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Dwight D. Koeberl

Professor of Pediatrics
Pediatrics, Medical Genetics
Box 103856 DUMC, Durham, NC 27710
595 LaSalle Street, Gsrbi, Room 4006, Durham, NC 27710

Selected Publications


The interplay of psychosis and non-compliance with fatal outcome in an adult with MSUD.

Journal Article Am J Med Genet A · April 29, 2024 Significant progress has been achieved in enhancing early outcomes for individuals with maple syrup urine disease (MSUD), a rare metabolic disorder that leads to the accumulation of branched-chain amino acids leucine, isoleucine, and valine, where leucine ... Full text Link to item Cite

Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia.

Journal Article Nature · April 2024 Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or β (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we r ... Full text Cite

Critical sample collection delayed? Urine organic acid analysis can still save the day! A new case of HMG-CoA synthase deficiency.

Journal Article Mol Genet Metab Rep · March 2024 Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS) deficiency is an autosomal recessive disorder of ketone body synthesis caused by biallelic pathogenic variants in HMGCS2. Clinical symptoms are precipitated by prolonged fasting and/or i ... Full text Link to item Cite

Gene therapy for glycogen storage diseases.

Journal Article J Inherit Metab Dis · January 2024 Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy ... Full text Link to item Cite

Correction to: Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia (Nature, (2024), 10.1038/s41586-024-07266-7)

Journal Article Nature · January 1, 2024 Correction to: Naturehttps://doi.org/10.1038/s41586-024-07266-7Published online 3 April 2024 In the version of the article initially published, the affiliation of Stephanie Grunewald (Great Ormond Street Hospital for Children and Institute for Child Health ... Full text Cite

Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency

Journal Article Molecular Genetics and Metabolism Reports · December 1, 2023 Background: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). The disorder is marked by developmental delay, especially speech delay. The biomarkers Aβ40, Aβ42 and total ... Full text Cite

Corrigendum to “Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency” (Molecular Genetics and Metabolism Reports (2023) 37, (S2214426923000472), (10.1016/j.ymgmr.2023.101001))

Journal Article Molecular Genetics and Metabolism Reports · December 1, 2023 We would like to make a correction to Table 1.CTD participant demographics, phenotype, and CSF biomarker levels. NW = no words; SW = single words; P = Phrases (i.e., uses multiple words together but not fluent speech). ABC = Vineland Adaptive Behavior Comp ... Full text Cite

Screening data from 19 patients with late-onset Pompe disease for a phase I clinical trial of AAV8 vector-mediated gene therapy.

Journal Article JIMD Rep · September 2023 Late-onset Pompe disease (LOPD) is a multisystem disorder with significant myopathy. The standard treatment is enzyme replacement therapy (ERT), a therapy that is lifesaving, yet with limitations. Clinical trials have emerged for other potential treatment ... Full text Link to item Cite

Successful AAV8 readministration: Suppression of capsid-specific neutralizing antibodies by a combination treatment of bortezomib and CD20 mAb in a mouse model of Pompe disease.

Journal Article J Gene Med · August 2023 BACKGROUND: A major challenge to adeno-associated virus (AAV)-mediated gene therapy is the presence of anti-AAV capsid neutralizing antibodies (NAbs), which can block viral vector transduction even at very low titers. In the present study, we examined the ... Full text Open Access Link to item Cite

Phase I study of liver depot gene therapy in late-onset Pompe disease.

Journal Article Mol Ther · July 5, 2023 Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid α-glucosidase (GAA) production. We report initial safety and bioactivity of ... Full text Link to item Cite

Genome editing using Staphylococcus aureus Cas9 in a canine model of glycogen storage disease Ia.

Journal Article Mol Ther Methods Clin Dev · June 8, 2023 Glycogen storage disease type Ia (GSD Ia) is the inherited deficiency of glucose-6-phosphatase (G6Pase), associated with life-threatening hypoglycemia and long-term complications, including hepatocellular carcinoma formation. Gene replacement therapy fails ... Full text Link to item Cite

Clenbuterol Treatment Is Safe and Associated With Slowed Disease Progression in a Small Open-Label Trial in Patients With Amyotrophic Lateral Sclerosis.

Journal Article J Clin Neuromuscul Dis · June 1, 2023 OBJECTIVE: Clenbuterol, a beta-agonist, has plausible mechanisms for treating amyotrophic lateral sclerosis (ALS). In this highly inclusive open-label trial (NCT04245709), we aimed to study the safety and efficacy of clenbuterol in patients with ALS. METHO ... Full text Link to item Cite

Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin.

Journal Article Mol Genet Metab · June 2023 Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive mitochondrial neurometabolic disorder of energy deficit resulting in high morbidity and mortality, with limited therapeutic options. The PC homotetramer has a critical role in gluconeogenes ... Full text Link to item Cite

Moving away from one disease at a time: Screening, trial design, and regulatory implications of novel platform technologies.

Journal Article Am J Med Genet C Semin Med Genet · March 2023 Most rare diseases are caused by single-gene mutations, and as such, lend themselves to a host of new gene-targeted therapies and technologies including antisense oligonucleotides, phosphomorpholinos, small interfering RNAs, and a variety of gene delivery ... Full text Link to item Cite

Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: A novel hypomorphic variant and high prevalence of tethered cord.

Journal Article Clin Genet · February 2023 ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in ZC4H2 have been associa ... Full text Link to item Cite

Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.

Journal Article Dis Model Mech · May 1, 2022 Triosephosphate isomerase (TPI) deficiency (TPI Df) is an untreatable glycolytic enzymopathy that results in hemolytic anemia, progressive muscular impairment and irreversible brain damage. Although there is a 'common' mutation (TPIE105D), other pathogenic ... Full text Link to item Cite

Minimum Effective Dose to Achieve Biochemical Correction with Adeno-Associated Virus Vector-Mediated Gene Therapy in Mice with Pompe Disease.

Journal Article Hum Gene Ther · May 2022 Pompe disease is an autosomal recessive lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA), resulting in skeletal muscle weakness and cardiomyopathy. Muscle weakness progresses despite currently available therapy, which has prompte ... Full text Link to item Cite

The interplay of psychosis and non-compliance with fatal outcome in an adult with MSUD.

Journal Article Am J Med Genet A · April 29, 2024 Significant progress has been achieved in enhancing early outcomes for individuals with maple syrup urine disease (MSUD), a rare metabolic disorder that leads to the accumulation of branched-chain amino acids leucine, isoleucine, and valine, where leucine ... Full text Link to item Cite

Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia.

Journal Article Nature · April 2024 Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or β (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we r ... Full text Cite

Critical sample collection delayed? Urine organic acid analysis can still save the day! A new case of HMG-CoA synthase deficiency.

Journal Article Mol Genet Metab Rep · March 2024 Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS) deficiency is an autosomal recessive disorder of ketone body synthesis caused by biallelic pathogenic variants in HMGCS2. Clinical symptoms are precipitated by prolonged fasting and/or i ... Full text Link to item Cite

Gene therapy for glycogen storage diseases.

