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Topic: Metabolic

Title: BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease Published: February 26, 2025 Publication: Science Translational Medicine

Authors: Jiaming Wang, Laura E. Poskitt, Jillian Gallagher, Erik G. Puffenberger, R. Max Wynn, Gauri Shisodia, David T. Chuang, Jonathan Beever, Donald L. Hardin, Karlla W. Brigatti, William C. Baker, Rachael Gately, Stephanie Bertrand, Ashlin Rodrigues, Hector R. Benatti, Toloo Taghian, Erin Hall, Rachel Prestigiacomo, Jialing Liang, Gong Chen, Xuntao Zhou, Lingzhi Ren, Nan Liu, Ran He, Qin Su, Jun Xie, Zhong Jiang, Alisha Gruntman, Heather Gray-Edwards, Guangping Gao, Kevin A. Strauss, Dan Wang

Abstract:
Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the branched-chain α-ketoacid dehydrogenase E1α (BCKDHA), E1β (BCKDHB), or dihydrolipoamide branched-chain transacylase (DBT) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.hA-BiP-hB) to the liver, muscle, heart, and brain. rAAV9.hA-BiP-hB restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in BCKDHA−/− HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 1014 vector genomes per kilogram. In two models of severe MSUD (Bckdha−/− and Bckdhb−/− mice) and a newborn calf homozygous for BCKDHA c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.
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Title: Domino liver transplant from a donor with maple syrup urine disease into a recipient with phenylketonuria Published: April 21, 2022 Publication: Molecular Genetics and Metabolism Reports

Authors: Vikram K Raghu, Steven F Dobrowolski, Rakesh Sindhi, Kevin A Strauss, George V Mazariegos, Jerry Vockley, Kyle Soltys

Abstract:
Classical phenylketonuria (PKU) presents a unique challenge for women of child-bearing age. In the context of pregnancy, poorly controlled hyperphenylalaninemia can result in a devastating constellation of outcomes for the baby referred to as the maternal PKU Syndrome. We present the case of a woman with classical PKU unable to maintain a restricted diet and refractory to pharmacological therapies. She elected to undergo a domino liver transplant, receiving an organ from a donor with classical branched chain ketoacid dehydrogenase deficiency (maple syrup urine disease). Plasma phenylalanine concentrations normalized within a few days after transplant and remained so on an unrestricted diet during the first year of follow-up. The patient reports subjective improvements in mood, energy level, and overall quality of life. In the appropriate clinical setting, liver transplant should be considered to provide metabolic stability for PKU patients, particularly women of childbearing age.
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Title: Disease burden and management of Crigler-Najjar syndrome: Report of a world registry Published: March 11, 2022 Publication: Liver International

Authors: Sem J Aronson, Norman Junge, Mediha Trabelsi, Wided Kelmemi, Aurelie Hubert, Karlla W Brigatti, Michael D Fox, Robert J de Knegt, Johanna C Escher, Virginia M Ginocchio, Raffaele Iorio, Yan Zhu, Figen Ozcay, Fakher Rahim, Mortada H F El-Shabrawi, Eyal Shteyer, Angelo Di Giorgio, Lorenzo D'Antiga, Federico Mingozzi, Nicola Brunetti-Pierri, Kevin A Strauss, Philippe Labrune, Ridha Mrad, Ulrich Baumann, Piter J Bosma, CureCN Consortium

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Title: Metabolic Control and “Ideal” Outcomes in Liver Transplantation for Maple Syrup Urine Disease Published: October 1, 2021 Publication: The Journal of Pediatrics

Authors: Caroline B Ewing, Kyle A Soltys, Kevin A Strauss, Rakesh Sindhi, Jerry Vockley, Patrick McKiernan, Robert H Squires, Geoffrey Bond, Armando Ganoza, Ajai Khanna, George V Mazariegos, James E Squires

Abstract:
To assess outcomes following liver transplantation for maple syrup urine disease by determining attainment and sustainability of metabolic control and apply an "ideal" outcome composite in long-term survivors.
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Title: Liver transplant for inherited metabolic disease among siblings Published: November 1, 2020 Publication: Clinical Transplantation

Authors: Patrick J McKiernan, James E Squires, Robert H Squires, Jerry Vockley, George V Mazariegos, Kyle Soltys, Armando Ganoza, Kevin Strauss, Ajai Khanna, Rakesh Sindhi

Abstract:
Liver transplantation is a successful option for inherited metabolic disease yet little is published on the outcome among siblings. We report outcomes of siblings who have undergone liver transplantation for metabolic disease in a single program. Seventy-one siblings (35 males) from 33 individual families underwent liver transplantation since 1982. Outcomes were compared over three consecutive eras. Twenty-eight families had two siblings, four had three siblings, and one had four siblings. In half of families where dates of listing were known, siblings were listed simultaneously. Mean (SD) age at listing for the oldest and second sibling was 13.2 (7.1) and 9.8 (5.7) years, respectively (p < .01). In 18/33 families, the oldest sibling underwent transplantation first. Mean (SD) age at transplant fell from the oldest to second sibling from 12.9 (7.2) to 9.5 (6.3) years, respectively (p < .001). Ten-year patient survival was 83.5% which improved over the eras: era 1 (1982-1994) 65.0%, era 2 (1995-2007) 87.5%, and era 3 (2008-2019) 93.8%: p < .03. Sex, age at transplant, order of transplant, and presence of structural liver disease did not significantly impact survival. When siblings undergo liver transplant for inherited metabolic disease, later siblings are listed and transplanted at a significantly younger age.
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Title: Biochemical phenotype and its relationship to treatment in 16 individuals with PCCB c.1606A>G (p.Asn536Asp) variant propionic acidemia Published: November 1, 2020 Publication: Molecular Genetics and Metabolism

Authors: Olivia Wenger, Miraides Brown, Brandon Smith, Devyani Chowdhury, Andrew H Crosby, Emma L Baple, Mark Yoder, William Laxen, Silvia Tortorelli, Kevin A Strauss

Abstract:
Propionic acidemia (PA) is caused by inherited deficiency of mitochondrial propionyl-CoA carboxylase (PCC) and results in significant neurodevelopmental and cardiac morbidity. However, relationships among therapeutic intervention, biochemical markers, and disease progression are poorly understood. Sixteen individuals homozygous for PCCB c.1606A > G (p.Asn536Asp) variant PA participated in a two-week suspension of therapy. Standard metabolic markers (plasma amino acids, blood spot methylcitrate, plasma/urine acylcarnitines, urine organic acids) were obtained before and after stopping treatment. These same markers were obtained in sixteen unaffected siblings. Echocardiography and electrocardiography were obtained from all subjects. We characterized the baseline biochemical phenotype of untreated PCCB c.1606A > G homozygotes and impact of treatment on PCC deficiency biomarkers. Therapeutic regimens varied widely. Suspension of therapy did not significantly alter branched chain amino acid levels, their alpha-ketoacid derivatives, or urine ketones. Carnitine supplementation significantly increased urine propionylcarnitine and its ratio to total carnitine. Methylcitrate blood spot and urine levels did not correlate with other biochemical measures or cardiac outcomes. Treatment of PCCB c.1606A > G homozygotes with protein restriction, prescription formula, and/or various dietary supplements has a limited effect on core biomarkers of PCC deficiency. These patients require further longitudinal study with standardized approaches to better understand the relationship between biomarkers and disease burden.
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Title: Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades Published: November 1, 2020 Publication: Molecular Genetics and Metabolism

