Neuropathology 2017 Aug 16. Epub 2017 Aug 16.

Inborn Errors of Metabolism and Screening Laboratory, National Institute of Pediatrics, Mexico City, Mexico State, Mexico.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle defect associated with severe and usually fatal hyperammonemia. This study describes a patient with early onset lethal OTCD due to a known pathogenic variant (c.298+1G>A), as well as the novel autopsy finding of kernicterus with relatively low blood concentration of unconjugated bilirubin (UCB) (11. Read More

Methods Mol Biol 2017 ;1633:219-234

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

We describe a liquid chromatography-tandem mass spectrometry assay for measurement of D-2-hydroxyglutaric acid and L-2-hydroxyglutaric acid. These metabolites are increased in specific inborn errors of metabolism and are now recognized as oncometabolites. The measurement of D-2-hydroxyglutarate in peripheral blood may be used as a biomarker for screening and follow-up of patients with IDH-mutated acute myeloid leukemia. Read More

Genet Med 2017 Jul 20. Epub 2017 Jul 20.

Division of Metabolism, University Children's Hospital, Zurich, Switzerland.

PurposeRecognizing individuals with inherited diseases can be difficult because signs and symptoms often overlap those of common medical conditions. Focusing on inborn errors of metabolism (IEMs), we present a method that brings the knowledge of highly specialized experts to professionals involved in early diagnoses. We introduce IEMbase, an online expert-curated IEM knowledge base combined with a prototype diagnosis support (mini-expert) system. Read More

Medicine (Baltimore) 2017 Jul;96(29):e7387

aDepartment of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine bAsan Institute for Life Sciences cMedical Genetics Center, Asan Medical Center Children's Hospital, Seoul dDepartment of Pediatrics, Pusan National University Children's Hospital eDepartment of Neurology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan fDepartment of Pediatrics, Seoul National University Children's Hospital, Seoul gDepartment of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine, Suwon hDepartment of Pediatrics, College of Medicine, Soonchunhyang University, Bucheon Hospital, Bucheon iDepartment of Pediatrics, College of Medicine, Soonchunhyang University, Seoul Hospital, Seoul jDepartment of Pediatrics, Chonnam National University Hwasun Hospital, Hwasun kDepartment of Pediatrics, Chungnam National University Hospital, Daejeon lDepartment of Cardiology, Bucheon Sejong Hospital, Bucheon mDepartment of Cardiology, Kyung Hee University Hospital nDepartment of Cardiology, Yonsei University Severance Hospital oDepartment of Nephrology, Chung-Ang University Hospital pDepartment of Cardiology, Eulji University Hospital, Seoul qDepartment of Nephrology, Kyungpook National University Hospital, Daegu rDivision of Nephrology, Department of Internal Medicine, Dankook University Hospital, Dankook University, College of Medicine, Cheonan sDepartment of Cardiology, Inje University Busan Paik Hospital, Busan, Republic of Korea.

Fabry disease is a rare X-linked lysosomal storage disorder caused by an α-galactosidase A deficiency. The progressive accumulation of globotriaosylceramide (GL-3) results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. This study investigated the phenotypic and molecular spectra of GLA mutations in Korean patients with Fabry disease using a nationwide survey. Read More

Bioessays 2017 Aug 13;39(8). Epub 2017 Jul 13.

Departments of Molecular and Human Genetics and Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.

Could 10-20% of autism be prevented? We hypothesize that nonsyndromic or "essential" autism involves extreme male bias in infants who are genetically normal, but they develop deficiency of carnitine and perhaps other nutrients in the brain causing autism that may be amenable to early reversal and prevention. That brain carnitine deficiency might cause autism is suggested by reports of severe carnitine deficiency in autism and by evidence that TMLHE deficiency - a defect in carnitine biosynthesis - is a risk factor for autism. A gene on the X chromosome (SLC6A14) likely escapes random X-inactivation (a mixed epigenetic and genetic regulation) and could limit carnitine transport across the blood-brain barrier in boys compared to girls. Read More

Pan Afr Med J 2017 13;26:201. Epub 2017 Apr 13.

Department of Pediatrics, ALL India Institute of Medical Sciences, Patna, Bihar, India.

Wilson's disease is a well-known leading cause of chronic liver disease in children. However it may remain undiagnosed in a resource limited setting for a long period. We describe a six year male child diagnosed Wilson's disease with extreme elevation of liver enzymes which is not reported earlier. Read More

Pol J Radiol 2017 16;82:320-321. Epub 2017 Jun 16.