Journal Article J Inherit Metab Dis · January 2024 Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy ... Full text Link to item Cite

Correction to: Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia (Nature, (2024), 10.1038/s41586-024-07266-7)

Journal Article Nature · January 1, 2024 Correction to: Naturehttps://doi.org/10.1038/s41586-024-07266-7Published online 3 April 2024 In the version of the article initially published, the affiliation of Stephanie Grunewald (Great Ormond Street Hospital for Children and Institute for Child Health ... Full text Cite

Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency

Journal Article Molecular Genetics and Metabolism Reports · December 1, 2023 Background: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). The disorder is marked by developmental delay, especially speech delay. The biomarkers Aβ40, Aβ42 and total ... Full text Cite

Corrigendum to “Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency” (Molecular Genetics and Metabolism Reports (2023) 37, (S2214426923000472), (10.1016/j.ymgmr.2023.101001))

Journal Article Molecular Genetics and Metabolism Reports · December 1, 2023 We would like to make a correction to Table 1.CTD participant demographics, phenotype, and CSF biomarker levels. NW = no words; SW = single words; P = Phrases (i.e., uses multiple words together but not fluent speech). ABC = Vineland Adaptive Behavior Comp ... Full text Cite

Screening data from 19 patients with late-onset Pompe disease for a phase I clinical trial of AAV8 vector-mediated gene therapy.

Journal Article JIMD Rep · September 2023 Late-onset Pompe disease (LOPD) is a multisystem disorder with significant myopathy. The standard treatment is enzyme replacement therapy (ERT), a therapy that is lifesaving, yet with limitations. Clinical trials have emerged for other potential treatment ... Full text Link to item Cite

Successful AAV8 readministration: Suppression of capsid-specific neutralizing antibodies by a combination treatment of bortezomib and CD20 mAb in a mouse model of Pompe disease.

Journal Article J Gene Med · August 2023 BACKGROUND: A major challenge to adeno-associated virus (AAV)-mediated gene therapy is the presence of anti-AAV capsid neutralizing antibodies (NAbs), which can block viral vector transduction even at very low titers. In the present study, we examined the ... Full text Open Access Link to item Cite

Phase I study of liver depot gene therapy in late-onset Pompe disease.

Journal Article Mol Ther · July 5, 2023 Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid α-glucosidase (GAA) production. We report initial safety and bioactivity of ... Full text Link to item Cite

Genome editing using Staphylococcus aureus Cas9 in a canine model of glycogen storage disease Ia.

Journal Article Mol Ther Methods Clin Dev · June 8, 2023 Glycogen storage disease type Ia (GSD Ia) is the inherited deficiency of glucose-6-phosphatase (G6Pase), associated with life-threatening hypoglycemia and long-term complications, including hepatocellular carcinoma formation. Gene replacement therapy fails ... Full text Link to item Cite

Clenbuterol Treatment Is Safe and Associated With Slowed Disease Progression in a Small Open-Label Trial in Patients With Amyotrophic Lateral Sclerosis.

Journal Article J Clin Neuromuscul Dis · June 1, 2023 OBJECTIVE: Clenbuterol, a beta-agonist, has plausible mechanisms for treating amyotrophic lateral sclerosis (ALS). In this highly inclusive open-label trial (NCT04245709), we aimed to study the safety and efficacy of clenbuterol in patients with ALS. METHO ... Full text Link to item Cite

Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin.

Journal Article Mol Genet Metab · June 2023 Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive mitochondrial neurometabolic disorder of energy deficit resulting in high morbidity and mortality, with limited therapeutic options. The PC homotetramer has a critical role in gluconeogenes ... Full text Link to item Cite

Moving away from one disease at a time: Screening, trial design, and regulatory implications of novel platform technologies.

Journal Article Am J Med Genet C Semin Med Genet · March 2023 Most rare diseases are caused by single-gene mutations, and as such, lend themselves to a host of new gene-targeted therapies and technologies including antisense oligonucleotides, phosphomorpholinos, small interfering RNAs, and a variety of gene delivery ... Full text Link to item Cite

Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: A novel hypomorphic variant and high prevalence of tethered cord.

Journal Article Clin Genet · February 2023 ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in ZC4H2 have been associa ... Full text Link to item Cite

Itavastatin and resveratrol increase triosephosphate isomerase protein in a newly identified variant of TPI deficiency.

Journal Article Dis Model Mech · May 1, 2022 Triosephosphate isomerase (TPI) deficiency (TPI Df) is an untreatable glycolytic enzymopathy that results in hemolytic anemia, progressive muscular impairment and irreversible brain damage. Although there is a 'common' mutation (TPIE105D), other pathogenic ... Full text Link to item Cite

Minimum Effective Dose to Achieve Biochemical Correction with Adeno-Associated Virus Vector-Mediated Gene Therapy in Mice with Pompe Disease.

Journal Article Hum Gene Ther · May 2022 Pompe disease is an autosomal recessive lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA), resulting in skeletal muscle weakness and cardiomyopathy. Muscle weakness progresses despite currently available therapy, which has prompte ... Full text Link to item Cite

Efficacious Androgen Hormone Administration in Combination with Adeno-Associated Virus Vector-Mediated Gene Therapy in Female Mice with Pompe Disease.

Journal Article Hum Gene Ther · May 2022 Pompe disease is an autosomal recessive lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA), resulting in skeletal muscle weakness and cardiomyopathy that progresses despite currently available therapy in some patients. The developm ... Full text Link to item Cite

AAV gene therapy for glycogen storage diseases

Conference EUROPEAN JOURNAL OF HUMAN GENETICS · 2022 Cite

A generic emergency protocol for patients with inborn errors of metabolism causing fasting intolerance: A retrospective, single-center study and the generation of www.emergencyprotocol.net.

Journal Article J Inherit Metab Dis · September 2021 Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking. This is a retrospective, observational, single-center study of the use of ... Full text Link to item Cite

Three-dimensional tissue-engineered human skeletal muscle model of Pompe disease.

Journal Article Commun Biol · May 5, 2021 In Pompe disease, the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) causes skeletal and cardiac muscle weakness, respiratory failure, and premature death. While enzyme replacement therapy using recombinant human GAA (rhGAA) can significan ... Full text Open Access Link to item Cite

Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood.

Journal Article Hum Gene Ther · April 2021 Alternating Hemiplegia of Childhood (AHC) is a devastating autosomal dominant disorder caused by ATP1A3 mutations, resulting in severe hemiplegia and dystonia spells, ataxia, debilitating disabilities, and premature death. Here, we determine the effects of ... Full text Link to item Cite

Person Ability Scores as an Alternative to Norm-Referenced Scores as Outcome Measures in Studies of Neurodevelopmental Disorders.

Journal Article Am J Intellect Dev Disabil · November 1, 2020 Although norm-referenced scores are essential to the identification of disability, they possess several features which affect their sensitivity to change. Norm-referenced scores often decrease over time among people with neurodevelopmental disorders who ex ... Full text Link to item Cite

A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females.

Journal Article Mol Genet Metab · July 2020 PURPOSE: Successful diagnosis of Fabry disease is often delayed or missed in patients, especially females, due to clinical heterogeneity and a lack of disease awareness. We present our experience testing for Fabry disease in high risk populations and discu ... Full text Link to item Cite

Comparisons of Infant and Adult Mice Reveal Age Effects for Liver Depot Gene Therapy in Pompe Disease.

Journal Article Mol Ther Methods Clin Dev · June 12, 2020 Featured Publication Pompe disease is caused by the deficiency of lysosomal acid α-glucosidase (GAA). It is expected that gene therapy to replace GAA with adeno-associated virus (AAV) vectors will be less effective early in life because of the rapid loss of vector genomes. AAV ... Full text Open Access Link to item Cite

Evaluation of antihypertensive drugs in combination with enzyme replacement therapy in mice with Pompe disease.

Journal Article Mol Genet Metab · February 2020 UNLABELLED: Pompe disease is caused by the deficiency of lysosomal acid α-glucosidase (GAA) leading to progressive myopathy. Enzyme replacement therapy (ERT) with recombinant human (rh) GAA has limitations, including inefficient uptake of rhGAA in skeletal ... Full text Open Access Link to item Cite

Improved muscle function in a phase I/II clinical trial of albuterol in Pompe disease.