Authors: Kevin A. Strauss, Katie B. Williams, Vincent J. Carson, Laura Poskitt, Lauren E. Bowser, Millie Young, Donna L. Robinson, Christine Hendrickson, Keturah Beiler, Cora M. Taylor, Barbara Haas-Givler, Jennifer Hailey, Stephanie Chopko, Erik G. Puffenberger, Karlla W. Brigatti, Freeman Miller, D. Holmes Morton

Abstract:
Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006–2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989–2018) were identified by NBS and treated with natural protein restriction (1.0–1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973–2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p < .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.
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Title: Orthopaedic manifestations of glutaric acidemia Type 1 Published: August 4, 2020 Publication: Journal of Children's Orthopaedics

Authors: Ahmet Imerci, Kevin A. Strauss, Geovanny F. Oleas-Santillan, Freeman Miller

Abstract:
Glutaric acidemia type 1 (GA1), a rare hereditary metabolic disease caused by biallelic mutations of GCDH, can result in acute or insidious striatal degeneration within the first few years of life. We reviewed the orthopaedic sequelae and management of 114 neurologically injured patients with a confirmed molecular diagnosis of GA1.
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Title: Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes Published: March 1, 2020 Publication: Molecular Genetics and Metabolism

Authors: Kevin A. Strauss, Vincent J. Carson, Kyle Soltys, Millie E. Young, Lauren E. Bowser, Erik G. Puffenberger, Karlla W. Brigatti, Katie B. Williams, Donna L. Robinson, Christine Hendrickson, Keturah Beiler, Cora M. Taylor, Barbara Haas-Givler, Stephanie Chopko, Jennifer Hailey, Emilie R. Muelly, Diana A. Shellmer, Zachary Radcliff, Ashlin Rodrigues, KaLynn Loeven, Adam D. Heaps, George V. Mazariegos, D. Holmes Morton

Abstract:
Over the past three decades, we studied 184 individuals with 174 different molecular variants of branched-chain α-ketoacid dehydrogenase activity, and here delineate essential clinical and biochemical aspects of the maple syrup urine disease (MSUD) phenotype. We collected data about treatment, survival, hospitalization, metabolic control, and liver transplantation from patients with classic (i.e., severe; n = 176), intermediate (n = 6) and intermittent (n = 2) forms of MSUD. A total of 13,589 amino acid profiles were used to analyze leucine tolerance, amino acid homeostasis, estimated cerebral amino acid uptake, quantitative responses to anabolic therapy, and metabolic control after liver transplantation. Standard instruments were used to measure neuropsychiatric outcomes. Despite advances in clinical care, classic MSUD remains a morbid and potentially fatal disorder. Stringent dietary therapy maintains metabolic variables within acceptable limits but is challenging to implement, fails to restore appropriate concentration relationships among circulating amino acids, and does not fully prevent cognitive and psychiatric disabilities. Liver transplantation eliminates the need for a prescription diet and safeguards patients from life-threatening metabolic crises, but is associated with predictable morbidities and does not reverse pre-existing neurological sequelae. There is a critical unmet need for safe and effective disease-modifying therapies for MSUD which can be implemented early in life. The biochemistry and physiology of MSUD and its response to liver transplantation afford key insights into the design of new therapies based on gene replacement or editing.
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Title: A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 2: cobalamin C deficiency Published: April 1, 2016 Publication: Genetics in Medicine

Authors: Manoli I, Myles JG, Sloan JL, Carrillo-Carrasco N, Morava E, Strauss KA, Morton H, Venditti CP

Abstract:
Cobalamin C (cblC) deficiency impairs the biosynthesis of 5'-deoxyadenosyl-adenosyl- and methyl-cobalamin, resulting in methylmalonic acidemia combined with hyperhomocysteinemia and hypomethioninemia. However, some patients with cblC deficiency are treated with medical foods, devoid of methionine and high in leucine content, that are formulated for patients with isolated propionate oxidative defects. We examined the effects of imbalanced branched-chain amino acid intake on growth outcomes in cblC-deficient patients.
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Title: Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency. Published: March 14, 2016 Publication: PLOS One

Authors: Motzek A, Knezevic J, Switzeny OJ, Cooper A, Baric I, Beluzic R, Strauss KA, Puffenberger EG, Mudd SH, Vugrek O, Zechner U

Abstract:
S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive disorder in methionine metabolism caused by mutations in the AHCY gene. Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly associated with hypermethioninaemia, elevated serum creatine kinase levels and increased genome wide DNA methylation. The prime function of AHCY is to hydrolyse and efficiently remove S-adenosylhomocysteine, the by-product of transmethylation reactions and one of the most potent methyltransferase inhibitors. In this study, we set out to more specifically characterize DNA methylation changes in blood samples from patients with AHCY deficiency. Global DNA methylation was increased in two of three analysed patients. In addition, we analysed the DNA methylation levels at differentially methylated regions (DMRs) of six imprinted genes (MEST, SNRPN, LIT1, H19, GTL2 and PEG3) as well as Alu and LINE1 repetitive elements in seven patients. Three patients showed a hypermethylation in up to five imprinted gene DMRs. Abnormal methylation in Alu and LINE1 repetitive elements was not observed. We conclude that DNA hypermethylation seems to be a frequent but not a constant feature associated with AHCY deficiency that affects different genomic regions to different degrees. Thus AHCY deficiency may represent an ideal model disease for studying the molecular origins and biological consequences of DNA hypermethylation due to impaired cellular methylation status.
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Title: Living related versus deceased donor liver transplantation for maple syrup urine disease Published: March 1, 2016 Publication: Molecular Genetics and Metabolism

Authors: Feier F, Schwartz IV, Benkert AR, Neto JS, Miura I, Chapchap P, da Fonseca EA, Vieira S, Zanotelli ML, Vairo FP, Camelo JS Jr, Margutti AV, Mazariegos GV, Puffenberger EG, Strauss KA

