Abstract
Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6 years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kölker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals.
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Abbreviations
- AA:
-
Amino acids
- AAM:
-
Amino acid mixture
- C5DC:
-
Glutarylcarnitine
- DBS:
-
Dried blood spots
- GA:
-
Glutaric acid
- GA-I:
-
Glutaric aciduria type I
- GCDH:
-
Glutaryl-CoA dehydrogenase
- GC/MS:
-
Gas chromatography/mass spectrometry
- GRADE:
-
Grading of recommendations, assessment, development and evaluation
- GDG:
-
Guideline development group
- IU:
-
International unit
- MRI:
-
Magnetic resonance imaging
- MS/MS:
-
Tandem mass spectrometry
- NBS:
-
Newborn screening
- 3-OH-GA:
-
3-Hydroxyglutaric acid
- SDH:
-
Subdural hemorrhage
- SIGN:
-
Scottish intercollegiate guidelines network
References
Air EL, Ostrem JL, Sanger TD et al (2011) Deep brain stimulation in children: experience and technical pearls. J Neurosurg Pediatr 8:566–574
Afroze B, Yunus ZM (2014) Glutaric aciduria type 1--importance of early diagnosis and treatment. J Pak Med Assoc 64:593–595
Al-Dirbashi OY, Jacob M, Al-Amoudi M, Al-Kahtani A-OA, El-Badaoui F, Rashed MS (2005) Quantification of glutaric and 3-hydroxyglutaric acids in urine of glutaric acidemia type I patients by HPLC with intramolecular excimer-forming fluorescence derivatization. Clin Chim Acta 359:179–188
Al-Dirbashi OY, Kölker S, Ng D et al (2010) Diagnosis of glutaric aciduria type 1 by measuring 3-hydroxyglutaric acid in dried urine spots by liquid chromatography tandem mass spectrometry. J Inherit Metab Dis 34:173–180
Badve MS, Bhuta S, Mcgill J (2015) Rare presentation of a treatable disorder: Glutaric aciduria type 1. N Z Med J 128:61–64
Bähr O, Mader I, Zschocke J, Dichgans J, Schulz JB (2002) Adult onset glutaric aciduria type I presenting with leukoencephalopathy. Neurology 59:1802–1804
Baric I, Wagner L, Feyh P, Liesert M, Buckel W, Hoffmann GF (1999) Sensitivity of free and total glutaric and 3-hydroxyglutaric acid measurement by stable isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis 22:867–882
Barry MJ, VanSwearingen JM, Albright AL (1999) Reliability and responsiveness of the Barry-Albright Dystonia Scale. Dev Med Child Neurol 41:404–411
Basinger AA, Booker JK, Frazier DM, Koeberl DD, Sullivan JA, Muenzer J (2006) Glutaric academia type 1 in patients of Lumbee heritage from North Carolina. Mol Genet Metab 88:90–92
Bayley Scales of Infant and Toddler Development (2006) ,3rd edn.