Journal Article Mol Genet Metab · February 2020 This 24-week, Phase I/II, double-blind, randomized, placebo-controlled study investigated the safety and efficacy of extended-release albuterol in late-onset Pompe disease stably treated with enzyme replacement therapy at the standard dose for 4.9 (1.0-9.4 ... Full text Open Access Link to item Cite

Fenofibrate rapidly decreases hepatic lipid and glycogen storage in neonatal mice with glycogen storage disease type Ia.

Journal Article Hum Mol Genet · January 15, 2020 Glycogen storage disease type Ia (GSD Ia) is caused by autosomal mutations in glucose-6-phosphatase α catalytic subunit (G6PC) and can present with severe hypoglycemia, lactic acidosis and hypertriglyceridemia. In both children and adults with GSD Ia, ther ... Full text Link to item Cite

Links between autophagy and disorders of glycogen metabolism - Perspectives on pathogenesis and possible treatments.

Journal Article Mol Genet Metab · January 2020 The glycogen storage diseases are a group of inherited metabolic disorders that are characterized by specific enzymatic defects involving the synthesis or degradation of glycogen. Each disorder presents with a set of symptoms that are due to the underlying ... Full text Link to item Cite

Pathogenesis of Hepatic Tumors following Gene Therapy in Murine and Canine Models of Glycogen Storage Disease.

Journal Article Mol Ther Methods Clin Dev · December 13, 2019 Featured Publication Glycogen storage disease type Ia (GSD Ia) is caused by mutations in the glucose-6-phosphatase (G6Pase) catalytic subunit gene (G6PC). GSD Ia complications include hepatocellular adenomas (HCA) with a risk for hepatocellular carcinoma (HCC) formation. Genom ... Full text Open Access Link to item Cite

Gene therapy for glycogen storage diseases.

Journal Article Hum Mol Genet · October 1, 2019 The focus of this review is the development of gene therapy for glycogen storage diseases (GSDs). GSD results from the deficiency of specific enzymes involved in the storage and retrieval of glucose in the body. Broadly, GSDs can be divided into types that ... Full text Open Access Link to item Cite

Immunomodulatory, liver depot gene therapy for Pompe disease.

Journal Article Cell Immunol · August 2019 Pompe disease is caused by mutations in acid alpha glucosidase (GAA) that causes accumulation of lysosomal glycogen affecting the heart and skeletal muscles, and can be fatal. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) improves mus ... Full text Link to item Cite

A Liver-Specific Thyromimetic, VK2809, Decreases Hepatosteatosis in Glycogen Storage Disease Type Ia.

Journal Article Thyroid · August 2019 Background: Glycogen storage disease type Ia (GSD Ia), also known as von Gierke disease, is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, the enzyme that catalyzes the final step of gluconeogenesis and ... Full text Link to item Cite

Salmeterol with Liver Depot Gene Therapy Enhances the Skeletal Muscle Response in Murine Pompe Disease.

Journal Article Hum Gene Ther · July 2019 Gene therapy for Pompe disease with adeno-associated virus (AAV) vectors has advanced into early phase clinical trials; however, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up acid ... Full text Link to item Cite

Liver depot gene therapy for Pompe disease.

Journal Article Ann Transl Med · July 2019 Gene therapy for Pompe disease has advanced to early phase clinical trials, based upon proof-of-concept data indicating that gene therapy could surpass the benefits of the current standard of care, enzyme replacement therapy (ERT). ERT requires frequent in ... Full text Link to item Cite

Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia.

Journal Article Mol Ther Methods Clin Dev · June 14, 2019 Featured Publication Glycogen storage disease type Ia (GSD Ia) is a rare inherited disease caused by mutations in the glucose-6-phosphatase (G6Pase) catalytic subunit gene (G6PC). Absence of G6Pase causes life-threatening hypoglycemia and long-term complications because of the ... Full text Open Access Link to item Cite

Erratum: Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction (Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction (2017) 4 (126–136), (S2329050117300049), (10.1016/j.omtm.2016.12.010))

Journal Article Molecular Therapy Methods and Clinical Development · June 14, 2019 (Molecular Therapy - Methods & Clinical Development 4, 126–136; March 17, 2017) An incorrect version of Figure 1E appeared in the published article due to an error in the calculation of plasma GAA. The correct figure appears below. [Figure Presented] ... Full text Cite

Bezafibrate induces autophagy and improves hepatic lipid metabolism in glycogen storage disease type Ia.

Journal Article Hum Mol Genet · January 1, 2019 Glucose-6-phosphatase α (G6Pase) deficiency, also known as von Gierke's Disease or Glycogen storage disease type Ia (GSD Ia), is characterized by decreased ability of the liver to convert glucose-6-phosphate to glucose leading to glycogen accumulation and ... Full text Link to item Cite

Long-term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy.

Conference J Inherit Metab Dis · November 2018 BACKGROUND: Glycogen storage disease type Ia (GSD Ia) in dogs closely resembles human GSD Ia. Untreated patients with GSD Ia develop complications associated with glucose-6-phosphatase (G6Pase) deficiency. Survival of human patients on intensive nutritiona ... Full text Link to item Cite

IRF2BPL Is Associated with Neurological Phenotypes.

Journal Article Am J Hum Genet · September 6, 2018 Full text Link to item Cite

Correction of Biochemical Abnormalities and Improved Muscle Function in a Phase I/II Clinical Trial of Clenbuterol in Pompe Disease.

Journal Article Mol Ther · September 5, 2018 This 52-week, phase I/II double-blind, randomized, placebo-controlled study investigated the novel use of clenbuterol in late-onset Pompe disease (LOPD) stably treated with ERT. Eleven of thirteen participants completed the study. No serious adverse events ... Full text Link to item Cite

IRF2BPL Is Associated with Neurological Phenotypes.

Journal Article Am J Hum Genet · August 2, 2018 Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Her ... Full text Link to item Cite

Treatment outcome of creatine transporter deficiency: international retrospective cohort study.

Journal Article Metab Brain Dis · June 2018 To evaluate the outcome of current treatment for creatine transporter (CRTR) deficiency, we developed a clinical severity score and initiated an international treatment registry. An online questionnaire was completed by physicians following patients with C ... Full text Link to item Cite

Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: An international retrospective cohort study.

Journal Article Eur J Paediatr Neurol · May 2018 PURPOSE: Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder caused by pathogenic variants in GAMT. Brain creatine depletion and guanidinoacetate accumulation cause developmental delay, seizures and movement disorder. Tr ... Full text Link to item Cite

CLINICAL COURSE AND OUTCOME IN ADULTS WITH PROPIONIC ACIDEMIA: CASE SERIES

Conference MOLECULAR GENETICS AND METABOLISM · March 1, 2018 Link to item Cite

OVERVIEW OF NUCLEIC ACID THERAPIES

Conference MOLECULAR GENETICS AND METABOLISM · March 1, 2018 Link to item Cite

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase.

Journal Article Sci Transl Med · November 29, 2017 Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid α-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. Enzyme replacement therap ... Full text Link to item Cite

Renal endoplasmic reticulum stress is coupled to impaired autophagy in a mouse model of GSD Ia.

Journal Article Molecular genetics and metabolism · November 2017 GSD Ia (von Gierke Disease, Glycogen Storage Disease Type Ia) is a devastating genetic disorder with long-term sequelae, such as non-alcoholic fatty liver disease and renal failure. Down-regulated autophagy is involved in the development of hepatic metabol ... Full text Cite

Albuterol as an adjunctive treatment to enzyme replacement therapy in infantile-onset Pompe disease.

