo Clinic
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Featured researches published by Si Houn Hahn.
Genetics in Medicine | 2007
Devin Oglesbee; Miao He; Nilanjana Majumder; Jerry Vockley; Ayesha Ahmad; Brad Angle; Barbara K. Burton; Joel Charrow; Regina Ensenauer; Can Ficicioglu; Laura Davis Keppen; Deborah Marsden; Silvia Tortorelli; Si Houn Hahn; Dietrich Matern
Purpose: Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. We identified 13 isobutyryl-CoA dehydrogenase–deficient patients through newborn screening due to an elevation of C4-acylcarnitine in dried blood spots. Because C4-acylcarnitine represents both isobutyryl- and butyrylcarnitine, elevations are not specific for isobutyryl-CoA dehydrogenase deficiency but are also observed in short-chain acyl-CoA dehydrogenase deficiency. To delineate the correct diagnosis, we have developed a follow-up algorithm for abnormal C4-acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions.Methods: Fibroblast cultures were established from infants with C4-acylcarnitine elevations, and the analysis of in vitro acylcarnitine profiles provided confirmation of either isobutyryl-CoA dehydrogenase or short-chain acyl-CoA dehydrogenase deficiency. Isobutyryl-CoA dehydrogenase deficiency was further confirmed by molecular genetic analysis of the gene encoding isobutyryl-CoA dehydrogenase (ACAD8). Plasma acylcarnitines, urine acylglycines, organic acids, and urine acylcarnitine results were compared between isobutyryl-CoA dehydrogenase– and short-chain acyl-CoA dehydrogenase–deficient patients.Results: Quantification of C4-acylcarnitine in plasma and urine as well as ethylmalonic acid in urine allows the differentiation of isobutyryl-CoA dehydrogenase–deficient from short-chain acyl-CoA dehydrogenase–deficient cases. In nine unrelated patients with isobutyryl-CoA dehydrogenase deficiency, 10 missense mutations were identified in ACAD8. To date, 10 of the 13 isobutyryl-CoA dehydrogenase–deficient patients remain asymptomatic, two were lost to follow-up, and one patient required frequent hospitalizations due to emesis and dehydration but is developing normally at 5 years of age.Conclusion: Although the natural history of isobutyryl-CoA dehydrogenase deficiency must be further defined, we have developed an algorithm for rapid laboratory evaluation of neonates with an isolated elevation of C4-acylcarnitine identified through newborn screening.
Genetics in Medicine | 2005
Regina Ensenauer; Jennifer L. Winters; Patricia A. Parton; David Kronn; Jong Won Kim; Dietrich Matern; Piero Rinaldo; Si Houn Hahn
Purpose: In contrast to its high prevalence in Caucasians, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is reported to be an extremely rare metabolic disorder in the Asian population. The common MCAD gene (ACADM) mutation 985A>G (p.K329E), accounting for the majority of cases in Caucasians, has not been detected in this ethnic group, and the spectrum of ACADM mutations has remained unknown.Method: Biochemical genetic testing including plasma acylcarnitine and urine acylglycine analyses, as well as sequencing of ACADM was performed in a Korean family with a newborn who had an elevated octanoyl (C8) carnitine concentration by newborn screening (NBS). Genotyping of 50 Korean newborns with normal NBS results was performed.Result: We report the identification of the first Korean patient with MCAD deficiency, caused by a novel missense mutation in ACADM, 843A>T (R281S), and a 4-bp deletion, c.449_452delCTGA. The patient became symptomatic before notification of the abnormal NBS result. Both the father and a brother who were identified as carriers for the 4-bp deletion had mildly elevated plasma C8 and C10:1 carnitine concentrations, whereas the acylcarnitine profile was normal in the mother who carries the missense mutation.Conclusion: The 4-bp deletion may represent a common Asian ACADM mutation, considering that it recently has also been found in two of the three Japanese patients in whom genotyping was performed. Greater availability of MCAD mutation analysis is likely to unravel the molecular basis of MCAD deficiency in the Asian population that might differ from Caucasians.