Beauchamp MH, Boneh A, Anderson V (2009) Cognitive, behavioural and adaptive profiles of children with glutaric aciduria type I detected through newborn screening. J Inherit Metab Dis. doi:10.1007/s10545-009-1167-z
Bijarnia S, Wiley V, Carpenter K, Christodoulou J, Ellaway CJ, Wilcken B (2008) Glutaric aciduria type I: out come following detection by newborn screening. J Inherit Metab Dis 31:503–507
Bjugstad KB, Goodman SI, Freed CR (2000) Age at symptom onset predicts severity of motor impairment and clinical onset of glutaric aciduria type I. J Pediatr 137:681–686
Boneh A, Beauchamp M, Humphrey M, Watkins J, Peters H, Yaplito-Lee J (2008) Newborn screening for glutaric aciduria type I in Victoria: treatment and outcome. Mol Genet Metab 94:287–291
Boy N, Haege G, Heringer J et al (2013) Low lysine diet in glutaric aciduria type I-effect on anthropometric and biochemical follow-up parameters. J Inherit Metab Dis 36:525–533
Boy N, Heringer J, Haege G et al (2015) A cross-sectional controlled developmental study of neuropsychological functions in patients with glutaric aciduria type I. Orphanet J Rare Dis 10:163
Brandt NJ, Gregersen N, Christensen E, Gron ICH, Rasmussen K (1979) Treatment of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria). J Pediatr 94:669–673
Brismar J, Ozand PT (1995) CT and MR of the brain in glutaric aciemia type I: a review of 59 published cases and a report of 5 new patients. Am J Neuroradiol 16:675–683
Bross P, Frederiksen JB, Bie AS et al (2012) Heterozygosity for an in-frame deletion causes glutaryl-CoA dehydrogenase deficiency in a patient detected by newborn screening: Investigation of the effect of the mutant allele. J Inherit Metab Dis 35:787–796
Brown A, Crowe L, Beauchamp MH et al (2015) Neurodevelopmental profiles of children with glutaric aciduria type I diagnosed by newborn screening: A follow-up case series. JIMD Rep 18:125–134
Burlina AP, Zara G, Hoffmann GF, Zschocke J, Burlina AB (2004) Management of movement disorders in glutaryl-CoA dehydrogenase deficiency : Anticholinergic drugs and botulinum toxin as additional therapeutic options. J Inherit Metab Dis 27:911–915
Burlina AP, Danieli D, Malfa F et al (2012) Glutaric aciduria type I and glioma: the first report in a young adult patient. J Inherit Metab Dis 35:S1–S182
Busquets C, Merinero B, Christensen E et al (2000) Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically and biochemically distinct. Pediatr Res 48:315–322
Carman KB, Aydogdu SD, Yakut A et al (2012) Glutaric aciduria type 1 presenting as subdural haematoma. J Paediatr Child Health 48:712
Castillo L, Chapman TE, Yu YM et al (1993) Dietary arginine uptake by the splanchnic region in adult humans. Am J Physiol 265:E532–539
Cerisola A, Campistol J, Pérez-Duenas B et al (2009) Seizures versus dystonia in encephalopathic crisis of glutaric aciduria type I. Pediatr Neurol 40:426–431
Chace DH, Kalas TA, Naylor EW (2003) Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns. Clin Chem 40:1797–1817
Chalmers RA, Bain MD, Zschocke J (2006) Riboflavin-responsive glutaryl-CoA dehydrogenase deficiency. Mol Genet Metab 29:162–172
Chow SL, Rohan C, Morris AA (2003) Rhabdomyolysis in glutaric aciduria type I. J Inherit Metab Dis 26:711–712
Christensen E (1983) Improved assay of glutaryl-CoA dehydrogenase in cultured cells and liver: application to glutaric aciduria type I. Clin Chim Acta 129:91–97
Christensen E, Ribes A, Merinero B, Zschocke J (2004) Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27:861–868