Journal Article Mol Genet Metab Rep · June 2017 BACKGROUND: Early initiation of enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase is an effective treatment for patients with infantile-onset Pompe disease (IOPD) but cannot prevent a slow progression of myopathy. Albuterol has ... Full text Link to item Cite

Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa).

Journal Article Sci Rep · March 20, 2017 Featured Publication Glycogen storage disease type Ia (GSDIa, von Gierke disease) is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, an enzyme which catalyses the final step of gluconeogenesis and glycogenolysis. Clinically, ... Full text Open Access Link to item Cite

Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction.

Journal Article Mol Ther Methods Clin Dev · March 17, 2017 Pompe disease results from acid α-glucosidase (GAA) deficiency, and enzyme replacement therapy (ERT) with recombinant human (rh) GAA has clinical benefits, although its limitations include the short half-life of GAA and the formation of antibody responses. ... Full text Link to item Cite

Beneficial effects of carvedilol with enzyme replacement therapy in Pompe disease

Conference Molecular Genetics and Metabolism · January 2017 Full text Cite

221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative.

Journal Article Mol Genet Metab · September 2016 INTRODUCTION: There is limited understanding of relationships between genotype, phenotype and other conditions contributing to health in neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) identified through newborn screening. METHO ... Full text Link to item Cite

Vision of correction for classic homocystinuria.

Journal Article J Clin Invest · June 1, 2016 Inherited metabolic disorders are often characterized by the lack of an essential enzyme and are currently treated by dietary restriction and other strategies to replace the substrates or products of the missing enzyme. Patients with homocystinuria lack th ... Full text Link to item Cite

Salmeterol enhances the cardiac response to gene therapy in Pompe disease.

Journal Article Mol Genet Metab · May 2016 Enzyme replacement therapy (ERT) with recombinant human (rh) acid α-glucosidase (GAA) has prolonged the survival of patients. However, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up ... Full text Open Access Link to item Cite

In Vivo Zinc Finger Nuclease-mediated Targeted Integration of a Glucose-6-phosphatase Transgene Promotes Survival in Mice With Glycogen Storage Disease Type IA.

Journal Article Mol Ther · April 2016 Featured Publication Glycogen storage disease type Ia (GSD Ia) is caused by glucose-6-phosphatase (G6Pase) deficiency in association with severe, life-threatening hypoglycemia that necessitates lifelong dietary therapy. Here we show that use of a zinc-finger nuclease (ZFN) tar ... Full text Link to item Cite

A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease.

Journal Article Mol Genet Metab · February 2016 Featured Publication UNLABELLED: Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) fails to completely reverse muscle weakness in Pompe disease. β2-agonists enhanced ERT by increasing receptor-mediated uptake of rhGAA in skeletal muscles. PURPO ... Full text Link to item Cite

Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency.

Journal Article J Hepatol · February 2016 Featured Publication BACKGROUND & AIMS: Glucose-6-phosphatase (G6Pase α, G6PC) deficiency, also known as von Gierke's disease or GSDIa, is the most common glycogen storage disorder. It is characterized by a decreased ability of the liver to convert glucose-6-phosphate (G6P) to ... Full text Link to item Cite

Synergistic Efficacy from Gene Therapy with Coreceptor Blockade and a β2-Agonist in Murine Pompe Disease.

Journal Article Hum Gene Ther · November 2015 Pompe disease (glycogen storage disease type II; acid maltase deficiency) is a devastating myopathy resulting from acid α-glucosidase (GAA) deficiency in striated and smooth muscle. Despite the availability of enzyme replacement therapy (ERT) with recombin ... Full text Link to item Cite

Complex III deficiency due to an in-frame MT-CYB deletion presenting as ketotic hypoglycemia and lactic acidosis.

Journal Article Mol Genet Metab Rep · September 2015 Featured Publication Complex III deficiency due to a MT-CYB mutation has been reported in patients with myopathy. Here, we describe a 15-year-old boy who presented with metabolic acidosis, ketotic hypoglycemia and carnitine deficiency. Electron transport chain analysis and mit ... Full text Link to item Cite

Large animal models and new therapies for glycogen storage disease.

Journal Article J Inherit Metab Dis · May 2015 Glycogen storage diseases (GSD), a unique category of inherited metabolic disorders, were first described early in the twentieth century. Since then, the biochemical and genetic bases of these disorders have been determined, and an increasing number of ani ... Full text Link to item Cite

The heart is just a muscle.

Journal Article Circulation · March 10, 2015 Featured Publication Full text Link to item Cite

A natural choice for hemophilia B.

Journal Article Blood · March 5, 2015 In this issue of Blood, Crudele et al describe a novel study of adeno-associated virus (AAV) vector-mediated gene therapy that induced immune tolerance to factor IX (FIX) in a hemophilia B (HB) dog with previously formed anti-FIX inhibitor antibodies (IAs) ... Full text Link to item Cite

Preclinical Development of New Therapy for Glycogen Storage Diseases.

Journal Article Curr Gene Ther · 2015 Featured Publication Glycogen storage disease (GSD) consists of more than 10 discrete conditions for which the biochemical and genetic bases have been determined, and new therapies have been under development for several of these conditions. Gene therapy research has generated ... Full text Open Access Link to item Cite

Enhanced efficacy from gene therapy in Pompe disease using coreceptor blockade.

Journal Article Hum Gene Ther · January 2015 Enzyme replacement therapy (ERT) is the standard-of-care treatment of Pompe disease, a lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA). One limitation of ERT with recombinant human (rh) GAA is antibody formation against GAA. Sim ... Full text Link to item Cite

Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics.

Journal Article Genet Med · November 2014 PURPOSE: Glycogen storage disease type I (GSD I) is a rare disease of variable clinical severity that primarily affects the liver and kidney. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal ... Full text Link to item Cite

Identification of differentially expressed microRNAs in human hepatocellular adenoma associated with type I glycogen storage disease: a potential utility as biomarkers.

Journal Article J Gastroenterol · August 2014 BACKGROUND: It is known that malignant transformation to hepatocellular carcinoma (HCC) occurs at a higher frequency in hepatocellular adenoma (HCA) from type I glycogen storage disease (GSD I) compared to HCA from other etiologies. In this study, we aimed ... Full text Link to item Cite

Adjunctive albuterol enhances the response to enzyme replacement therapy in late-onset Pompe disease.

Journal Article FASEB J · May 2014 Effective dosages for enzyme replacement therapy (ERT) in Pompe disease are much higher than for other lysosomal storage disorders, which has been attributed to low cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle. We have previo ... Full text Open Access Link to item Cite

Adjunctive β2-agonist treatment reduces glycogen independently of receptor-mediated acid α-glucosidase uptake in the limb muscles of mice with Pompe disease.

Journal Article FASEB J · May 2014 Enzyme or gene replacement therapy with acid α-glucosidase (GAA) has achieved only partial efficacy in Pompe disease. We evaluated the effect of adjunctive clenbuterol treatment on cation-independent mannose-6-phosphate receptor (CI-MPR)-mediated uptake an ... Full text Open Access Link to item Cite

Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease.

Journal Article Mol Ther Methods Clin Dev · 2014 Featured Publication A preclinical safety study was conducted to evaluate the short- and long-term toxicity of a recombinant adeno-associated virus serotype 8 (AAV2/8) vector that has been developed as an immune-modulatory adjunctive therapy to recombinant human acid α-glucosi ... Full text Open Access Link to item Cite

The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia.