Molecular Genetics and Metabolism | 2002
Soon Nam Kim; Kyung Hwa Ryu; Eun Ha Lee; Jong-Soo Kim; Si Houn Hahn
Propionic acidemia (PA) is an autosomal recessive inborn error in the catabolism of methionine, isoleucine, threonine, and valine, odd-numbered chain length fatty acids and cholesterol. Clinical symptoms are very heterogeneous and present as a severe neonatal-onset or a late-onset form. It is caused by a deficiency of propionyl-CoA carboxylase (PCC, EC 6.4.1.3), a biotin-dependent enzyme that catalyzes the carboxylation of propionyl-CoA to D-methylmalonyl-CoA. PCC is a heteropolymeric enzyme composed of alpha- and beta-subunits. A greater heterogeneity is observed in the PCCA gene, while for the PCCB gene, a limited number of mutations is responsible for the majority of the alleles characterized in both Caucasian and Oriental populations. We identified eight Korean patients with PA by organic acid analysis confirmed in five patients by the PCC enzyme assay in the lymphoblasts. Two neonatal-onset patients showed undetectable PCC activities while three cases with residual enzyme activities had relatively late manifestations. In the molecular analysis, we identified five novel mutations, Y439C, 1527del3, 1357insT, IVS12-8T-->A, and 31del10, and one known mutation, T428I in PCCB gene. Alleleic frequency of T428I in Korean patients with PA was 56.3% in this study. Two neonatal-onset patients with null enzyme activities were homozygotes with 1527del3 and T428I, respectively. This finding implies that T428I and 1527del3 mutation could be responsible for their severe clinical courses and null enzyme activities. The mRNA of PCCB gene in T428I and 1527del3 homozygotes were normal but in Western blot analysis, the betaPCC-subunit was only absent in 1527del3 homozygote patient suggesting different molecular pathology.
Journal of Proteome Research | 2017
Sunhee Jung; Jeffrey R. Whiteaker; Lei Zhao; Han-Wook Yoo; Amanda G. Paulovich; Si Houn Hahn
Wilsons Disease (WD), a copper transport disorder caused by a genetic defect in the ATP7B gene, has been a long time strong candidate for newborn screening (NBS), since early interventions can give better results by preventing irreversible neurological disability or liver cirrhosis. Several previous pilot studies measuring ceruloplasmin (CP) in infants or children showed that this marker alone was insufficient to meet the universal screening for WD. WD results from mutations that cause absent or markedly diminished levels of ATP7B. Therefore, ATP7B could serve as a marker for the screening of WD, if the protein can be detected from dried blood spots (DBS). This study demonstrates that the immuno-SRM platform can quantify ATP7B in DBS in the picomolar range, and that the assay readily distinguishes affected cases from normal controls (p < 0.0001). The assay precision was <10% CV, and the protein was stable for a week in DBS at room temperature. These promising proof-of-concept data open up the possibility of screening WD in newborns and the potential for a multiplexed assay for screening a variety of congenital disorders using proteins as biomarkers in DBS.
Genetics in Medicine | 2018
Si Houn Hahn; David Kronn; Nancy Leslie; Loren D.M. Pena; Pranoot Tanpaiboon; Michael J. Gambello; James B. Gibson; Richard Hillman; David W. Stockton; John W. Day; Raymond Y. Wang; Kristina An Haack; Raheel Shafi; Susan Sparks; Yang Zhao; Catherine Wilson; Priya S. Kishnani
PurposePompe disease results from lysosomal acid α-glucosidase (GAA) deficiency and its associated glycogen accumulation and muscle damage. Alglucosidase alfa (recombinant human GAA (rhGAA)) received approval in 2006 as a treatment for Pompe disease at the 160 L production scale. In 2010, larger-scale rhGAA was approved for patients up to 8 years old without cardiomyopathy. NCT01526785 evaluated 4,000 L rhGAA efficacy/safety in US infantile- or late-onset Pompe disease (IOPD, LOPD) patients up to 1 year old transitioned from 160 L rhGAA.MethodsA total of 113 patients (87 with IOPD; 26 with LOPD) received 4,000 L rhGAA for 52 weeks dosed the same as previous 160 L rhGAA. Efficacy was calculated as the percentage of patients stable/improved at week 52 (without death, new requirement for invasive ventilation, left ventricular mass z-score increase >1 if baseline was >2, upright forced vital capacity decrease ≥15% predicted, or Gross Motor Function Measure–88 decrease ≥8 percentage points). Safety evaluation included an extension ≤20 months.ResultsWeek 52 data was available for 104 patients, 100 of whom entered the extension. At week 52, 87/104 (83.7%) were stable/improved. Overall survival was 98.1% overall, 97.6% IOPD, 100% LOPD; 92.4% remained invasive ventilator–free (93.4% IOPD, 88.7% LOPD). Thirty-five patients had infusion-associated reactions. Eight IOPD patients died of drug-unrelated causes.ConclusionsMost Pompe disease patients were clinically stable/improved after transitioning to 4,000 L rhGAA. Safety profiles of both rhGAA forms were consistent.