Department of Radiology, Gazi University, Faculty of Medicine, Ankara, Turkey.

Background: Absent ductus venosus (ADV) is a rare condition, but it should be known that this embryonic anomaly may be detected by fetal echocardiographic or newborn ultrasound examinations.

Case Report: We present a baby with an ADV and an accompanying alternative porto-caval shunt between the right portal vein and inferior vena cava detected on postnatal ultrasound examination.

Conclusions: Variations in the fetal umbilical or porto-systemic circulations should be detected by fetal or newborn ultrasound examinations and kept in mind before common interventions such as UV catheterizations. Read More

Int J Mol Sci 2017 Jul 2;18(7). Epub 2017 Jul 2.

Department of Pediatrics and Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Children's Hospital of Western Ontario and London Health Sciences Centre, London, ON N6A5W9, Canada.

Inborn errors of metabolism (IEM) are a rare cause of epilepsy, but seizures and epilepsy are frequently encountered in patients with IEM. Since these disorders are related to inherited enzyme deficiencies with resulting effects on metabolic/biochemical pathways, the term "metabolic epilepsy" can be used to include these conditions. These epilepsies can present across the life span, and share features of refractoriness to anti-epileptic drugs, and are often associated with co-morbid developmental delay/regression, intellectual, and behavioral impairments. Read More

Medicine (Baltimore) 2017 Jun;96(26):e7365

aDepartment of Pediatrics, West China Second University Hospital bKey Laboratory of Obstetric & Gynaecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, Sichuan, China.

Rationale: The carbamoyl phosphate synthetase I deficiency (CPS1D) was rare and hard to diagnose due to its atypical symptoms. Brain magnetic resonance imaging (MRI) was typically unavailable in other reports because most patients died before diagnosis was confirmed. Furthermore, it was found a new mutation that had not been described previously. Read More

J Inherit Metab Dis 2017 Jul 26;40(4):609-620. Epub 2017 Jun 26.

Paediatrician for Inborn Errors of Metabolism, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands.

In recent years the number of disorders known to affect amino acid synthesis has grown rapidly. Nor is it just the number of disorders that has increased: the associated clinical phenotypes have also expanded spectacularly, primarily due to the advances of next generation sequencing diagnostics. In contrast to the "classical" inborn errors of metabolism in catabolic pathways, in which elevated levels of metabolites are easily detected in body fluids, synthesis defects present with low values of metabolites or, confusingly, even completely normal levels of amino acids. Read More

Mol Genet Metab Rep 2016 Sep 2;8:4-7. Epub 2016 Jun 2.

LaFarge Medical Clinic, LaFarge, WI, USA.

Propionic acidemia (PA) is an inborn error of protein metabolism with a variable clinical presentation ranging from neonatal encephalopathy to seemingly asymptomatic individuals who present with cardiomyopathy or sudden death. PA is recognized in the Amish population, often with an early asymptomatic course and eventual cardiac complications. Thus, Amish women with PA may reach reproductive age without clinical sequelae, but are at increased risk for metabolic decompensation during pregnancy, delivery and postpartum period. Read More

Anal Chem 2017 Aug 11;89(15):8112-8121. Epub 2017 Jul 11.

Department of Chemistry and Chemical Biology, McMaster University , Hamilton L8S 4M1, Canada.

Mass spectrometry (MS)-based metabolomic initiatives that use conventional separation techniques are limited by low sample throughput and complicated data processing that contribute to false discoveries. Herein, we introduce a new strategy for unambiguous identification and accurate quantification of biomarkers for inborn errors of metabolism (IEM) from dried blood spots (DBS) with quality assurance. A multiplexed separation platform based on multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS) was developed to provide comparable sample throughput to flow injection analysis-tandem MS (FIA-MS/MS) but with greater selectivity as required for confirmatory testing and discovery-based metabolite profiling of volume-restricted biospecimens. Read More

Stem Cell Res Ther 2017 Jun 24;8(1):150. Epub 2017 Jun 24.

Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.

Background: Disorders of the oxidative phosphorylation (OXPHOS) system represent a large group among the inborn errors of metabolism. The most frequently observed biochemical defect is isolated deficiency of mitochondrial complex I (CI). No effective treatment strategies for CI deficiency are so far available. Read More

Int J Mol Sci 2017 Jun 23;18(7). Epub 2017 Jun 23.

Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Read More

J Pediatr 2017 Jun 16. Epub 2017 Jun 16.

Department of Metabolic Medicine, Royal Children's Hospital and Murdoch Children's Research Institute, Melbourne, Australia; Department of Nutrition, Dietetics and Food, Monash University, Melbourne, Australia; Department of Pediatrics, University of Melbourne, Melbourne, Australia.

Objectives: To examine relationships between dietary intake, growth and body composition patterns in patients with inborn errors of intermediary protein metabolism and to determine a safe protein:energy ratio (P:E ratio) associated with optimal growth outcomes.

Study Design: Retrospective longitudinal data of growth and dietary intake in patients (n = 75) with isovaleric acidemia (IVA; n = 7), methylmalonic acidemia/propionic acidemia (MMA/PA; n = 14), urea cycle defects (UCD; n = 44), classical maple syrup urine disease (MSUD; n = 10) were collected. Prospective longitudinal data of growth, dietary intake, and body composition from 21 patients: IVA (n = 5), MMA/PA (n = 6), UCD (n = 7), and MSUD (n = 3) were collected at clinic visits. Read More

Gene 2017 Sep 13;627:149-156. Epub 2017 Jun 13.

Department of Pediatrics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China. Electronic address:

Glycogen storage disease (GSD) type IXa is caused by PHKA2 mutation, which accounts for about 75% of all the GSD type IX cases. Here we first summarized the clinical data and analyzed the PHKA2 gene of 17 Chinese male patients suspected of having GSD type IXa. Clinical symptoms of our patients included hepatomegaly, growth retardation, and liver dysfunction. Read More

Pediatr Int 2017 Jul 14;59(7):835-836. Epub 2017 Jun 14.

Division of Inborn Errors of Metabolism and Nutrition, Department of Pediatrics, Gazi University Faculty of Medicine, Ankara, Turkey.

Bioorg Med Chem Lett 2017 Aug 30;27(15):3431-3435. Epub 2017 May 30.

Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.

N-Functionalized amino(hydroxymethyl)cyclopentanetriols are potent inhibitors of β-d-galactosidases and, for the first time, could be shown to act as pharmacological chaperones for GM1-gangliosidosis-associated lysosomal acid β-galactosidase thus representing a new structural type of pharmacological chaperones for this lysosomal storage disease. Read More

Clin Chem 2017 Aug 7;63(8):1363-1369. Epub 2017 Jun 7.

Department of Chemistry, University of Washington, Seattle, WA;

Background: Deficiency of the lysosomal enzyme galactosylcerebrosidase (GALC) causes Krabbe disease. Newborn screening for Krabbe disease is ongoing, but improved methods for follow-up analysis of screen-positive babies are needed to better advise families and to optimize treatment. We report a new assay for the enzymatic activity of GALC in lymphocytes. Read More

N Engl J Med 2017 06;376(23):2266-2275

From the Department of Pediatrics, Massachusetts General Hospital (R.W.C., M.L.K., E.P., H.J.), the Department of Pediatrics, Harvard Medical School (R.W.C., M.L.K., E.P., H.J.), and Joslin Diabetes Center (M.L.K.) - all in Boston.

Mol Genet Metab 2017 Jul 22;121(3):206-215. Epub 2017 May 22.

Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany; Division of Clinical Chemistry & Biochemistry and Children's Research Center, University Children's Hospital, Zürich, Switzerland; Bioanalytics & Biochemistry, Department of Natural Sciences, University of Applied Sciences, Rheinbach, Germany. Electronic address:

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused by mutations in the HMGCL gene. In order to obtain a comprehensive view on this disease, we have collected clinical and biochemical data as well as information on HMGCL mutations of 37 patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey. All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation. Read More

Fertil Steril 2017 Jul 1;108(1):168-174. Epub 2017 Jun 1.

Department of Pediatrics and Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands. Electronic address:

Objective: To study pregnancy chance in adult women with classic galactosemia and primary ovarian insufficiency. Despite dietary treatment, >90% of women with classic galactosemia develop primary ovarian insufficiency, resulting in impaired fertility. For many years, chance of spontaneous conception has not been considered, leading to counseling for infertility. Read More

Am J Hum Genet 2017 Jun;100(6):969-977

Department of Molecular Neuroscience, University College London, London WC1N 3BG, UK; Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.

Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. Read More

BMC Med Genet 2017 May 31;18(1):59. Epub 2017 May 31.

Institute of Medical Biology, Genetics and Clinical Genetics, Comenius University, Faculty of Medicine & University Hospital Bratislava, Sasinkova 4, 811 08, Bratislava, Slovakia.

Background: Primary hyperoxaluria type 2 is a rare monogenic disorder inherited in an autosomal recessive pattern. It results from the absence of the enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR). As a consequence of deficient enzyme activity, excessive amounts of oxalate and L-glycerate are excreted in the urine, and are a source for the formation of calcium oxalate stones that result in recurrent nephrolithiasis and less frequently nephrocalcinosis. Read More

Pediatrics 2017 May 11;139(5). Epub 2017 Apr 11.

Cleveland Clinic Children's, Cleveland, Ohio.

A 9-day-old infant girl presented with diarrhea and weight loss of 19% since birth. She was born via spontaneous vaginal delivery at 39 weeks' gestation to a mother positive for group B Streptococcus who received adequate intrapartum prophylaxis. The infant was formula-fed every 2 to 3 hours with no reported issues with feeding or swallowing. Read More

Pediatrics 2017 May;139(5)

Department of General Pediatrics and Division of Pediatric Endocrinology and Diabetes, University Children's Hospital Heidelberg, Heidelberg, Germany; and.

Amyloidosis cutis dyschromica is a rare form of primary cutaneous amyloidosis without systemic involvement and characterized by asymptomatic, progressive hyper- and hypopigmentation. We present the first case of a patient with amyloidosis cutis dyschromica diagnosed previously elsewhere as having Addison disease with generalized hyperpigmentation of the skin. This case suggests that in patients presenting with asymptomatic cutaneous dyschromia a skin biopsy for histopathological examination should be considered. Read More

Dev Med Child Neurol 2017 Aug 25;59(8):815-821. Epub 2017 May 25.

Molecular Medicine Unit and Child Neurology, IRCCS Fondazione Stella Maris, Pisa, Italy.

Aim: To characterize the phenotypic profile of a cohort of children affected with CLN5, a rare form of neuronal ceroid-lipofuscinosis (NCL), and to trace the features of the natural history of the disease.

Method: Records of 15 children (nine males, six females) were obtained from the data sets of the DEM-CHILD International NCL Registry. Disease progression was measured by rating six functional domains at different time points along the disease course. Read More

J Nutr 2017 Jul 17;147(7):1251-1257. Epub 2017 May 17.

US Department of Agriculture/Agricultural Research Service, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX

Mitochondrial disorders result from dysfunctional mitochondria that are unable to generate sufficient energy to meet the needs of various organs. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most frequent maternally inherited mitochondrial disorders. There is growing evidence that nitric oxide (NO) deficiency occurs in MELAS syndrome and results in impaired blood perfusion that contributes significantly to several complications in this disease. Read More

Neurochem Res 2017 Jun 16;42(6):1661-1675. Epub 2017 May 16.

Department of Pediatrics, University of Maryland School of Medicine, 655 W. Baltimore Street, BRB 13-019, Baltimore, MD, 21201, USA.

L-Carnitine functions to transport long chain fatty acyl-CoAs into the mitochondria for degradation by β-oxidation. Treatment with L-carnitine can ameliorate metabolic imbalances in many inborn errors of metabolism. In recent years there has been considerable interest in the therapeutic potential of L-carnitine and its acetylated derivative acetyl-L-carnitine (ALCAR) for neuroprotection in a number of disorders including hypoxia-ischemia, traumatic brain injury, Alzheimer's disease and in conditions leading to central or peripheral nervous system injury. Read More

BMC Med Genet 2017 May 15;18(1):55. Epub 2017 May 15.

Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: Gastrointestinal involvement in Gaucher disease is very rare, and appears to be unresponsive to enzyme replacement therapy (ERT).

Case Presentation: Here, we describe identical twin, splenectomized, non-neuronopathic Gaucher patients on long-term ERT for 9 years, who complained of epigastric discomfort due to Gaucher cell infiltration of the gastroduodenal mucosa. Rare compound heterozygous mutations (p. Read More

Paediatr Drugs 2017 Aug;19(4):303-311

Division of Rheumatology, Department of Pediatrics, Hacettepe University Faculty of Medicine, 06100, Ankara, Turkey.