Journal Article Mol Genet Metab · November 2013 Glycogen storage disease type-Ia (GSD-Ia) patients deficient in glucose-6-phosphatase-α (G6Pase-α or G6PC) manifest impaired glucose homeostasis characterized by fasting hypoglycemia, growth retardation, hepatomegaly, nephromegaly, hyperlipidemia, hyperuri ... Full text Open Access Link to item Cite

Elevation of guanidinoacetate in newborn dried blood spots and impact of early treatment in GAMT deficiency.

Journal Article Mol Genet Metab · June 2013 Guanidinoacetate methyltransferase (GAMT) deficiency is a good candidate disorder for newborn screening because early treatment appears to improve outcomes. We report elevation of guanidinoacetate in archived newborn dried blood spots for 3 cases (2 famili ... Full text Link to item Cite

Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia.

Journal Article Mol Genet Metab · June 2013 Featured Publication Glycogen Storage Disease type Ia (GSD-Ia) in humans frequently causes delayed bone maturation, decrease in final adult height, and decreased growth velocity. This study evaluates the pathogenesis of growth failure and the effect of gene therapy on growth i ... Full text Open Access Link to item Cite

Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease.

Journal Article FASEB J · January 2013 Featured Publication Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-agonist drugs, which increased CI-MPR ex ... Full text Open Access Link to item Cite

Enhanced gene expression of systemically administered plasmid DNA in the liver with therapeutic ultrasound and microbubbles.

Journal Article IEEE Trans Ultrason Ferroelectr Freq Control · January 2013 Ultrasound-mediated delivery (USMD) of novel therapeutic agents in the presence of microbubbles is a potentially safe and effective method for gene therapy offering many desired characteristics, such as low toxicity, potential for repeated treatment, and o ... Full text Link to item Cite

Characterization of a canine model of glycogen storage disease type IIIa.

Journal Article Dis Model Mech · November 2012 Glycogen storage disease type IIIa (GSD IIIa) is an autosomal recessive disease caused by deficiency of glycogen debranching enzyme (GDE) in liver and muscle. The disorder is clinically heterogeneous and progressive, and there is no effective treatment. Pr ... Full text Open Access Link to item Cite

Aerobic training as an adjunctive therapy to enzyme replacement in Pompe disease.

Journal Article Mol Genet Metab · November 2012 BACKGROUND: Aerobic exercise may be used in conjunction with enzyme replacement therapy (ERT) to attenuate cardiovascular deconditioning, skeletal muscle wasting, and loss of motor function in Pompe disease (glycogen storage disease type II; GSDII), but th ... Full text Link to item Cite

QUANTIFICATION OF GLYCOSAMINOGLYCANS IN HUMAN URINE AND MOUSE TISSUE BY UPLC-MS/MS

Journal Article JOURNAL OF INHERITED METABOLIC DISEASE · September 1, 2012 Link to item Cite

In search of proof-of-concept: gene therapy for glycogen storage disease type Ia.

Journal Article J Inherit Metab Dis · July 2012 The emergence of life threatening long-term complications in glycogen storage disease type Ia (GSD-Ia) has emphasized the need for new therapies, such as gene therapy, which could achieve biochemical correction of glucose-6-phosphatase deficiency and rever ... Full text Link to item Cite

Deficiency in MyD88 Signaling Results in Decreased Antibody Responses to an Adeno-Associated Virus Vector in Murine Pompe Disease.

Journal Article Biores Open Access · June 2012 We have previously shown that antibody and T cell responses limit the efficacy of an adeno-associated virus (AAV) pseudotype 8 (2/8) vector containing the universally active cytomegalovirus enhancer/chicken β-actin regulatory cassette (AAV2/8-CBhGAA) in tr ... Full text Link to item Cite

Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease.

Journal Article Hum Gene Ther · May 2012 Featured Publication Pompe disease can be treated effectively, if immune tolerance to enzyme replacement therapy (ERT) with acid α-glucosidase (GAA) is present. An adeno-associated viral (AAV) vector carrying a liver-specific regulatory cassette to drive GAA expression (AAV-LS ... Full text Open Access Link to item Cite

Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia.

Journal Article Gene Ther · April 2012 Glycogen storage disease type Ia (GSD-Ia) stems from glucose-6-phosphatase (G6Pase) deficiency and causes hypoglycemia, hepatomegaly, hypercholesterolemia and lactic acidemia. Three dogs with GSD-Ia were initially treated with a helper-dependent adenovirus ... Full text Link to item Cite

Long-term efficacy following readministration of an adeno-associated virus vector in dogs with glycogen storage disease type Ia.

Journal Article Hum Gene Ther · April 2012 Featured Publication Glycogen storage disease type Ia (GSD-Ia) is the inherited deficiency of glucose-6-phosphatase (G6Pase), primarily found in liver and kidney, which causes life-threatening hypoglycemia. Dogs with GSD-Ia were treated with double-stranded adeno-associated vi ... Full text Link to item Cite

β2 Agonists enhance the efficacy of simultaneous enzyme replacement therapy in murine Pompe disease.

Journal Article Mol Genet Metab · February 2012 Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor r ... Full text Link to item Cite

Hepatorenal correction in murine glycogen storage disease type I with a double-stranded adeno-associated virus vector.

Journal Article Mol Ther · November 2011 Featured Publication Glycogen storage disease type Ia (GSD-Ia) is caused by the deficiency of glucose-6-phosphatase (G6Pase). Long-term complications of GSD-Ia include life-threatening hypoglycemia and proteinuria progressing to renal failure. A double-stranded (ds) adeno-asso ... Full text Link to item Cite

Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle.

Journal Article Mol Genet Metab · June 2011 Enzyme replacement therapy (ERT) with acid α-glucosidase has become available for Pompe disease; however, the response of skeletal muscle, as opposed to the heart, has been attenuated. The poor response of skeletal muscle has been attributed to the low abu ... Full text Open Access Link to item Cite

Metabolic myopathies: clinical features and diagnostic approach.

Journal Article Rheum Dis Clin North Am · May 2011 The rheumatologist is frequently called on to evaluate patients with complaints of myalgia, muscle cramps, and fatigue. The evaluation of these patients presents a diagnostic challenge given the nonspecific and intermittent nature of their complaints, ofte ... Full text Link to item Cite

Hydrostatic isolated limb perfusion with adeno-associated virus vectors enhances correction of skeletal muscle in Pompe disease.

Journal Article Gene Ther · December 2010 Glycogen storage disease type II (Pompe disease; MIM 232300) stems from the inherited deficiency of acid-α-glucosidase (GAA; acid maltase; EC 3.2.1.20), which primarily involves cardiac and skeletal muscles. We hypothesized that hydrostatic isolated limb p ... Full text Open Access Link to item Cite

Enhanced gene transfection of plasmid DNA in the liver with ultrasound and microbubbles

Journal Article Proceedings - IEEE Ultrasonics Symposium · December 1, 2010 Ultrasound mediated delivery (USMD) in the presence of microbubbles is a potentially safe and effective method for gene therapy, offering many desired characteristics such as low toxicity, potential for repeated treatment, as well as organ specificity. In ... Full text Cite

Antibody formation and mannose-6-phosphate receptor expression impact the efficacy of muscle-specific transgene expression in murine Pompe disease.

Journal Article J Gene Med · November 2010 BACKGROUND: Lysosomal storage disorders such as Pompe disease can be more effectively treated, if immune tolerance to enzyme or gene replacement therapy can be achieved. Alternatively, immune responses against acid α-glucosidase (GAA) might be evaded in Po ... Full text Open Access Link to item Cite

The role of hepatocyte hemojuvelin in the regulation of bone morphogenic protein-6 and hepcidin expression in vivo.