Abstract:
Maple syrup urine disease (MSUD) is an inherited disorder of branched chain ketoacid (BCKA) oxidation associated with episodic and chronic brain disease. Transplantation of liver from an unrelated deceased donor restores 9-13% whole-body BCKA oxidation capacity and stabilizes MSUD. Recent reports document encouraging short-term outcomes for MSUD patients who received a liver segment from mutation heterozygous living related donors (LRDT). To investigate effects of living related versus deceased unrelated grafts, we studied four Brazilian MSUD patients treated with LRDT who were followed for a mean 19 ± 12 postoperative months, and compared metabolic and clinical outcomes to 37 classical MSUD patients treated with deceased donor transplant. Patient and graft survival for LRDT were 100%. Three of 4 MSUD livers were successfully domino transplanted into non-MSUD subjects. Following LRDT, all subjects resumed a protein-unrestricted diet as mean plasma leucine decreased from 224 ± 306 μM to 143 ± 44 μM and allo-isoleucine decreased 91%. We observed no episodes of hyperleucinemia during 80 aggregate postoperative patient-months. Mean plasma leucine:isoleucine:valine concentration ratios were ~2:1:4 after deceased donor transplant compared to ~1:1:1.5 following LRDT, resulting in differences of predicted cerebral amino acid uptake. Mutant heterozygous liver segments effectively maintain steady-state BCAA and BCKA homeostasis on an unrestricted diet and during most catabolic states, but might have different metabolic effects than grafts from unrelated deceased donors. Neither living related nor deceased donor transplant affords complete protection from metabolic intoxication, but both strategies represent viable alternatives to nutritional management.
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Title: Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency Published: September 1, 2015 Publication: Molecular Genetics and Metabolism

Authors: Strauss KA, Ferreira C, Bottiglieri T, Zhao X, Arning E, Zhang S, Zeisel SH, Escolar ML, Presnick N, Puffenberger EG, Vugrek O, Kovacevic L, Wagner C, Mazariegos GV, Mudd SH, Soltys K

Abstract:
A child with severe S-adenosylhomocysteine hydrolase (AHCY) deficiency (AHCY c.428A N G, p.Tyr143Cys; c.982 T N G, p.Tyr328Asp) presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy, hepatopathy, and factor VII deficiency. Plasma methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) were markedly elevated and the molar concentration ratio of AdoMet:AdoHcy, believed to regulate a myriad of methyltransferase reactions, was 15% of the control mean. Dietary therapy failed to normalize biochemical markers or alter the AdoMet to AdoHcy molar concentration ratio. At 40 months of age, the proband received a liver segment from a healthy, unrelated living donor. Mean AdoHcy decreased 96% and the AdoMet:AdoHcy concentration ratio improved from 0.52 ± 0.19 to 1.48 ± 0.79 mol:mol (control 4.10 ± 2.11 mol:mol). Blood methionine and AdoMet were normal and stable during 6 months of follow-up on an unrestricted diet. Average calculated tissue methyltransferase activity increased from 43 ± 26% to 60 ± 22%, accompanied by signs of increased transmethylation in vivo. Factor VII activity increased from 12% to 100%. During 6 postoperative months, head growth accelerated 4-fold and the patient made promising gains in gross motor, language, and social skills.
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Title: Biochemical correlates of neuropsychiatric illness in maple syrup urine disease Published: March 8, 2013 Publication: The Journal of Clinical Investigation

Authors: Muelly ER, Moore GJ, Bunce SC, Mack J, Bigler DC, Morton DH, Strauss KA

Abstract:
Maple syrup urine disease (MSUD) is an inherited disorder of branched chain amino acid metabolism presenting with neonatal encephalopathy, episodic metabolic decompensation, and chronic amino acid imbalances. Dietary management enables survival and reduces risk of acute crises. Liver transplantation has emerged as an effective way to eliminate acute decompensation risk. Psychiatric illness is a reported MSUD complication, but has not been well characterized and remains poorly understood. We report the prevalence and characteristics of neuropsychiatric problems among 37 classical MSUD patients (ages 5–35 years, 26 on dietary therapy, 11 after liver transplantation) and explore their underlying mechanisms. Compared with 26 age-matched controls, MSUD patients were at higher risk for disorders of cognition, attention, and mood. Using quantitative proton magnetic resonance spectroscopy, we found lower brain glutamate, N-acetylaspartate (NAA), and creatine concentrations in MSUD patients, which correlated with specific neuropsychiatric outcomes. Asymptomatic neonatal course and stringent longitudinal biochemical control proved fundamental to optimizing long-term mental health. Neuropsychiatric morbidity and neurochemistry were similar among transplanted and nontransplanted MSUD patients. In conclusion, amino acid dysregulation results in aberrant neural networks with neurochemical deficiencies that persist after transplant and correlate with neuropsychiatric morbidities. These findings may provide insight into general mechanisms of psychiatric illness.
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Title: Liver transplantation for classical maple syrup urine disease: long-term follow-up in 37 patients and comparative United Network for Organ Sharing experience Published: January 1, 2012 Publication: The Journal of Pediatrics

Authors: Mazariegos GV, Morton DH, Sindhi R, Soltys K, Nayyar N, Bond G, Shellmer D, Shneider B, Vockley J, Strauss KA

Abstract:
To assess clinical and neurocognitive function in children who have undergone liver transplantation for classical maple syrup urine disease (MSUD).
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Title: Safety, efficacy and physiological actions of a lysine-free, arginine-rich formula to treat glutaryl-CoA dehydrogenase deficiency: focus on cerebral amino acid influx. Published: September 1, 2011 Publication: Molecular Genetics and Metabolism

Authors: Strauss KA, Brumbaugh J, Duffy A, Wardley B, Robinson D, Hendrickson C, Tortorelli S, Moser AB, Puffenberger EG, Rider NL, Morton DH

Abstract:
Striatal degeneration from glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type 1, GA1) is associated with cerebral formation and entrapment of glutaryl-CoA and its derivatives that depend on cerebral lysine influx. In 2006 we designed a lysine-free study formula enriched with arginine to selectively block lysine transport across cerebral endothelia and thereby limit glutaryl-CoA production by brain. Between 2006 and present, we treated twelve consecutive children with study formula (LYSx group) while holding all other treatment practices constant. Clinical and biochemical outcomes were compared to 25 GA1 patients (PROx group) treated between 1995 and 2005 with natural protein restriction (dietary lysine/arginine ratio of 1.7±0.3 mg:mg). We used published kinetic parameters of the y+and LAT1 blood-brain barrier transporters to model the influx of amino acids into the brain. Arginine fortification to achieve a mean dietary lysine/arginine ratio of 0.7±0.2 mg:mg was neuroprotective. All 12 LYSx patients are physically and neurologically healthy after 28 aggregate patient-years of follow up (current ages 28±21 months) and there were no adverse events related to formula use. This represents a 36% reduction of neurological risk (95% confidence interval 14-52%, p=0.018) that we can directly attribute to altered amino acid intake. During the first year of life, 20% lower lysine intake and two-fold higher arginine intake by LYSx patients were associated with 50% lower plasma lysine, 3-fold lower plasma lysine/arginine concentration ratio, 42% lower mean calculated cerebral lysine influx, 54% higher calculated cerebral arginine influx, 15-26% higher calculated cerebral influx of several anaplerotic precursors (isoleucine, threonine, methionine, and leucine), 50% less 3-hydroxyglutarate excretion, and a 3-fold lower hospitalization rate (0.8 versus 2.3 hospitalizations per patient per year). The relationship between arginine fortification and plasma lysine indicates that transport competition exists at both cerebrovascular and gastrointestinal barriers, suggesting their co-administration is key to efficacy. Monitoring the ratio between lysine and arginine in diet and plasma may prove a useful strategy for treating children with GA1.
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Title: Erythrocyte pyruvate kinase deficiency in an old-order Amish cohort: longitudinal risk and disease management Published: September 1, 2011 Publication: American Journal of Hematology