Autoinflammatory diseases are disorders of the innate immune system characterized by uncontrolled inflammation. The most commonly encountered autoinflammatory diseases are the hereditary periodic fever syndromes, which present with fever and other features of the skin, serosal membranes, and musculoskeletal system. The main inherited (monogenic) periodic fever syndromes are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD). Read More

Pediatr Allergy Immunol 2017 Aug 20;28(5):495-497. Epub 2017 Jun 20.

Division of Allergy and Clinical Immunology, Department of Pediatrics. Federal, University of São Paulo, São Paulo, Brazil.

BMC Med Genet 2017 May 4;18(1):51. Epub 2017 May 4.

Third Department of Pediatrics, Athens University Medical School, University General Hospital "Attikon", 1 Rimini Str, 12464 -Haidari, Athens, Greece.

Background: Niemann-Pick type C disease (NPC) is an autosomal recessive, neurovisceral, lysosomal storage disorder with protean and progressive clinical manifestations, resulting from mutations in either of the two genes, NPC1 (~95% of families) and NPC2. Contrary to other populations, published evidence regarding NPC disease in Greece is sparse.

Methods: The study population consisted of two Greek NPC patients and their extended pedigree. Read More

Arch Dis Child 2017 May 3. Epub 2017 May 3.

Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester NHS Trust, Manchester Academic Health Science Centre, Manchester, UK.

Background: Inborn errors of metabolism (IEMs) underlie a substantial proportion of paediatric disease burden but their genetic diagnosis can be challenging using the traditional approaches.

Methods: We designed and validated a next-generation sequencing (NGS) panel of 226 IEM genes, created six overlapping phenotype-based subpanels and tested 102 individuals, who presented clinically with suspected childhood-onset IEMs.

Results: In 51/102 individuals, NGS fully or partially established the molecular cause or identified other actionable diagnoses. Read More

J Biol Chem 2017 Jun 2;292(25):10328-10346. Epub 2017 May 2.

From the Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037,

The lysosomal storage disease cystinosis, caused by cystinosin deficiency, is characterized by cell malfunction, tissue failure, and progressive renal injury despite cystine-depletion therapies. Cystinosis is associated with defects in chaperone-mediated autophagy (CMA), but the molecular mechanisms are incompletely understood. Here, we show CMA substrate accumulation in cystinotic kidney proximal tubule cells. Read More

Blood 2017 Jul 2;130(3):245-257. Epub 2017 May 2.

Department of Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA.

The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens (Yersinia enterocolitica O9) by controlling non-transferrin-bound iron (NTBI) rather than iron-transferrin concentration. Read More

Mol Genet Metab 2017 Jun 20;121(2):80-82. Epub 2017 Apr 20.

Bioanalytics & Biochemistry, Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, von-Liebig-Str. 20, 53359 Rheinbach, Germany. Electronic address:

Historically, d-glyceric aciduria was thought to cause an uncharacterized blockage to the glycine cleavage enzyme system (GCS) causing nonketotic hyperglycinemia (NKH) as a secondary phenomenon. This inference was reached based on the clinical and biochemical results from the first d-glyceric aciduria patient reported in 1974. Along with elevated glyceric acid excretion, this patient exhibited severe neurological symptoms of myoclonic epilepsy and absent development, and had elevated glycine levels and decreased glycine cleavage system enzyme activity. Read More

Clin Chem 2017 Jul 27;63(7):1271-1277. Epub 2017 Apr 27.

Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA.

Background: Deficiency of the lysosomal enzyme acid α-glucosidase (GAA) causes Pompe disease. Newborn screening for Pompe disease is ongoing, and improved methods for distinguishing affected patients from those with pseudodeficiency, especially in the Asian population, would substantially reduce the number of patient referrals for clinical follow-up.

Methods: We measured the enzymatic activity of GAA in dried blood spots on newborn screening cards (DBS) using a tandem mass spectrometry (MS/MS) assay. Read More

N Engl J Med 2017 04;376(17):1668-1678

From the Departments of Neurology (H.M.R.), Radiology (W.A.C.), Pediatrics (A.K.), and Pathology (D.H.O.), Massachusetts General Hospital, and the Departments of Neurology (H.M.R.), Radiology (W.A.C.), Pediatrics (A.K.), and Pathology (D.H.O.), Harvard Medical School - both in Boston.

Brain Dev 2017 Sep 21;39(8):714-716. Epub 2017 Apr 21.

