Multicenter Targeted Population Screening of Late Onset Pompe Disease in Unspecified Myopathy Patients in Korea

Background@#Pompe disease is a rare autosomal recessive disorder caused by the deficiency of a lysosomal enzyme, acid alpha-glucosidase (GAA). Early diagnosis and initiation of treatment with enzyme replacement therapy have remarkable effects on the prognosis of Pompe disease. We performed the expanded screening for late onset Pompe disease (LOPD) at eight centers in Korea. @*Methods@#From September 1, 2015, GAA activity were measured from both dried blood spot (DBS) and mixed leukocyte for 188 available patients. For 12 patients with low GAA activity, we performed Sanger sequencing of GAA gene. @*Results@#Among 188 patients, 115 were males. The mean of age of symptom onset and diagnosis were 34.3 years and 41.6 years. Among 12 patients with decreased GAA activity, two patients were confirmed to have LOPD with genetic test (c.1316T>A [p.M439K] + c.2015G>A [p.R672Q], c.1857C>G [p.S619R] + c.546G>C [leaky splicing]). Other two patients had homozygous G576S and E689K mutation, known as pseudodeficiency allele. @*Conclusions@#This study is expanded study of LOPD screening for targeted Korean population. We found two patients with LOPD, and the detection rate of LOPD is 1.06%. With application of modified GAA cutoff value (0.4), which was previously reported, there were no false positive results of GAA activity test using DBS. Therefore, it could be an appropriate screening test for LOPD in especially East-Asian population, in which pseudodeficiency allele is frequent.

Multicenter Targeted Population Screening of Late Onset Pompe Disease in Unspecified Myopathy Patients in Korea

Background@#Pompe disease is a rare autosomal recessive disorder caused by the deficiency of a lysosomal enzyme, acid alpha-glucosidase (GAA). Early diagnosis and initiation of treatment with enzyme replacement therapy have remarkable effects on the prognosis of Pompe disease. We performed the expanded screening for late onset Pompe disease (LOPD) at eight centers in Korea. @*Methods@#From September 1, 2015, GAA activity were measured from both dried blood spot (DBS) and mixed leukocyte for 188 available patients. For 12 patients with low GAA activity, we performed Sanger sequencing of GAA gene. @*Results@#Among 188 patients, 115 were males. The mean of age of symptom onset and diagnosis were 34.3 years and 41.6 years. Among 12 patients with decreased GAA activity, two patients were confirmed to have LOPD with genetic test (c.1316T>A [p.M439K] + c.2015G>A [p.R672Q], c.1857C>G [p.S619R] + c.546G>C [leaky splicing]). Other two patients had homozygous G576S and E689K mutation, known as pseudodeficiency allele. @*Conclusions@#This study is expanded study of LOPD screening for targeted Korean population. We found two patients with LOPD, and the detection rate of LOPD is 1.06%. With application of modified GAA cutoff value (0.4), which was previously reported, there were no false positive results of GAA activity test using DBS. Therefore, it could be an appropriate screening test for LOPD in especially East-Asian population, in which pseudodeficiency allele is frequent.

A neonate with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome from a consanguineous Pakistani family

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive urea cycle disorder. HHH is caused by a deficiency of the mitochondrial ornithine transporter protein, which is encoded by the solute carrier family 25, member 15 (SLC25A15) gene. Recently, government supported Korean newborn screening has been expanded to include a tandem mass spectrometry (MS/MS) measurement of ornithine level. We report a case of a neonate with HHH syndrome showing a normal MS/MS measurement of ornithine level. A female newborn was admitted to neonatal intensive unit due to familial history of HHH syndrome. Her parents were consanguineous Parkistani couple. The subject's older sister was diagnosed with HHH syndrome at age of 30 months based on altered mental status and liver dysfunction. Even though the subject displayed normal ammonia and ornithine levels based on MS/MS analysis, a molecular test confirmed the diagnosis of HHH syndrome. At 1 month of age, amino acid analysis of blood and urine showed high levels of ornithine and homocitrulline. After 11 months of follow up, she showed normal growth and development, whereas affected sister showed progressive cognitive impairment despite no further hyperammonemia after protein restriction and standard therapy. Our report is in agreement with a previous Canadian study, which showed that neonatal samples from HHH syndrome patients demonstrate normal ornithine levels despite having known mutations. Considering the delayed rise of ornithine in affected patients, genetic testing, and repetitive metabolic testing is needed to prevent patient loss in high risk patients.

Twenty-one-year follow-up of variable onset MELAS syndrome with heteroplasmic nt3243A>G mtDNA mutation: A case report

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder of which m.3243A>G is the most commonly associated mutation, resulting in an inability to meet the energy requirements of various organs. MELAS poses a diagnostic challenge owing to its multiple organ involvement and great clinical variability due to its heteroplasmic nature. We report three cases from a family who were initially misdiagnosed with myasthenia gravis or undiagnosed. Although there is no optimal consensus treatment approach for patients with MELAS because of the disease's heterogeneity, our 21-year-long therapy regimen of l-arginine, l-carnitine, and coenzyme Q10 supplementation combined with dietary management appeared to provide noticeable protection from the symptoms and complications. Prompt early diagnosis is important, as optimal multidisciplinary management and early intervention may improve outcomes.