Journal Article J Biol Chem · May 28, 2010 Both hemojuvelin (HJV) and bone morphogenic protein-6 (BMP6) are essential for hepcidin expression. Hepcidin is the key peptide hormone in iron homeostasis, and is secreted predominantly by hepatocytes. HJV expression is detected in hepatocytes, as well as ... Full text Link to item Cite

Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice.

Journal Article Blood · April 22, 2010 Hereditary hemochromatosis is caused by mutations in the hereditary hemochromatosis protein (HFE), transferrin-receptor 2 (TfR2), hemojuvelin, hepcidin, or ferroportin genes. Hepcidin is a key iron regulator, which is secreted by the liver, and decreases s ... Full text Link to item Cite

Stone forming risk factors in patients with type Ia glycogen storage disease.

Journal Article J Urol · March 2010 PURPOSE: Patients with type Ia glycogen storage disease have an increased recurrent nephrolithiasis rate. We identified stone forming risk factors in patients with type Ia glycogen storage disease vs those in stone formers without the disease. MATERIALS AN ... Full text Link to item Cite

Immunomodulatory gene therapy prevents antibody formation and lethal hypersensitivity reactions in murine pompe disease.

Journal Article Mol Ther · February 2010 Featured Publication Infantile Pompe disease progresses to a lethal cardiomyopathy in absence of effective treatment. Enzyme-replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA) has been effective in most patients with Pompe disease, but efficacy was ... Full text Link to item Cite

Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants.

Journal Article Mol Genet Metab · January 2010 Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy. Patients synthesize a non-functional form of GAA or are unable to form native enzyme. Enzyme replacement therapy with recombinant human GAA ... Full text Link to item Cite

Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease.

Journal Article Hum Mol Genet · December 15, 2009 Hepatocellular adenoma (HCA) is a frequent long-term complication of glycogen storage disease type I (GSD I) and malignant transformation to hepatocellular carcinoma (HCC) is known to occur in some cases. However, the molecular pathogenesis of tumor develo ... Full text Link to item Cite

Immunomodulatory gene therapy in lysosomal storage disorders.

Journal Article Curr Gene Ther · December 2009 Significant advances in therapy for lysosomal storage disorders have occurred with an accelerating pace over the past decade. Although enzyme replacement therapy has improved the outcome of lysosomal storage disorders, antibody responses have occurred and ... Full text Link to item Cite

Impaired clearance of accumulated lysosomal glycogen in advanced Pompe disease despite high-level vector-mediated transgene expression.

Journal Article J Gene Med · October 2009 Featured Publication BACKGROUND: Infantile-onset glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) causes death early in childhood from cardiorespiratory failure in the absence of effective treatment, whereas late-onset Pompe disease causes a progressive ske ... Full text Link to item Cite

Liver transplantation for glycogen storage disease type Ia.

Journal Article J Hepatol · September 2009 BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) most often occurs within hepatocellular adenomas (HCAs) in glycogen storage disease Ia (GSD Ia) patients. The objective of this retrospective study is to assess outcomes after liver transplantation (LT) for G ... Full text Link to item Cite

Activation of glycolysis and apoptosis in glycogen storage disease type Ia.

Journal Article Mol Genet Metab · August 2009 Featured Publication The deficiency of glucose-6-phosphatase (G6Pase) underlies glycogen storage disease type Ia (GSD-Ia, von Gierke disease; MIM 232200), an autosomal recessive disorder of metabolism associated with life-threatening hypoglycemia, growth retardation, renal fai ... Full text Link to item Cite

Emerging therapies for glycogen storage disease type I.

Journal Article Trends Endocrinol Metab · July 2009 Featured Publication Glycogen storage disease type I (GSD I) is caused by deficiency of the glucose-6-phosphatase catalytic subunit in type Ia or of glucose-6-phosphate transporter in type Ib. The cellular bases for disruptions of homeostasis have been increasingly understood ... Full text Link to item Cite

Gene therapy for inherited metabolic disorders in companion animals.

Journal Article ILAR J · 2009 Scientists first described inborn errors of metabolism, also termed inherited disorders of metabolism, early in the 20th century and since then have determined the biochemical and genetic bases of a great number of these disorders both in humans and in an ... Full text Link to item Cite

Improvement with ongoing Enzyme Replacement Therapy in advanced late-onset Pompe disease: a case study.

Journal Article Mol Genet Metab · December 2008 Benefits of enzyme replacement therapy with Myozyme (alglucosidase alfa), anecdotally reported in late-onset Pompe disease, range from motor and pulmonary improvement in less severely affected patients, to stabilization with minimal improvement in those wi ... Full text Link to item Cite

Correction of multiple striated muscles in murine Pompe disease through adeno-associated virus-mediated gene therapy.

Journal Article Mol Ther · August 2008 Featured Publication Glycogen storage disease type II (Pompe disease; MIM 232300) stems from the deficiency of acid alpha-glucosidase (GAA; acid maltase; EC 3.2.1.20), which primarily involves cardiac and skeletal muscles. An adeno-associated virus 2/8 (AAV2/8) vector containi ... Full text Link to item Cite

A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency.

Journal Article Mol Genet Metab · April 2008 Featured Publication 3-MCC deficiency is among the most common inborn errors of metabolism identified on expanded newborn screening (1:36,000 births). However, evidence-based guidelines for diagnosis and management of this disorder are lacking. Using the traditional Delphi met ... Full text Link to item Cite

AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia.

Journal Article Mol Ther · April 2008 Featured Publication Glycogen storage disease type Ia (GSD-Ia) profoundly impairs glucose release by the liver due to glucose-6-phosphatase (G6Pase) deficiency. An adeno-associated virus (AAV) containing a small human G6Pase transgene was pseudotyped with AAV8 (AAV2/8) to opti ... Full text Link to item Cite

Efforts to enhance AAV8-mediated gene therapy of Pompe disease

Conference CLINICAL THERAPEUTICS · January 1, 2008 Link to item Cite

Pompe's disease: Enzyme replacement therapy

Journal Article Drugs of the Future · December 1, 2007 The approval of Myozyme® (alglucosidase alfa; Genzyme) represented the first significant advance in therapy for Pompe's disease. Pompe's disease is the inherited deficiency of acid α-glucosidase (GAA), and hence the rationale for treatment with Myozyme®, a ... Full text Cite

Boosting evolutionary support vector machine for designing tumor classifiers from microarray data

Conference 2007 IEEE Symposium on Computational Intelligence and Bioinformatics and Computational Biology, CIBCB 2007 · December 1, 2007 Since there are multiple sets of relevant genes having the same high accuracy in fitting training data called model uncertainty, to identify a small set of informative genes from microarray data for designing an accurate tumor classifier for unknown sample ... Cite

Resection of hepatocellular adenoma in patients with glycogen storage disease type Ia.

Journal Article J Hepatol · November 2007 BACKGROUND/AIMS: Because dietary modifications have prolonged the life expectancy of patients with glycogen storage disease type Ia (GSD Ia), the incidence of hepatocellular adenoma (HCA) to carcinoma (HCC) transformation is increasing. The objective of th ... Full text Link to item Cite

Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance.

Journal Article Am J Hum Genet · November 2007 Featured Publication Pompe disease, which results from mutations in the gene encoding the glycogen-degrading lysosomal enzyme acid alpha -glucosidase (GAA) (also called "acid maltase"), causes death in early childhood related to glycogen accumulation in striated muscle and an ... Full text Link to item Cite

Three successful pregnancies through dietary management of fructose-1,6-bisphosphatase deficiency.

Journal Article J Inherit Metab Dis · October 2007 Fructose-1,6-bisphosphatase (FBPase) deficiency (OMIM 229700) has been characterized as the cause of life-threatening hypoglycaemia and lactic acidaemia following prolonged fasting. The patient, an adult African-American woman, presented during the second ... Full text Link to item Cite

Efficacy of helper-dependent adenovirus vector-mediated gene therapy in murine glycogen storage disease type Ia.