Authors: Rider NL, Strauss KA, Brown K, Finkenstedt A, Puffenberger EG, Hendrickson CL, Robinson DL, Muenke N, Tselepis C, Saunders L, Zoller H, Morton DH

Abstract:
Pyruvate kinase deficiency is a chronic illness with age specific consequences. Newborns suffer life-threatening hemolytic crisis and hyperbilirubinemia. Adults are at risk for infections because of asplenia, pregnancy-related morbidity, and may suffer organ damage because of systemic iron overload. We describe 27 Old Order Amish patients (ages 8 months-52 years) homozygous for c.1436G>A mutations in PKLR. Each subject had a predictable neonatal course requiring packed red blood cell transfusions (30 ± 5 mL/kg) to control hemolytic disease and intensive phototherapy to prevent kernicterus. Hemochromatosis affected 29% (n = 4) of adult patients, who had inappropriately normal serum hepcidin (34.5 ± 12.7 ng/mL) and GDF-15 (595 ± 335pg/mL) relative to hyperferritinemia (769 ± 595 mg/dL). A high prevalence of HFE gene mutations exists in this population and may contribute to iron-related morbidity. Based on our observations, we present a strategy for long-term management of pyruvate kinase deficiency.
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Title: Cognitive and adaptive functioning after liver transplantation for maple syrup urine disease: a case series Published: February 1, 2011 Publication: Pediatric Transplantation

Authors: Shellmer DA, DeVito Dabbs A, Dew MA, Noll RB, Feldman H, Strauss KA, Morton DH, Vockley J, Mazariegos GV

Abstract:
MSUD is a complex metabolic disorder that has been associated with central nervous system damage, developmental delays, and neurocognitive deficits. Although liver transplantation provides a metabolic cure for MSUD, changes in cognitive and adaptive functioning following transplantation have not been investigated. In this report we present data from 14 patients who completed cognitive and adaptive functioning testing pre- and one year and/or three years postliver transplantation. Findings show either no significant change or improvement in IQ scores preto post-liver transplantation. Greater variability was observed in adaptive functioning scores, but the majority of patients evidenced either no significant change or improvement in adaptive scores. In general, findings may indicate that liver transplantation curtails additional central nervous system damage and neurocognitive decline providing an opportunity for stabilization or improvement in functioning.
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Title: Classical maple syrup urine disease and brain development: principles of management and formula design Published: April 1, 2010 Publication: Molecular Genetics and Metabolism

Authors: Strauss KA, Wardley B, Robinson D, Hendrickson C, Rider NL, Puffenberger EG, Shellmer D, Moser AB, Morton DH

Abstract:
Branched-chain ketoacid dehydrogenase deficiency results in complex and volatile metabolic derangements that threaten brain development. Treatment for classical maple syrup urine disease (MSUD) should address this underlying physiology while also protecting children from nutrient deficiencies. Based on a 20-year experience managing 79 patients, we designed a study formula to (1) optimize transport of seven amino acids (Tyr, Trp, His, Met, Thr, Gln, Phe) that compete with branched-chain amino acids (BCAAs) for entry into the brain via a common transporter (LAT1), (2) compensate for episodic depletions of glutamine, glutamate, and alanine caused by reverse transamination, and (3) correct deficiencies of omega-3 essential fatty acids, zinc, and selenium widespread among MSUD patients. The formula was enriched with LAT1 amino acid substrates, glutamine, alanine, zinc, selenium, and alpha-linolenic acid (18:3n-3). Fifteen Old Order Mennonite children were started on study formula between birth and 34 months of age and seen at least monthly in the office. Amino acid levels were checked once weekly and more often during illnesses. All children grew and developed normally over a period of 14-33 months. Energy demand, leucine tolerance, and protein accretion were tightly linked during periods of normal growth. Rapid shifts to net protein degradation occurred during illnesses. At baseline, most LAT1 substrates varied inversely with plasma leucine, and their calculated rates of brain uptake were 20-68% below normal. Treatment with study formula increased plasma concentrations of LAT1 substrates and normalized their calculated uptakes into the nervous system. Red cell membrane omega-3 polyunsaturated fatty acids and serum zinc and selenium levels increased on study formula. However, selenium and docosahexaenoic acid (22:6n-3) levels remained below normal. During the study period, hospitalizations decreased from 0.35 to 0.14 per patient per year. There were 28 hospitalizations managed with MSUD hyperalimentation solution; 86% were precipitated by common infections, especially vomiting and gastroenteritis. The large majority of catabolic illnesses were managed successfully at home using 'sick-day' formula and frequent amino acid monitoring. We conclude that the study formula is safe and effective for the treatment of classical MSUD. In principle, dietary enrichment protects the brain against deficiency of amino acids used for protein accretion, neurotransmitter synthesis, and methyl group transfer. Although the pathophysiology of MSUD can be addressed through rational formula design, this does not replace the need for vigilant clinical monitoring, frequent measurement of the complete amino acid profile, and ongoing dietary adjustments that match nutritional intake to the metabolic demands of growth and illness.
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Title: Cerebral haemodynamics in patients with glutaryl-coenzyme A dehydrogenase deficiency Published: January 1, 2010 Publication: Brain