Compound heterozygous mutations of ACADS gene in newborn with short chain acyl-CoA dehydrogenase deficiency: case report and literatures review / 소아과

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive mitochondrial disorder of fatty acid β-oxidation, and is associated with mutations in the acyl-CoA dehydrogenase (ACADS) gene. Recent advances in spectrometric screening for inborn errors of metabolism have helped detect several metabolic disorders, including SCADD, without symptoms in the neonate period. This allows immediate initiation of treatment and monitoring, so they remain largely symptomless metabolic disease. Here, we report a 15-month-old asymptomatic male, who was diagnosed with SCADD by newborn screening. Spectrometric screening for inborn errors of metabolism 72 hours after birth revealed an elevated butyrylcarnitine (C4) concentration of 2.25 µmol/L (normal, T (p.Pro55Leu) and c.1031A>G (p.Glu344Gly) on exons 2 and 9, respectively. The patient is now growing up, unretarded by symptoms such as seizure and developmental delay.

Cytogenetic evaluation of a patient with ring chromosome 9 presenting failure to thrive and developmental delay / 소아과

We report clinical, cytogenetic, and fluorescence in situ hybridization (FISH) studies of a patient with ring chromosome 9. She presented with failure to thrive, facial dysmorphysm and mild psychomotor development delay in the absence of major malformations. Peripheral blood karyotype of the patient was 46,XX,r(9)(p24q34). G-band analysis suggested no loss of material in the ring chromosomes. FISH analysis using the subtelomere-specific sequences on chromosome 9p and 9q, revealed 46,XX,r(9)(p24q34),ish r(9)(D9S913-,D9S325+). Failure to detect any hybridization of a probe for the subtelomeric sequences in the ring 9p terminal suggested that this ring arose from breakage in the distal short arm. The cytogenetic and FISH data in our case provided further evidence for the existence of a "complete ring" phenotype with incomplete subtelomeric sequences.

Serum Amino Acid Levels in Term and Preterm Neonates

PURPOSE: This study was aimed to analyze the level of serum amino acids according to the sex, birth weight, gestational age in neonates. METHODS: Amino acid was measured by tandem mass spectrometry from the dried blood spots. We measured serum alanine, citrulline, glycine, methionine, ornitine, tyrosine, valine, leucine, phenylalanine levels in 172 neonates admitted to the NICU at Chungnam National University hospital from March 2003 to September 2003 and the data was analyzed according to the sex, birth weight, gestational age. RESULTS: There were no differences of serum amino acid level between term and preterm neonates according to the sex. However, there were significant statistical differences in serum amino acid level according to the birth weight (> or =2,500 g vs. or =37 weeks vs. <37 weeks). The level of alanine, citrulline, glycine, methionine, ornitine, tyrosine, valine, leucine was low in under 2,500 g (P<0.05), and in preterm neonates (P<0.05). Especially, preterm neonates under 1,800 g had low levels of valine and leucine (P<0.05). The serum levels of methionine, ornitine, valine, leucine were low in neonates with gestational age of less than 34 weeks (P<0.05). CONCLUSION: Awareness of low serum amino acid levels in preterm neonates is essential to improve nutritional supplements and catch-up growth.

End-stage Renal Disease Caused by Primary Hyperoxaluria / 대한신장학회잡지

Primary hyperoxaluria is a rare autosomal recessive inherited metabolic disease which results from endogenous overproduction of oxalic acid. It causes variant phenotypes from renal failure in infancy to mere urolithiasis in late adulthood. We report a case of primary hyperoxaluria in a 11-year-old boy. He presented with recurrent multiple renal stones since 3 years of age. He had renal failure and markedly increased hyperoxaluria (568.26 microgram/mg of creatinine (normal: 0.04-0.15)) and his stones consisted of a mixture of calcium oxalate (30%) and calcium phosphate (10%) in contrast to pure calcium oxalate monohydrate in the other primary hyperoxaluria type 1 patients. A renal biopsy showed interstitial cellular infiltration with crystals which are birefringent under polarized light within the tubules. His general conditions were improved after hemodialysis treatment. For definite cure of disease, combined liver-kidney transplantation is considered.

Lesch-Nyhan syndrome and purine and pyrimidine metabolism didorders / 한양의대학술지

Purine & pyrimidine nucleotides are basic constituents of cellular DNA and RNA polynucleotides. Their function includes regulation of cell metabolism and function, energy conservation and transport and formation of coenzymes and active intermediates of phospholipids and carbohydrate metabolism. The origin of cellular purines and pyrimidines is almost exclusively endogenous source, and the dietary purines play only a minor role. Diagnostic and clinical markers of purine and pyrimidine nucleotide disorders are the level of uric acid, xanthine, hypoxanthine, orotic acid, uracil, thymine, dihydrouracil, dihydrothymine, and succinyladenosine. Clinical manifestations of purine and pyrimidine metabolic disorders are crystalluria and acute renal failure, infections, failure to thrive, and anemia. One of purine metabolic disorders, Lesch-Nyhan disease, is X-linked recessive disorder, presenting motor delay, cerebral palsy, involuntary movements, self-injurious behavior, hyperurcemia, uricosuria, urinary calculi and gouty arthritis. Hypoxanthine-guanine phosphoribosyl transferase(HPRT) is deficient.