Couce ml, López-Suárez O, Bóveda MD et al (2013) A Glutaric aciduria type I: Outcome of patients with early- versus late-diagnosis. Eur J Paediatr Neurol 17:383–389
Crombez EA, Cederbaum SD, Spector E, Chan E, Salazar D, Neidich J, Goodman S (2008) Maternal glutaric acidemia type I identified by newborn screening. Mol Genet Metab 94:132–134
de Ridder D, Geenen R, Kuijer R et al (2008) Psychological adjustment to chronic disease. The Lancet 372:246–255
Desai NK, Runge VM, Crisp DE, Crisp MB, Naul LG (2003) Magnetic resonance imaging of the brain in glutaric aciduria type I. Invest Radiol 38:489–496
Deutsche Gesellschaft für Ernährung, Österreichische Gesellschaft für Ernährung, Schweizerische Gesellschaft für Ernährungsforschung, Schweizerische Vereinigung für Ernährung (D-A-CH) (2000) Referenzwerte für die Nährstoffzufuhr. 1. Aufl. Frankfurt am Main; Umschau/Braus
Deutsche Gesellschaft für Ernährung, Österreichische Gesellschaft für Ernährung, Schweizerische Gesellschaft für Ernährungsforschung, Schweizerische Vereinigung für Ernährung (D-A-CH) (2015): Referenzwerte für die Nährstoffzufuhr. Bonn, 2. Auflage; Neuer Umschau Buchverlag
Dewey KG, Heinig MJ, Nommsen-Rivers LA (1995) Differences in morbidity between breast-fed and formula-fed infants. J Pediatr 126:696–702
Dewey KG, Beaton G, Fjeld C, Lonnerdal B, Reeds P (1996) Protein requirements of infants and children. Eur J Clin Nutr 50:119–147
Dixon M, Leonard JV (1992) Intercurrent illness in inborn errors of intermediary metabolism. Arch Dis Child 67:1387–1391
Doraiswamy A, Kesavamurthy B, Ranganatha L (2015) Batwing appearance e A neuroradiologic clue to glutaric aciduria-type 1. Int J Epidemiol 2:44–48
Elster AW (2004) Value of diffusion-weighted resonance imaging for diagnosing acute striatal necrosis. J Comput Assist Tomogr 28:98–100
Elze MC, Gimeno H, Tustin K, Baker L, Lumsden DE, Hutton JL, Lin JP (2016) Burke-Fahn-Marsden dystonia severity, Gross Motor, Manual Ability, and Communication Function Classification scales in childhood hyperkinetic movement disorders including cerebral palsy: a Rosetta Stone study. Dev Med Child Neurol 58:145–153
Estrella J, Wilcken B, Carpenter K et al (2014) Expanded newborn screening in New South Wales: missed cases. J Inherit Metab Dis 37:881–887
Fernández-Álvarez E, García-Cazorla A, Sans A et al (2003) Hand tremor and orofacial dyskinesia: clinical manifestations of glutaric aciduria type I in a young girl. Mov Disord 18:1076–1077
Forstner R, Hoffmann GF, Gassner I et al (1999) Glutaric aciduria type I: ultrasonographic demonstration of early signs. Pediatr Radiol 29:138–143
Fraidakis MJ, Liadinioti C, Stefanis L et al (2015) Rare late-onset presentation of glutaric aciduria type i in a 16-year-old woman with a novel gcdh mutation. JIMD Rep 1:85–92
Francis DEM, Smith I (1981) Breast-feeding regime for the treatment of infants with phenylketonuria. In: Bateman C (ed) Applied nutrition. John Libbey, London, pp 82–83
Fu Z, Wang M, Paschke R, Rao S, Frerman FE, Kim JJP (2004) Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions. Biochemistry 43:9674–9684
Gallagher RC, Cowan TM, Goodman SI, Enns GM (2005) Glutaryl-CoA dehydrogenase deficiency and newborn screening: Retrospective analysis of a low excreter provides further evidence that some cases may be missed. Mol Genet Metab 86:417–420
Garbade SF, Greenberg CR, Demirkol M et al (2014) Unravelling the complex mri pattern in glutaric aciduria type I using statistical models-a cohort study in 180 patients. J Inherit Metab Dis 37:763–773
Garcia P, Martins E, Diogo L et al (2008) Outcome of three cases of untreated maternal glutaric aciduria type I. Eur J Pediatr 167:569–573