Authors: Strauss KA, Donnelly P, Wintermark M

Abstract:
In glutaric aciduria type 1, glutaryl-coenzyme A and its derivatives are produced from intracerebral lysine and entrapped at high concentrations within the brain, where they interfere with energy metabolism. Biochemical toxicity is thought to trigger stroke-like striatal degeneration in susceptible children under 2 years of age. Here, we explore vascular derangements that might also contribute to brain damage. We studied injured and non-injured Amish glutaric aciduria type 1 patients using magnetic resonance imaging (n = 26), transcranial Doppler ultrasound (n = 35) and perfusion computed tomography (n = 6). All glutaric aciduria type 1 patients had wide middle cerebral, internal carotid and basilar arteries. In non-injured patients, middle cerebral artery velocities were 18-26% below control values throughout late infancy and early childhood, whereas brain-injured children had an early velocity peak (18 months) and low values thereafter. Perfusion scans from six patients showed that tissue blood flow did not undergo a normal developmental surge. We observed four different perfusion patterns. (i) Three children (two non-injured) had low cerebral blood flow, prolonged mean transit time, elevated cerebral blood volume and high mean transit time/cerebral blood flow and cerebral blood volume/cerebral blood flow ratios. This pattern optimizes substrate extraction at any given flow rate but indicates low perfusion pressure and limited autoregulatory reserve. (ii) Ten hours after the onset of striatal necrosis in an 8-month-old infant, mean transit time and cerebral blood volume were low relative to cerebral blood flow, which varied markedly from region to region. This pattern indicates disturbed autoregulation, regional perfusion pressure gradients, or redistribution of flow from functional capillaries to non-exchanging vessels. (iii) In an infant with atrophic putaminal lesions, striatal flow was normal but mean transit time and cerebral blood volume were low, consistent with perfusion in excess of metabolic demand. (iv) Finally, a brain-injured adult with glutaric aciduria type 1 had regional perfusion values within the normal range, but the putamina, which normally have the highest regional perfusion, had cerebral blood flow values 24% below cortical grey matter. Although metabolic toxicity appears central to the pathophysiology of striatal necrosis, cerebrovascular changes probably also contribute to the process. These changes may be the primary cause of expanded cerebrospinal fluid volume in newborns, intracranial and retinal haemorrhages in infants and interstitial white matter oedema in children and adults. This pilot study suggests important new areas for clinical investigation.
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Title: Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: impaired association of enzyme subunits that is due to an A421V substitution causes glutaric acidemia type I in the Amish Published: July 16, 2009 Publication: Annual Review of Genomics and Human Genetics

Authors: Biery BJ, Stein DE, Morton DH, Goodman SI

Abstract:
The structure of the human glutaryl coenzyme A dehydrogenase (GCD) gene was determined to contain 11 exons and to span approximately 7 kb. Fibroblast DNA from 64 unrelated glutaric acidemia type I (GA1) patients was screened for mutations by PCR amplification and analysis of SSCP. Fragments with altered electrophoretic mobility were subcloned and sequenced to detect mutations that caused GA1. This report describes the structure of the GCD gene, as well as point mutations and polymorphisms found in 7 of its 11 exons. Several mutations were found in more than one patient, but no one prevalent mutation was detected in the general population. As expected from pedigree analysis, a single mutant allele causes GA1 in the Old Order Amish of Lancaster County, Pennsylvania. Several mutations have been expressed in Escherichia coli, and all produce diminished enzyme activity. Reduced activity in GCD encoded by the A421V mutation in the Amish may be due to impaired association of enzyme subunits.
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Title: Mutations in cystathionine beta-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans Published: December 1, 2008 Publication: The FASEB Journal

Authors: Jakubowski H, Boers GH, Strauss KA

Abstract:
Severely elevated plasma homocysteine(Hcy) levels observed in genetic disorders of Hcymetabolism are associated with pathologies in multipleorgans and lead to premature death due to vascularcomplications. In addition to elevating plasma Hcy,mutations in cystathionine ␤-synthase (CBS) or methyl-enetetrahydrofolate reductase (MTHFR) gene lead tomarkedly elevated levels of circulating Hcy-thiolactone.The thiooester chemistry of Hcy-thiolactone underliesits ability to form isopeptide bonds with protein lysineresidues (N-Hcy-protein), which may impair or alter theprotein’s function. However, it was not known whethergenetic deficiencies in Hcy metabolism affect N-Hcy-protein levels in humans. Here we show that plasmaN-Hcy-protein levels are significantly elevated in CBS-and MTHFR-deficient patients. We also show that CBS-deficient patients have significantly elevated plasma levelsof prothrombotic N-Hcy-fibrinogen. These results pro-vide a possible explanation for increased atherothrombo-sis observed in CBS-deficient patients.
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Title: Genetic mapping of glutaric aciduria, type 3, to chromosome 7 and identification of mutations in c7orf10 Published: November 17, 2008 Publication: The American Journal of Human Genetics

Authors: Sherman EA, Strauss KA, Tortorelli S, Bennett MJ, Knerr I, Morton DH, Puffenberger EG

Abstract:
While screening Old Order Amish children for glutaric aciduria type 1 (GA1) between 1989 and 1993, we found three healthy children who excreted abnormal quantities of glutaric acid but low 3-hydroxyglutaric acid, a pattern consistent with glutaric aciduria type 3 (GA3). None of these children had the GCDH c.1262C→T mutation that causes GA1 among the Amish. Using single-nucleotide polymorphism (SNP) genotypes, we identified a shared homozygous 4.7 Mb region on chromosome 7. This region contained 25 genes including C7orf10, an open reading frame with a putative mitochondrial targeting sequence and coenzyme-A transferase domain. Direct sequencing of C7orf10 revealed that the three Amish individuals were homozygous for a nonsynonymous sequence variant (c.895C→T, Arg299Trp). We then sequenced three non-Amish children with GA3 and discovered two nonsense mutations (c.322C→T, Arg108Ter, and c.424C→T, Arg142Ter) in addition to the Amish mutation. Two pathogenic alleles were identified in each of the six patients. There was no consistent clinical phenotype associated with GA3. In affected individuals, urine molar ratios of glutarate to its derivatives (3-hydroxyglutarate, glutarylcarnitine, and glutarylglycine) were elevated, suggesting impaired formation of glutaryl-CoA. These observations refine our understanding of the lysine-tryptophan degradation pathway and have important implications for the pathophysiology of GA1.
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Title: Second-tier test for quantification of alloisoleucine and branched-chain amino acids in dried blood spots to improve newborn screening for maple syrup urine disease (MSUD) Published: March 1, 2008 Publication: Clinical Chemistry

Authors: Oglesbee D, Sanders KA, Lacey JM, Magera MJ, Casetta B, Strauss KA, Tortorelli S, Rinaldo P, Matern D

Abstract:
Newborn screening for maple syrup urine disease (MSUD) relies on finding increased concentrations of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine by tandem mass spectrometry (MS/MS). d-Alloisoleucine (allo-Ile) is the only pathognomonic marker of MSUD, but it cannot be identified by existing screening methods because it is not differentiated from isobaric amino acids. Furthermore, newborns receiving total parenteral nutrition often have increased concentrations of BCAAs. To improve the specificity of newborn screening for MSUD and to reduce the number of diet-related false-positive results, we developed a LC-MS/MS method for quantifying allo-Ile.
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Title: Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency Published: July 1, 2007 Publication: Brain