Division of Endocrinology and Metabolism, Department of Pediatrics, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

3-Methylglutaconic aciduria is a member of inborn errors of leucine metabolism pathway. 3-Methylglutaconic aciduria type I (MGA1) causes neurological problems which are present during infancy or childhood but the diagnosis may be delayed until adulthood. Here we report a 3years old patient with developmental delay from a relative parent's that his medical evaluations include analyses of urinary organic acid and blood acylcarnitine showed high level of 3-methylglutacoic acid, 3-hydroxyisovaleric acid and increased level of 3-hydroxyisovalerylcarnitine respectively. Read More

JAMA Neurol 2017 Jun;74(6):727-732

Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas3Department of Physiology, University of Texas Southwestern Medical Center, Dallas4Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas5Eugene McDermott Center for Human Growth & Development/Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas.

Importance: Case reports regularly document unique or unusual aspects of glucose transporter type 1 deficiency (G1D). In contrast, population studies from which to draw global inferences are lacking. Twenty-five years after the earliest case reports, this deficiency still particularly affects treatment and prognostic counseling. Read More

Clin Chem 2017 Jun 20;63(6):1118-1126. Epub 2017 Apr 20.

Departments of Chemistry,

Background: We expanded the use of tandem mass spectrometry combined with liquid chromatography (LC-MS/MS) for multiplex newborn screening of seven lysosomal enzymes in dried blood spots (DBS). The new assays are for enzymes responsible for the mucopolysaccharidoses (MPS-I, -II, -IIIB, -IVA, -VI, and -VII) and type 2 neuronal ceroid lipofuscinosis (LINCL).

Methods: New substrates were prepared and characterized for tripeptidyl peptidase 1 (TPP1), α-N-acetylglucosaminidase (NAGLU), and lysosomal β-glucuronidase (GUSB). Read More

Sci Rep 2017 Apr 19;7(1):957. Epub 2017 Apr 19.

Folkhälsan Research Center, Helsinki, Finland.

Mitochondrial disorders are among the most prevalent inborn errors of metabolism but largely lack treatments and have poor outcomes. High-fat, low-carbohydrate ketogenic diets (KDs) have shown beneficial effects in mouse models of mitochondrial myopathies, with induction of mitochondrial biogenesis as the suggested main mechanism. We fed KD to mice with respiratory chain complex III (CIII) deficiency and progressive hepatopathy due to mutated BCS1L, a CIII assembly factor. Read More

J Child Neurol 2017 May 16;32(6):560-565. Epub 2017 Mar 16.

3 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

STT3A encodes the catalytic subunit of the oligosaccharyltransferase complex. A congenital disorder of glycosylation caused by mutations in STT3A has only been reported in one family to date, associated with a Type I congenital disorder of glycosylation pattern of transferrin glycoforms. The authors describe a further 5 related individuals with a likely pathogenic variant in STT3A, 2 of whom also had variants in TUSC3. Read More

JAMA Neurol 2017 Jun;74(6):710-717

Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis.

Importance: Untreated childhood cerebral adrenoleukodystrophy (cALD) is a fatal disease associated with progressive cerebral demyelination and rapid, devastating neurologic decline. The standard of care to enhance long-term survival and stabilize cerebral disease is a hematopoietic stem cell transplant (HSCT). Neurologic outcomes are better when HSCT occurs at an earlier stage of cALD, yet there is limited understanding of the neurocognitive trajectory of patients who undergo HSCT. Read More

Neurology 2017 May 14;88(20):1919-1924. Epub 2017 Apr 14.

From Child and Adolescent Neurology (M.K.K.), University of Texas Medical School, Houston; Neurology (R.H., P.L.P.), Boston Children's Hospital, Harvard Medical School, MA; Child Neurology (J.J.R., W.C., J.B., C.A.C.), Columbia University School of Medicine, New York, NY; Neurology (K.I., M.T.), Kanagawa Children's Medical Center, Yokohama; Pediatrics (H.O.), Jichi Medical School, Tochigi, Japan; Experimental and Systems Pharmacology (K.M.G.), Washington State University, Spokane; and Molecular and Human Genetics (P.E.B.), Baylor College of Medicine, Houston, TX.

Objective: We report a case series of 10 patients with γ-aminobutyric acid (GABA)-transaminase deficiency including a novel therapeutic trial and an expanded phenotype.

Methods: Case ascertainment, literature review, comprehensive evaluations, and long-term treatment with flumazenil.