German Society for Newborn Screening [Deutsche Gesellschaft für Neugeborenenscreening e.V., DGNS] (2015) National Screening Report Germany 2013; URL: http://www.screening-dgns.de/reports.php
Gitiaux C, Roze E, Kinugawa K et al (2008) Spectrum of movement disorders associated with glutaric aciduria type 1: a study of 16 patients. Mov Disord 23:2392–2397
Glasziou P, Irwig L, Mant D (2005) Monitoring in chronic disease: a rational approach. BMJ 330:644–648
Gokmen-Ozel H, MacDonald A, Daly A et al (2012) Dietary practices in glutaric aciduria type 1 over 16 years. J Hum Nutr Diet 25:514–519
Goodman SI, Markey SP, Moe PG, Miles BS, Teng CC (1975) Glutaric aciduria: a new inborn error of amino acid metabolism. Biochem Med 12:12–21
Goodman SI, Stein DE, Schlesinger S et al (1998) Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (Type I): Review and report of thirty novel mutations. Hum Mutat 12:141–144
Gramer G, Haege G, Glahn EM, Hoffmann GF, Lindner M, Burgard P (2014) Living with an inborn error of metabolism detected by newborn screening-parents’ perspectives on child development and impact on family life. J Inherit Metab Dis 37:189–195
Greenberg CR, Reimer D, Singal R et al (1995) A G-to-T transversion at the +5 position of intron 1 in the glutaryl-CoA dehydrogenase gene is associated with the Island Lake variant of glutaric acidemia type I. Hum Mol Genet 4:493–495
Greenberg CR, Prasad AN, Dilling LA et al (2002) Outcome of the three years of a DNA-based neonatal screening program for glutaric aciduria type I in Manitoba and Northwestern Ontaria, Canada. Mol Genet Metab 75:70–78
Gupta N, Singh PK, Kumar M et al (2015) Glutaric acidemia type 1-clinico-molecular profile and novel mutations in GCDH gene in Indian patients. JIMD Rep 21:45–55
Guyatt G, Oxman AD, Akl EA et al (2011) GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 64:383–394
Hald JK, Nakstad PH, Skjeldal OH, Stromme P (1991) Bilateral arachnoid cysts of the temporal fossa in four children with glutaric aciduria type I. Am J Neuroradiol 12:407–409
Harting I, Neumaier-Probst E, Seitz A et al (2009) Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain 132:1764–1782
Harting I, Boy N, Heringer J et al (2015) (1)H-MRS in glutaric aciduria type 1: Impact of biochemical phenotype and age on the cerebral accumulation of neurotoxic metabolites. J Inherit Metab Dis 38:829–838
Hartley LM, Khwaja OS, Verity CM (2000) Glutaric aciduria type 1 and nonaccidental head injury. Pediatrics 107:174–175
Haworth JC, Booth FA, Chudley AE et al (1991) Phenotypic variability in glutaric aciduria type I: report of fourteen cases in five Canadian Indian kindreds. J Pediatr 118:52–58
Hennermann JB, Roloff S, Gellerman J et al (2009) False-positive newborn screening mimicking glutaric aciduria type I in infants with renal insufficiency. J Inherit Metab Dis. doi:10.1007/s10545-009-9017-6
Heringer J, Boy SPN, Ensenauer R et al (2010) Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann Neurol 68:743–752
Herskovitz M, Goldsher D, Sela BA et al (2013) Subependymal mass lesions and peripheral polyneuropathy in adult-onset glutaric aciduria type I. Neurology 81:849–850
Hoffmann GF, Trefz FK, Barth PG et al (1991) Glutaryl-CoA dehydrogenase deficiency: A distinct encephalopathy. Pediatrics 88:1194–1203
Hoffmann GF, Athanassopoulos S, Burlina AB et al (1996) Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics 27:115–123
Huner G, Baykal T, Demir F, Demirkol M (2005) Breast-feeding experience in inborn errors of metabolism other than phenylketonuria. J Inherit Metab Dis 28:457–465