Authors: Strauss KA, Lazovic J, Wintermark M, Morton DH

Abstract:
Despite early diagnosis, one-third of Amish infants with glutaryl-CoA dehydrogenase deficiency (GA1) develop striatal lesions that leave them permanently disabled. To better understand mechanisms of striatal degeneration, we retrospectively studied imaging results from 25 Amish GA1 patients homozygous for 1296C>T mutations in GCDH. Asymptomatic infants had reduced glucose tracer uptake and increased blood volume throughout gray matter, which may signify a predisposition to brain injury. Nine children (36%) developed striatal lesions: three had sudden motor regression during infancy whereas six had insidious motor delay associated with striatal lesions of undetermined onset. Acute striatal necrosis consisted of three stages: (1) an acute stage, within 24 h of motor regression, characterized by cytotoxic oedema within the basal ganglia, cerebral oligemia, and rapid transit of blood throughout gray matter; (2) a sub-acute stage, 4–5 days after the onset of clinical signs, characterized by reduced striatal perfusion and glucose uptake, and supervening vasogenic oedema; and (3) a chronic stage of striatal atrophy. Apparent diffusion coefficient maps revealed that at least two of the six patients with insidious motor delay suffered striatal injuries before or shortly after birth, followed by latent periods of several months before disability was apparent. Thus, acute and insidious presentations may occur by similar mechanisms, and differ only with regard to the timing of injury. Intravenous fluid and dextrose therapy for illnesses during the first 2 years of life was the only intervention that was clearly neuroprotective in this cohort (odds ratio for brain injury = 0.04, 95% confidence interval = 0.01–0.34; P < 0.001).
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Title: Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency Published: June 1, 2007 Publication: Molecular Genetics and Metabolism

Authors: Strauss KA, Morton DH, Puffenberger EG, Hendrickson C, Robinson DL, Wagner C, Stabler SP, Allen RH, Chwatko G, Jakubowski H, Niculescu MD, Mudd SH

Abstract:
Over a four-year period, we collected clinical and biochemical data from five Amish children who were homozygous for missense mutations in 5,10-methylenetetrahydrofolate reductase (MTHFR c.1129C>T). The four oldest patients had irreversible brain damage prior to diagnosis. The youngest child, diagnosed and started on betaine therapy as a newborn, is healthy at her present age of three years. We compared biochemical data among four groups: 16 control subjects, eight heterozygous parents, and five affected children (for the latter group, both before and during treatment with betaine anhydrous). Plasma amino acid concentrations were used to estimate changes in cerebral methionine uptake resulting from betaine therapy. In all affected children, treatment with betaine (534+/-222 mg/kg/day) increased plasma S-adenosylmethionine, improved markers of tissue methyltransferase activity, and resulted in a threefold increase of calculated brain methionine uptake. Betaine therapy did not normalize plasma total homocysteine, nor did it correct cerebral 5-methyltetrahydrofolate deficiency. We conclude that when the 5-methyltetrahydrofolate content of brain tissue is low, dietary betaine sufficient to increase brain methionine uptake may compensate for impaired cerebral methionine recycling. To effectively support the metabolic requirements of rapid brain growth, a large dose of betaine should be started early in life.
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Title: Elective liver transplantation for the treatment of classical maple syrup urine disease Published: March 1, 2006 Publication: American Journal of Transplantation

Authors: Strauss KA, Mazariegos GV, Sindhi R, Squires R, Finegold DN, Vockley G, Robinson DL, Hendrickson C, Virji M, Cropcho L, Puffenberger EG, McGhee W, Seward LM, Morton DH

Abstract:
An 8.5-year-old girl with classical maple syrup urine disease (MSUD) required liver transplantation for hypervitaminosis A and was effectively cured of MSUD over an 8-year clinical follow-up period. We developed a collaborative multidisciplinary effort to evaluate the effects of elective liver transplantation in 10 additional children (age range 1.9–20.5 years) with classical MSUD. Patients were transplanted with whole cadaveric livers under a protocol designed to optimize safe pre- and post-transplant management of MSUD. All patients are alive and well with normal allograft function after 106 months of follow-up in the index patient and a median follow-up period of 14 months (range 4–18 months) in the 10 remaining patients. Leucine, isoleucine and valine levels stabilized within 6 hours post-transplant and remained so on an unrestricted protein intake in all patients. Metabolic cure was documented as a sustained increase in weight-adjusted leucine tolerance, normalization of plasma concentration relationships among branched-chain and other essential and nonessential amino acids, and metabolic and clinical stability during protein loading and intercurrent illnesses. Costs and risks associated with surgery and immune suppression were similar to other pediatric liver transplant populations.
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Title: Maintenance treatment of glutaryl-CoA dehydrogenase deficiency Published: January 1, 2004 Publication: Journal of Inherited Metabolic Disease

Authors: Mühlhausen C, Hoffmann GF, Strauss KA, Kölker S, Okun JG, Greenberg CR, Naughten ER, Ullrich K

Abstract:
This paper summarizes the published experience as well as results of the 3rd International Workshop on Glutaryl-CoA Dehydrogenase Deficiency held in October 2003 in Heidelberg, Germany, on the topic treatment of patients with glutaryl-CoA dehydrogenase (GCDH) deficiency. So far no international recommendation for treatment of GCDH deficiency exists. Such an approach is hampered by several facts, namely the lack of an in-depth understanding of the pathophysiology of the disease, the lack of prospective studies, including the evaluation of drug monotherapy, and lack of objective documentation of clinical changes (e.g. video documentation) during pharmacotherapy.
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Title: Challenges for basic research in glutaryl-CoA dehydrogenase deficiency Published: January 1, 2004 Publication: Journal of Inherited Metabolic Disease

Authors: Kölker S, Strauss KA, Goodman SI, Hoffmann GF, Okun JG, Koeller DM

Abstract:
During the last decades, efforts have been made to elucidate the complex mechanisms underlying neuronal damage in glutaryl-CoA dehydrogenase deficiency. A combination of in vitro and in vivo investigations have facilitated the development of several hypotheses, including the probable pathogenic role of accumulating glutaric acid and 3-hydroxyglutaric acid. However, there are still many shortcomings that limit an evidence-based approach to treating this inborn error of metabolism. Major future goals should include generation of a suitable animal model for acute striatal necrosis, investigation of the formation, distribution and exact intra- and extracellular concentrations of accumulating metabolites, a deeper understanding of striatal vulnerability, and systematic investigation of effects on cerebral gene expression during development and of the modulatory role of inflammatory cytokines.
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Title: Vascular dysfunction as an additional pathomechanism in glutaric aciduria type I Published: January 1, 2004 Publication: Journal of Inherited Metabolic Disease