Journal Article Mol Ther · July 2007 Featured Publication Genetic deficiency of glucose-6-phosphatase (G6Pase) underlies glycogen storage disease type Ia (GSD-Ia, also known as von Gierke disease; MIM 232200), an autosomal recessive disorder of metabolism associated with life-threatening hypoglycemia and growth r ... Full text Link to item Cite

Efficacy of gene therapy in canine glycogen storage disease type IA.

Journal Article JOURNAL OF VETERINARY INTERNAL MEDICINE · May 1, 2007 Link to item Cite

Glycogen storage disease types I and II: treatment updates.

Journal Article J Inherit Metab Dis · April 2007 Featured Publication Prior to 2006 therapy for glycogen storage diseases consisted primarily of dietary interventions, which in the case of glycogen storage disease (GSD) type II (GSD II; Pompe disease) remained essentially palliative. Despite improved survival and growth, lon ... Full text Link to item Cite

Lysosomal storage and transport disorders

Chapter · January 1, 2007 Lysosomes were discovered in 1959 through a series of brilliant investigations by de Duve and coworkers (14,15). These cytoplasmic organelles, ubiquitous in distribution in living cells, show great diversity in form, origin, and function. Varying in diamet ... Cite

Disorders of amino acid metabolism

Chapter · January 1, 2007 Of the many genetic disorders that express themselves as specific defects of amino acid metabolism, some, including two of Garrod’s four original “inborn errors of metabolism” (albinism, alkaptonuria), produce significant abnormalities in the ocular tissue ... Cite

Mucolipidoses

Chapter · January 1, 2007 First delineated by Spranger and Wiedemann (36) in 1970, the seven or eight entities originally described shared clinical and radiographical features of both the mucopolysaccharidoses (MPSs) (see Chapter 40) and the sphingolipidoses (see Chapter 41); hence ... Cite

Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II.

Journal Article Mol Ther · December 2006 Featured Publication Glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) is an inherited muscular dystrophy caused by deficiency in the activity of the lysosomal enzyme acid alpha-glucosidase (GAA). We hypothesized that chimeric GAA containing an alternative s ... Full text Link to item Cite

Clinical experience with array CGH: case presentations from nine months of practice.

Journal Article Am J Med Genet A · October 1, 2006 A total of 124 individuals were tested in the initial 9 months that array CGH technology was offered to clinical genetics patients. In 11 of these patients array CGH identified a previously unsuspected diagnosis. A suspected diagnosis was confirmed in thre ... Full text Link to item Cite

Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia.

Journal Article Gene Ther · September 2006 The deficiency of glucose-6-phosphatase (G6Pase) underlies life-threatening hypoglycemia and growth retardation in glycogen storage disease type Ia (GSD-Ia). An adeno-associated virus (AAV) vector encoding G6Pase was pseudotyped as AAV8 and administered to ... Full text Link to item Cite

Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening.

Journal Article Pediatr Res · September 2006 The isobutyryl-CoA dehydrogenase (IBD) enzyme is involved in the degradation of valine. IBD deficiency was first reported in 1998 and subsequent genetic investigations identified acyl-CoA dehydrogenase (ACAD) 8, now IBD, as the gene responsible for IBD def ... Full text Link to item Cite

Glycogen storage disease type I and type II: Treatment updates

Journal Article JOURNAL OF INHERITED METABOLIC DISEASE · August 1, 2006 Link to item Cite

Glutaric acidemia type 1 in patients of Lumbee heritage from North Carolina.

Journal Article Mol Genet Metab · May 2006 Glutaric acidemia type I (GA-I) is an autosomal recessive disorder of the catabolism of lysine, hydroxylysine, and tryptophan caused by deficiency of glutaryl-CoA dehydrogenase (GCD). Among our patients with GA-I, we noted a prevalence of Lumbee individual ... Full text Link to item Cite

Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria.

Journal Article Gene Ther · March 2006 Featured Publication Novel recombinant adeno-associated virus vectors pseudotyped with serotype 8 capsid (rAAV2/8) have recently shown exciting promise as effective liver-directed gene transfer reagents. We have produced a novel liver-specific rAAV2/8 vector expressing the mou ... Full text Link to item Cite

The tandem mass spectrometry newborn screening experience in North Carolina: 1997-2005.

Journal Article J Inherit Metab Dis · February 2006 North Carolina (NC) was the first US state to initiate universal tandem mass spectrometry (MS/MS) newborn screening. This began as a statewide pilot project in 1997 to determine the incidence and feasibility of screening for fatty acid oxidation, organic a ... Full text Link to item Cite

Evasion of immune responses to introduced human acid alpha-glucosidase by liver-restricted expression in glycogen storage disease type II.

Journal Article Mol Ther · November 2005 Featured Publication Glycogen storage disease type II (GSD-II; Pompe disease) is caused by a deficiency of acid alpha-glucosidase (GAA; acid maltase) and manifests as muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. Adeno-associated virus vectors containi ... Full text Link to item Cite

Correction of glycogen storage disease type II by an adeno-associated virus vector containing a muscle-specific promoter.

Journal Article Mol Ther · June 2005 Featured Publication Glycogen storage disease type II (Pompe disease) causes death in infancy from cardiorespiratory failure due to acid alpha-glucosidase (GAA; acid maltase) deficiency. An AAV2 vector pseudotyped as AAV6 (AAV2/6 vector) transiently expressed high-level human ... Full text Link to item Cite

Efficacy of an adeno-associated virus 8-pseudotyped vector in glycogen storage disease type II.

Journal Article Mol Ther · January 2005 Featured Publication Glycogen storage disease type II (GSD-II; Pompe disease) causes death in infancy from cardiorespiratory failure. The underlying deficiency of acid alpha-glucosidase (GAA; acid maltase) can be corrected by liver-targeted gene therapy in GSD-II, if secretion ... Full text Link to item Cite

A comparison of in vitro acylcarnitine profiling methods for the diagnosis of classical and variant short chain acyl-CoA dehydrogenase deficiency.

Journal Article Clin Chim Acta · November 2003 BACKGROUND: Homozygosity and compound heterozygosity for the short chain acyl-CoA dehydrogenase (SCAD) gene sequence variants 625G-->A and 511C-->T are associated with ethylmalonic aciduria (EMA), a biochemical indicator of SCAD deficiency. The clinical an ... Full text Link to item Cite

Rare disorders of metabolism with elevated butyryl- and isobutyryl-carnitine detected by tandem mass spectrometry newborn screening.

Journal Article Pediatr Res · August 2003 Featured Publication Tandem mass spectrometry was adopted for newborn screening by North Carolina in April 1999. Since then, three infants with short-chain acyl-CoA dehydrogenase (SCAD) and one with isobutyryl-CoA dehydrogenase deficiency were detected on the basis of elevated ... Full text Link to item Cite

Packaging of an AAV vector encoding human acid alpha-glucosidase for gene therapy in glycogen storage disease type II with a modified hybrid adenovirus-AAV vector.

Journal Article Mol Ther · April 2003 Featured Publication We have developed an improved method for packaging adeno-associated virus (AAV) vectors with a replication-defective adenovirus-AAV (Ad-AAV) hybrid virus. The AAV vector encoding human acid alpha-glucosidase (hGAA) was cloned into an E1, polymerase/preterm ... Full text Link to item Cite

Long-term correction of glycogen storage disease type II with a hybrid Ad-AAV vector.