Ituk US, Allen TK, Habib AS (2013) The peripartum management of a patient with glutaric aciduria type 1. J Clin Anesth 25:141–145
Jamiolkowski D, Kölker S, Glahn EM, Barić I, Zeman J, Baumgartner MR, Mühlhausen C, Garcia-Cazorla A, Gleich F, Haege G, Burgard P, E-IMD consortium (2016) Behavioural and emotional problems, intellectual impairment and health-related quality of life in patients with organic acidurias and urea cycle disorders. J Inherit Metab Dis 39:231–241
Jamjoom ZA, Okamoto E, Jamjoom AH, Al-Hajery O, Abu-Melha A (1995) Bilateral arachnoid cysts of the sylvian region in female siblings with glutaric aciduria type I. Report of two cases. J Neurosurg 82:1078–1081
Jamuar SS, Newton SA, Prabhu SP et al (2012) Rhabdomyolysis, acute renal failure, and cardiac arrest secondary to status dystonicus in a child with glutaric aciduria type I. Mol Genet Metab 106:488–490
Kamate M, Patil V, Chetal V et al (2012) Glutaric aciduria type I: A treatable neurometabolic disorder. Ann Indian Acad Neurol 15:31–34
Koeth RA, Wang Z, Levison BS et al (2013) Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19:576–585
Köhler M, Hoffmann GF (1998) Subdural haematoma in a child with glutaric aciduria type I. Pediatr Radiol 28:582
Kölker S, Hoffmann GF, Schor DS et al (2003) Glutaryl-CoA dehydrogenase deficiency: region-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen. Neuropediatrics 34:253–260
Kölker S, Garbade S, Greenberg CR et al (2006) Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res 59:840–847
Kölker S, Garbade SF, Boy N et al (2007a) Decline of acute encephalopathic crises in children with glutaryl-CoA dehydrogenase deficiency identified by neonatal screening in Germany. Pediatr Res 62:353–362
Kölker S, Christensen E, Leonard JV et al (2007b) Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I). J Inherit Metab Dis 30:5–22
Kölker S, Christensen E, Leonard JV (2011) Diagnosis and management of glutaric aciduria type I--revised recommendations. J Inherit Metab Dis 34:677–694
Kölker S, Boy SP, Heringer J et al (2012) Complementary dietary treatment using lysine-free, arginine-fortified amino acid supplements in glutaric aciduria type I - a decade of experience. Mol Genet Metab 107:72–80
Kölker S, Cazorla AG, Valayannopoulos V et al (2015a) The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis 38:1041–1057
Kölker S, Valayannopoulos V, Burlina AB et al (2015b) The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis 38:1059–1074
Korman SH, Jakobs C, Darmin PS et al (2007) Glutaric aciduria type 1: clinical, biochemical and molecular findings in patients from Israel. Eur J Paediatr Neurol 11:81–89
Krstulovic AM, Brown PR, Rosie DM, Champlin PB (1977) High-performance liquid-chromatographic analysis for tryptophan in serum. Clin Chem 23:1984–1988
Külkens S, Harting I, Sauer S et al (2005) Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency. Neurology 64:2142–2144
Kurtcan S, Aksu B, Alkan A et al (2015) MRS features during encephalopathic crisis period in 11 years old case with GA-1. Brain Dev 37:546–551
Kyllerman M, Skjeldal OH, Lundberg M et al (1994) Dystonia and dyskinesia in glutaric aciduria type I: Clinical heterogeneity and therapeutic considerations. Mov Disord 9:22–30
Kyllerman M, Skjeldal O, Christensen E et al (2004) Long-term follow-up, neurological outcome and survival rate in 28 Nordic patients with glutaric aciduria type 1. Eur J Paediatr Neurol 8:121–129