Authors: Mühlhausen C, Ergün S, Strauss KA, Koeller DM, Crnic L, Woontner M, Goodman SI, Ullrich K, Braulke T

Abstract:
The metabolic hallmark of glutaric aciduria type I (GA I) is the deficiency of glutaryl-CoA dehydrogenase (GCDH) with subsequent accumulation of glutaric acid, 3-hydroxglutaric acid (3-OH-GA) and glutaconic acid. Current concepts regarding pathomechanisms of GA I focus on investigations of excitotoxic effects of 3-OH-GA. To identify pathogenetically relevant genes, microarray analyses were performed using brain material from GCDH-deficient (GCDH (-/-)) and control mice. These microarray data confirmed recent pathogenic models, but also revealed alterations in genes that had previously not been correlated to the disease, e.g. genes concerning vascular biology. Subsequent in vitro and in vivo experiments confirmed direct effects of 3-OH-GA on vascular permeability and endothelial integrity. Clinical observations underscore the involvement of vascular dysfunction. In MRI scans of GA I patients, subdural effusions as well as dilated transarachnoid vascular plexuses were detected independently of encephalopathic crises. In fact, some of these findings are already detectable shortly after birth. MRI scans of a GA I patient performed during an acute encephalopathic crisis detected a dilated intrastriatal vasculature with perivascular hyperintensity, indicating local extravasation. In conclusion, we hypothesize that 3-OH-GA affects prenatal development of vessels, thus leading to an increased vulnerability of endothelial structures and subsequent vascular dysfunction. These observations display an additional pathomechanism in GA I and might explain frontotemporal hypoplasia and chronic subdural effusions in this disease. Elucidation of the pathomechanisms of vascular dysfunction may give further insights into the pathogenesis of GA I.
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Title: Type I glutaric aciduria, part 2: a model of acute striatal necrosis Published: August 15, 2003 Publication: American Journal of Medical Genetics Part C

Authors: Strauss KA, Morton DH

Abstract:
Type I glutaric aciduria (GA1) is an inborn error of organic acid metabolism that is associated with acute neurological crises, typically precipitated by an infectious illness. The neurological crisis coincides with swelling, metabolic depression, and necrosis of basal ganglia gray matter, especially the putamina and can be visualized as focal, stroke-like, signal hyperintensity on MRI. Here we focus on the stroke-like nature of striatal necrosis and its similarity to brain injury that occurs in infants after hypoxia-ischemia or systemic intoxication with 3-nitropropionic acid (NPA). These conditions share several features including abrupt onset, preferential effect in the striatum and age-specific susceptibility. The pathophysiology of the conditions is reviewed and a model proposed herein. We encourage investigators to test this model in an appropriate experimental system.
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Title: Type I glutaric aciduria, part 1: natural history of 77 patients Published: August 15, 2003 Publication: American Journal of Medical Genetics Part C

Authors: Strauss KA, Puffenberger EG, Robinson DL, Morton DH

Abstract:
Type I glutaric aciduria (GA1) results from mitochondrial matrix flavoprotein glutaryl-CoA dehydrogenase deficiency and is a cause of acute striatal necrosis in infancy. We present detailed clinical, neuroradiologic, molecular, biochemical, and functional data on 77 patients with GA1 representative of a 14-year clinical experience. Microencephalic macrocephaly at birth is the earliest sign of GA1 and is associated with stretched bridging veins that can be a cause of subdural hematoma and acute retinal hemorrhage. Acute striatal necrosis during infancy is the principal cause of morbidity and mortality and leads to chronic oromotor, gastroesophageal, skeletal, and respiratory complications of dystonia. Injury to the putamen is heralded by abrupt-onset behavioral arrest. Tissue degeneration is stroke-like in pace, radiologic appearance, and irreversibility. It is uniformly symmetric, regionally selective, confined to children under 18 months of age, and occurs almost always during an infectious illness. Our knowledge of disease mechanisms, though incomplete, is sufficient to allow a rational approach to management of encephalopathic crises. Screening of asymptomatic newborns with GA1 followed by thoughtful prospective care reduces the incidence of radiologically and clinically evident basal ganglia injury from approximately 90% to 35%. Uninjured children have good developmental outcomes and thrive within Amish and non-Amish communities.
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Title: Branched-chain Ketoacyl Dehydrogenase Deficiency: Maple Syrup Disease Published: July 1, 2003 Publication: Current Treatment Options in Neurology

Authors: Strauss KA, Morton DH

Abstract:
Classic maple syrup disease can be managed to allow a benign neonatal course, normal growth, and low hospitalization rates. The majority of affected infants that are prospectively managed have good neurodevelopmental outcome; however, acute metabolic intoxication and neurologic deterioration can develop rapidly at any age. Each episode is associated with a risk for cerebral edema, cerebrovascular compromise, and brain herniation. High plasma leucine and, possibly, alpha-ketoisocaproate are the principal neurotoxins in maple syrup disease. Plasma levels rise rapidly in association with net protein catabolism provoked by common infections and injuries. Transient periods of maple syrup disease encephalopathy appear fully reversible, leaving no clinically detectable neurologic sequelae. In contrast, prolonged amino acid imbalance, particularly if occurring during the critical period of brain development, leads to neuronal hypoplasia, a paucity of synapses, and undermyelination. Stagnated maturation and inadequate nutritional maintenance of brain structure have lifelong neurologic and behavioral consequences. Core elements of effective long-term therapy include screening and identification of asymptomatic newborns, frequent plasma amino acid monitoring, careful attention to branched-chain amino acid nurtriture, prevention of cerebral essential amino acid deficiencies, adequate provision of essential omega-3 class fatty acids and micronutrients deficient in commercial formulas, methods for home monitoring of metabolic control, and a commitment to lifelong therapy. Recognizing the risk for acute leucine intoxication depends on anticipating effects of common childhood infection and physiologic stresses on whole body protein turnover. Successful management of metabolic decompensation is based on the use of home sick-day regimens, rapid availability of branched-chain amino acid-free hyperalimentation solutions for hospitalized children, prevention of hyponatremia in patients with leucinosis, and frequent adjustments of intravenous therapies guided by plasma amino acid levels and indices of metabolic and clinical response.
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Title: Tyrosine supplementation in phenylketonuria: diurnal blood tyrosine levels and presumptive brain influx of tyrosine and other large neutral amino acids Published: September 1, 2001 Publication: The Journal of Pediatrics

Authors: Kalsner LR, Rohr FJ, Strauss KA, Korson MS, Levy HL

Abstract:
Tyrosine supplementation has not consistently been found to improve neuropsychologic function in phenylketonuria (PKU), possibly because of failure to achieve adequate levels of tyrosine in the brain.
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Title: The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism Published: February 1, 2001 Publication: The American Journal of Human Genetics