Genetics in Medicine | 2000
Si Houn Hahn; E H Lee; B L Eun; Piero Rinaldo
Ethylmalonic encephalopathy is a complex organic aciduria characterized by ethylmalonic aciduria, lactic acidemia with developmental delay, acrocyanosis, petechia and chronic mucoid diarrhea. Since 1994, less than 30 patients have been reported and the underlying metabolic defect is unknown.We report 2 affected sibs with typical clinical and biochemical phenotypes, and brain MRI findings. Patient I is a 5 years old girl who presents with developmental delay, spastic quadriplegia, and chronic diarrhea. She was hospitalized several times due to chronic diarrhea and pneumonia in the early infancy. She developed frequent skin petechiae on compression sites and cyanosis on the lower extremities. Brain MRI taken at the age of 25 months was suggestive of hypoxic ischemic encepahlopathy and no further evaluation was undertaken. Patient 2, her younger sister, is a 34 months old girl who presents with a similar clinical course but had no evaluation until recently when she developed respiratory difficulty due to pneumonia which required hospitalization. She was able to control her head at 4 months of age and crawl at 9 months of age but never sit, stand or talk. Her spastic quadriplegia became worse after this episode and she is almost wheel chair bound. Brain MRI showed multifocal nodular T2 high signals in both basal ganglia with enhancement, patchy T2 high signals in both periventricular white matter, centrum semiovale, and cerebellum. Muscle biopsy showed diffuse atrophy but no evidence of mitocnondrial disorder. Organic acid and acylglycine profiles showed markedly elevated excretion of ethylmalonic acid (134 mmol/mol creatinine: controls: <18), isobutyrylglycine, butyrylglycine, methylbutyrylglycine, and isovalerylglycine were also elevated. Serum lactate was 3.2 mmol/L (control: 0.7-2.0). 100 mg/kg/day oral carnitine supplementation for 2 months had no visible effect. However, they became significantly more active and alert on riboflavin treatment (100 mg/day). Patient 1 rolled over and was socially more active with laughing and sounds. In patient 2, motor improvement was not significant but she became more alert and socially active. Notably, the chronic mucoid diarrhea subsided considerably in both children, but petechiae were unaffected.Our observations suggest that some cases with ethylmalonic encephalopathy could be responsive to riboflavin. In vitro evaluation of fatty acid and branched chain amino acid metabolism is in progress.
Clinical Chemistry | 2004
Jean M. Lacey; Carla Z. Minutti; Mark J. Magera; Angela L. Tauscher; Bruno Casetta; Mark McCann; James F. Lymp; Si Houn Hahn; Piero Rinaldo; Dietrich Matern
American Journal of Human Genetics | 2004
Valeria Tiranti; Pio D’Adamo; Egill Briem; Gianfrancesco Ferrari; Rossana Mineri; Eleonora Lamantea; Hanna Mandel; Paolo Balestri; Maria-Teresa Garcia-Silva; Brigitte Vollmer; Piero Rinaldo; Si Houn Hahn; J. V. Leonard; Shamima Rahman; Carlo Dionisi-Vici; Barbara Garavaglia; Paolo Gasparini; Massimo Zeviani
The Journal of Clinical Endocrinology and Metabolism | 2004
Carla Z. Minutti; Jean M. Lacey; Mark J. Magera; Si Houn Hahn; Mark McCann; Andreas Schulze; David Cheillan; Claude Dorche; Donald H. Chace; James F. Lymp; Donald Zimmerman; Piero Rinaldo; Dietrich Matern
Molecular Genetics and Metabolism | 2004
J.T McKinney; Nicola Longo; Si Houn Hahn; Dietrich Matern; Piero Rinaldo; Arnold W. Strauss; Steven F. Dobrowolski