Results: All patients presented with neonatal or early infantile-onset encephalopathy; other features were hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. Read More

Methods Mol Biol 2017 ;1595:329-342

Department Paediatric Neurology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, AZ, 1105, The Netherlands.

The peroxisomal disorders (PDs) are a heterogeneous group of genetic diseases in man caused by an impairment in peroxisome biogenesis or one of the metabolic functions of peroxisomes. Thanks to the revolutionary technical developments in gene sequencing methods and their increased use in patient diagnosis, the field of genetic diseases in general and peroxisomal disorders in particular has dramatically changed in the last few years. Indeed, several novel peroxisomal disorders have been identified recently and in addition it has been realized that the phenotypic spectrum of patients affected by a PD keeps widening, which makes clinical recognition of peroxisomal patients increasingly difficult. Read More

J Inherit Metab Dis 2017 Apr 13. Epub 2017 Apr 13.

Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, 2145, Australia.

Clinical finding of cutis laxa, characterized by wrinkled, redundant, sagging, nonelastic skin, is of growing significance due to its occurrence in several different inborn errors of metabolism (IEM). Metabolic cutis laxa results from Menkes syndrome, caused by a defect in the ATPase copper transporting alpha (ATP7A) gene; congenital disorders of glycosylation due to mutations in subunit 7 of the component of oligomeric Golgi (COG7)-congenital disorders of glycosylation (CDG) complex; combined disorder of N- and O-linked glycosylation, due to mutations in ATPase H+ transporting V0 subunit a2 (ATP6VOA2) gene; pyrroline-5-carboxylate reductase 1 deficiency; pyrroline-5-carboxylate synthase deficiency; macrocephaly, alopecia, cutis laxa, and scoliosis (MACS) syndrome, due to Ras and Rab interactor 2 (RIN2) mutations; transaldolase deficiency caused by mutations in the transaldolase 1 (TALDO1) gene; Gerodermia osteodysplastica due to mutations in the golgin, RAB6-interacting (GORAB or SCYL1BP1) gene; and mitogen-activated pathway (MAP) kinase defects, caused by mutations in several genes [protein tyrosine phosphatase, non-receptor-type 11 (PTPN11), RAF, NF, HRas proto-oncogene, GTPase (HRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), MEK1/2, KRAS proto-oncogene, GTPase (KRAS), SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2), leucine rich repeat scaffold protein (SHOC2), NRAS proto-oncogene, GTPase (NRAS), and Raf-1 proto-oncogene, serine/threonine kinase (RAF1)], which regulate the Ras-MAPK cascade. Here, we further expand the list of inborn errors of metabolism associated with cutis laxa by describing the clinical presentation of a 17-month-old girl with Leigh-like syndrome due to enoyl coenzyme A hydratase, short chain, 1, mitochondria (ECHS1) deficiency, a mitochondrial matrix enzyme that catalyzes the second step of the beta-oxidation spiral of fatty acids and plays an important role in amino acid catabolism, particularly valine. Read More

Orphanet J Rare Dis 2017 Apr 11;12(1):68. Epub 2017 Apr 11.

Australian Paediatric Surveillance Unit, Kids Research Institute, Westmead, NSW, 2145, Australia.

Background: Children and families living with rare disease often experience significant health, psychosocial, economic burdens and diagnostic delays. Experiences appear to be constant, regardless of the specific rare disease diagnosis. Systematically collected Australian data to support policy response on rare diseases are scarce. Read More

Clin Biochem 2017 Aug 4;50(12):729-732. Epub 2017 Apr 4.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria.

Objectives: Although high phenylalanine (phe) exposure has been shown to influence the DNA methylation status of leukocytes in hyperphenylalaninemia (HPA), the potential of DNA methylation changes as a biomarker of pretreatment high phe exposure in diet free newborns with HPA has not been explored. We therefore investigated the DNA methylation pattern of the phenylalanine hydroxylase (PAH) gene promoter at different phe levels, and the possibility of DNA methylation pattern changes being a biomarker of high phe exposure in diet free newborns with HPA.

Design And Methods: With a combination of methylated PCR, high resolution melting, and sequencing, the cytosine phosphodiester bond guanine (CpG) dinucleotides in the 5' untranslated region of the PAH gene were analysed 2-15days after birth using leukocyte DNA from diet free 16 newborns with HPA and 16 healthy controls. Read More