Journal Article Mol Ther · February 2003 Featured Publication We administered an adenovirus-adeno-associated virus (Ad-AAV) vector encoding human acid alpha-glucosidase (hGAA) to acid alpha-glucosidase-knockout (GAA-KO) mice on day 3 of life by gastrocnemius injection. In contrast to previous results for muscle-targe ... Full text Link to item Cite

Evaluation of 3-methylcrotonyl-CoA carboxylase deficiency detected by tandem mass spectrometry newborn screening.

Journal Article J Inherit Metab Dis · 2003 Since the addition of tandem mass spectrometry (MS/MS) to the North Carolina Newborn Screening Program, 20 infants with two consecutive elevated 3-hydroxyisovalerylcarnitine (C5OH) levels have been evaluated for evidence of inborn errors of metabolism asso ... Full text Link to item Cite

Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors.

Journal Article Gene Ther · August 2002 Featured Publication Therapy in glycogen storage disease type Ia (GSD Ia), an inherited disorder of carbohydrate metabolism, relies on nutritional support that postpones but fails to prevent long-term complications of GSD Ia. In the canine model for GSD Ia, we evaluated the po ... Full text Link to item Cite

Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons.

Journal Article Ann Neurol · April 2002 Multiple gene defects cause Batten disease. Accelerated apoptosis accounts for neurodegeneration in the late infantile and juvenile forms that are due to defects in the CLN3 and CLN2 genes. Extensive neuronal death is seen in CLN2- and CLN3-deficient human ... Full text Link to item Cite

Glutaric acidemia, type I, missed by newborn screening in an infant with dystonia following promethazine administration.

Journal Article Pediatrics · May 2001 Featured Publication We report a child initially diagnosed with promethazine-induced dystonia despite a lack of response to diphenhydramine therapy. On further evaluation, the child was diagnosed with glutaric acidemia, type I (GA-I), an autosomal recessive inborn error of met ... Full text Link to item Cite

Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia).

Journal Article Vet Pathol · January 2001 A canine model of glycogen storage disease Ia (GSD Ia), similar clinically, biochemically, and pathologically to the human disease, was established by crossbreeding Maltese and Beagle dogs carrying a mutated, defective glucose-6-phosphatase (G-6-Pase) gene ... Full text Link to item Cite

Systemic production of human granulocyte colony-stimulating factor in nonhuman primates by transplantation of genetically modified myoblasts.

Journal Article Hum Gene Ther · June 10, 2000 Clinical use of human granulocyte-colony stimulating factor (hG-CSF) to treat various diseases involving neutropenia has been previously shown to (1) successfully increase circulating neutrophils, (2) reduce condition-related infections, and (3) cause few ... Full text Link to item Cite

Persistent, therapeutically relevant levels of human granulocyte colony-stimulating factor in mice after systemic delivery of adeno-associated virus vectors.

Journal Article Hum Gene Ther · September 1, 1999 Featured Publication Adeno-associated virus (AAV) vectors have been shown to preferentially transduce hepatocytes after systemic administration in adult mice and to provide long-term expression of introduced genes. One application of this technology would be for the production ... Full text Link to item Cite

Persistent expression of human clotting factor IX from mouse liver after intravenous injection of adeno-associated virus vectors.

Journal Article Proc Natl Acad Sci U S A · February 18, 1997 Featured Publication We previously found that gene transduction by adeno-associated virus (AAV) vectors in cell culture can be stimulated over 100-fold by treatment of the target cells with agents that affect DNA metabolism, such as irradiation or topoisomerase inhibitors. Her ... Full text Link to item Cite

Prenatal diagnosis of 45,X/46,XX.

Journal Article Am J Hum Genet · March 1996 Link to item Cite

Prenatal diagnosis of 45,X/46,XX mosaicism and 45,X: implications for postnatal outcome.

Journal Article Am J Hum Genet · September 1995 Featured Publication The prognosis for 45,X/46,XX mosaicism diagnosed prenatally has yet to be established. We report our experience with 12 patients in whom prenatal diagnosis of 45,X/46,XX mosaicism was detected by amniocentesis for advanced maternal age or decreased materna ... Link to item Cite

Sequences within the coding regions of clotting factor VIII and CFTR block transcriptional elongation.

Journal Article Hum Gene Ther · April 1995 The clotting factor VIII (FVIII) and cystic fibrosis transmembrane conductance regulator (CFTR) cDNAs have dramatically reduced levels of expression compared to clotting factor IX (FIX) and other cDNAs (100 and 1,000-fold lower, respectively), when produce ... Full text Link to item Cite

T296----M, a common mutation causing mild hemophilia B in the Amish and others: founder effect, variability in factor IX activity assays, and rapid carrier detection.

Journal Article Hum Genet · July 1991 By direct genomic sequencing, we have delineated the causative mutation in 64 families of European decent with hemophilia B. Six (9%) had a C----T transition at base 31008, which substitutes methionine for threonine 296 (T296----M) in the catalytic domain ... Full text Link to item Cite

Mutations causing hemophilia B: direct estimate of the underlying rates of spontaneous germ-line transitions, transversions, and deletions in a human gene.

Journal Article Am J Hum Genet · August 1990 Featured Publication Spontaneous mutation provides the substrate for evolution on one hand and for genetic susceptibility to disease on the other hand. X-linked diseases such as hemophilia B offer an opportunity to examine recent germ-line mutations in humans. By utilizing the ... Link to item Cite

A past mutation at isoleucine 397 is now a common cause of moderate/mild haemophilia B.

Journal Article Br J Haematol · June 1990 Of the factor IX sequence changes that we have identified in 65 consecutive males with haemophilia B, 11 (17%) are the same mutation. This mutation is a T----C transition at base 31311 which substitutes threonine for isoleucine397 (ile397) in the factor IX ... Full text Link to item Cite

Recurrent nonsense mutations at arginine residues cause severe hemophilia B in unrelated hemophiliacs.

Journal Article Hum Genet · April 1990 Direct sequencing of the regions of the factor IX gene of likely functional significance was performed in four patients with severe hemophilia B. In two of the individuals, a transition at the dinucleotide CpG caused a nonsense mutation at arginine 333. In ... Full text Link to item Cite

Direct sequencing of the activation peptide and the catalytic domain of the factor IX gene in six species.

Journal Article Genomics · January 1990 By means of RNA amplification with transcript sequencing (RAWTS) under low stringency conditions, sequence was obtained directly without cloning for the activation peptide and the catalytic domain of factor IX from six species--sheep, pig, rabbit, guinea p ... Full text Link to item Cite

Direct carrier testing in 14 families with haemophilia B.

Journal Article Lancet · September 2, 1989 Featured Publication Direct carrier testing was done in 54 at-risk female relatives of haemophilic patients by initially analysing 2.46 kb of the factor IX gene in 1 haemophiliac per family by genomic amplification with transcript sequencing. A presumptive mutation was found i ... Full text Link to item Cite

Functionally important regions of the factor IX gene have a low rate of polymorphism and a high rate of mutation in the dinucleotide CpG.

Journal Article Am J Hum Genet · September 1989 Featured Publication We have recently described genomic amplification with transcript sequencing (GAWTS), a three-step procedure that allows direct genomic sequencing. By GAWTS more than 100,000 bp of sequence have been generated from eight regions of the factor IX gene, which ... Link to item Cite

Genomic amplification with transcript sequencing.

Journal Article Science · January 29, 1988 Featured Publication A sequencing method called genomic amplification with transcript sequencing (GAWTS) is described that is based on amplification with the polymerase chain reaction (PCR). GAWTS bypasses cloning and increases the rate of sequence acquisition by at least five ... Full text Link to item Cite