Authors: M. Esther Gallardo, Lourdes R. Desviat, José M. Rodríguez, Jorge Esparza-Gordillo, Celia Pérez-Cerdá, Belén Pérez, Pilar Rodríguez-Pombo, Olga Criado, Raul Sanz, D. Holmes Morton, K. Michael Gibson, Thuy P. Le, Antonia Ribes, Santiago Rodríguez de Córdoba, Magdalena Ugarte, and Miguel Á. Peñalva

Abstract:
3-Methylcrotonylglycinuria is an inborn error of leucine catabolism and has a recessive pattern of inheritance that results from the deficiency of 3-methylcrotonyl-CoA carboxylase (MCC). The introduction of tandem mass spectrometry in newborn screening has revealed an unexpectedly high incidence of this disorder, which, in certain areas, appears to be the most frequent organic aciduria. MCC, an heteromeric enzyme consisting of α (biotin-containing) and β subunits, is the only one of the four biotin-dependent carboxylases known in humans that has genes that have not yet been characterized, precluding molecular studies of this disease. Here we report the characterization, at the genomic level and at the cDNA level, of both the MCCA gene and the MCCB gene, encoding the MCCα and MCCβ subunits, respectively. The 19-exon MCCA gene maps to 3q25-27 and encodes a 725-residue protein with a biotin attachment site; the 17-exon MCCB gene maps to 5q12-q13 and encodes a 563-residue polypeptide. We show that disease-causing mutations can be classified into two complementation groups, denoted “CGA” and “CGB.” We detected two MCCA missense mutations in CGA patients, one of which leads to absence of biotinylated MCCα. Two MCCB missense mutations and one splicing defect mutation leading to early MCCβ truncation were found in CGB patients. A fourth MCCB mutation also leading to early MCCβ truncation was found in two nonclassified patients. A fungal model carrying an mccA null allele has been constructed and was used to demonstrate, in vivo, the involvement of MCC in leucine catabolism. These results establish that 3-methylcrotonylglycinuria results from loss-of-function mutations in the genes encoding the α and β subunits of MCC and complete the genetic characterization of the four human biotin-dependent carboxylases.
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Title: Diagnosis and management of glutaric aciduria type I Published: June 1, 1998 Publication: Journal of Inherited Metabolic Disease

Authors: Baric I, Zschocke J, Christensen E, Duran M, Goodman SI, Leonard JV, Müller E, Morton DH, Superti-Furga A, Hoffmann GF

Abstract:
Glutaric aciduria type I (GA1) is a preventable cause of acute brain damage in early childhood, leading to a severe dystonic-dyskinetic disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Degeneration of the putamen and caudate typically occurs between 6 and 18 months of age and is probably linked to changes in metabolic demand caused by normal maturational changes and superimposed catabolic stress. Recognition of this biochemical disorder before the brain has been injured is essential to outcome. Diagnosis depends upon the recognition of relatively non-specific physical findings such as hypotonia, irritability and macrocephaly, and on performance of urine organic acid quantification by gas chromatography--mass spectrometry or selective searches of urine or blood specimens by tandem mass spectrometry for glutarylcarnitine. The diagnosis may also be suggested by characteristic findings on neuroimaging. In selected patients diagnosis can only be reached by enzyme assay. Specific current management by the authors of this paper includes pharmacological doses of L-carnitine, as well as dietary protein restriction. Metabolic decompensation must be treated aggressively to avoid permanent brain damage. Multicentre studies are needed to establish best methods of diagnosis and optimal therapy of this disorder.
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Title: 3-Methylcrotonyl-coenzyme A carboxylase deficiency in Amish/Mennonite adults identified by detection of increased acylcarnitines in blood spots of their children Published: March 1, 1998 Publication: The Journal of Pediatrics

Authors: Gibson KM, Bennett MJ, Naylor EW, Morton DH

Abstract:
Isolated 3-methylcrotonyl coenzyme A carboxylase (MCC) deficiency was documented in four adult women from the Amish/Mennonite population of Lancaster County, Pennsylvania. Metabolic and enzymatic investigations in these individuals were instituted after the detection of abnormal acylcarnitine profiles in blood spots obtained from their newborn children, in whom MCC activity was normal.
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Title: Brain magnetic resonance imaging in suspected extrapyramidal cerebral palsy: observations in distinguishing genetic-metabolic from acquired causes Published: August 1, 1997 Publication: The Journal of Pediatrics

Authors: Hoon AH Jr, Reinhardt EM, Kelley RI, Breiter SN, Morton DH, Naidu SB, Johnston MV

Abstract:
Experienced clinicians recognize that some children who appear to have static cerebral palsy (CP) actually have underlying genetic-metabolic disorders. We report a series of patients with motor disorders seen in children with extrapyramidal CP in whom brain magnetic resonance imaging abnormalities provided important diagnostic clues in distinguishing genetic-metabolic disorders from other causes. One cause of static extrapyramidal CP, hypoxic-ischemic encephalopathy at the end of a term gestation, produces a characteristic pattern of hyperintense signal and atrophy in the putamen and thalamus. Other signal abnormalities and atrophy in the putamen, globus pallidus, or caudate can point to genetic-metabolic diseases, including disorders of mitochondrial and organic acid metabolism. Progress in understanding and treating genetic diseases of the developing brain makes it essential to diagnose disorders that masquerade as static CP. Brain magnetic resonance imaging is a useful diagnostic tool in the initial evaluation of children who appear to have CP.
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Title: Glutaric aciduria type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania Published: October 1, 1991 Publication: American Journal of Medical Genetics

Authors: Morton DH, Bennett MJ, Seargeant LE, Nichter CA, Kelley RI

Abstract:
We have diagnosed type I glutaric aciduria (GA-I) in 14 children from 7 Old Order Amish families in Lancaster County, Pennsylvania. An otherwise rare disorder, GA-I appears to be a common cause of acute encephalopathy and cerebral palsy among the Amish. The natural history of the disease, which was previously unrecognized in this population, is remarkably variable and ranges from acute infantile encephalopathy and sudden death to static extrapyramidal cerebral palsy to normal adult. Ten patients first manifested the disease between 3 and 18 months at the time of an acute infectious illness. Four of these children died in early childhood, also during acute illnesses. However, there has been little progression of the neurological disease after age 5 years in the surviving children and intellect usually has been preserved, even in children with severe spastic paralysis. When well, patients have plasma glutaric acid concentrations ranging from 4.8 to 14.2 mumol/liter (nl 0-5.6 mumol/liter) and urinary glutaric acid concentrations from 12.5 to 196 mg/g creatinine (nl 0.5-8.4 mg/g creatinine). We have found that GA-I can be diagnosed in the Amish by measurement of urinary glutaric acid concentrations using isotope-dilution gas chromatography/mass spectrometry, whereas the diagnosis can easily be missed by routine urine organic acid gas chromatography.
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