Laich A, Neurauter G, Widner B, Fuchs D (2002) More rapid method for simultaneous measurement of trytophan and kynurenine by HPLC. Clin Chem 48:579–581
Lee CS, Chien YH, Peng SF et al (2013) Promising outcomes in glutaric aciduria type I patients detected by newborn screening. Metab Brain Dis 28:61–67
Lin SK, Hsu SG, Ho ES et al (2002) Novel mutations and prenatal sonographic findings of glutaric aciduria (type I) in two Taiwanese families. Prenat Diagn 22:725–729
Lindner M, Kölker S, Schulze A, Christensen E, Greenberg CR, Hoffmann GF (2004) Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27:851–859
Lindner M, Ho S, Fang-Hoffmann J, Hoffmann GF, Kölker S (2006) Neonatal screening for glutaric aciduria type I: strategies to proceed. J Inherit Metab Dis 29:378–382
Liow NY, Gimeno H, Lumsden DE et al (2016) Gabapentin can significantly improve dystonia severity and quality of life in children. Eur J Paediatr Neurol 20:100–107
Lipkin PH, Roe CR, Goodman SI, Batshaw ml (1988) A case of glutaric aciduria type I: effect of riboflavin and carnitine. J Pediatr 112:62–65
Loeber JG, Burgard P, Cornel MC et al (2012) Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 1. From blood spot to screening result. J Inherit Metab Dis 35:603–611
Luiking YC, Poeze M, Ramsay G, Deutz NE (2005) The role of arginine in infection and sepsis. JPEN J Parenter Enteral Nutr 29:S70–S74
Lumsden DE, Kaminska M, Gimeno H, Tustin K, Baker L, Perides S, Ashkan K, Selway R, Lin JP (2013) Proportion of life lived with dystonia inversely correlates with response to pallidal deep brain stimulation in both primary and secondary childhood dystonia. Dev Med Child Neurol 55:567–574
Lütcherath V, Waaler PE, Jellum E, Wester K (2000) Children with bilateral temporal arachnoid cysts may have glutaric aciduria type 1 (GAT1); operation without knowing that may be harmful. Acta Neurochir (Wien) 142:1025–1030
Ma J, Tan L, Chen S (2013a) A case of choreoathetosis due to glutaric aciduria type 1. Mov Disord 28:1808
Ma L, Savory S, Agim NG (2013b) Acquired protein energy malnutrition in glutaric acidemia. Pediatr Dermatol 30:502–504
MacDonald A, Depondt E, Evans S, Daly A, Hendriksz C, Chakrapani AA, Saudubray JM (2006) Breast feeding in IMD. J Inherit Metab Dis 29:299–303
Marigliano M, Anton G, Sabbion A et al (2013) Difficult management of glucose homeostasis in a 21-month-old child with type 1 diabetes and unknown glutaric aciduria type I: a case report. Diabetes Care 36:e135–e136
Marti-Masso JF, Ruiz-Martínez J, Makarov V et al (2012) Exome sequencing identifies GCDH (glutaryl-CoA dehydrogenase) mutations as a cause of a progressive form of early-onset generalized dystonia. Hum Genet 131:435–442
Martinez-Lage JF, Casas C, Fernandez MA, Puche A, Rodriguez Costa T, Poza M (1994) Macrocephaly, dystonia, and bilateral temporal arachnoid cysts : glutaric aciduria type 1. Childs Nerv Syst 10:198–203
McClelland VM, Bakalinova DB, Hendriksz C, Singh RP (2009) Glutaric aciduria type1 presenting with epilepsy. Dev Med Child Neurol 51:235–239
Mohammad SA, Abdelkhalek HS, Ahmed KA et al (2015) Glutaric aciduria type 1: Neuroimaging features with clinical correlation. Pediatr Radiol 45:1696–1705
Monavari AA, Naughten ER (2000) Prevention of cerebral palsy in glutaric aciduria type I by dietary management. Arch Dis Child 82:67–70
Monbaliu E, Ortibus E, Roelens F, Desloovere K, Deklerck J, Prinzie P, de Cock P, Feys H (2010) Rating scales for dystonia in cerebral palsy: reliability and validity. Dev Med Child Neurol 52:570–575
Moore T, Le A, Cowan TM (2012) An improved LC-MS/MS method for the detection of classic and low excreter glutaric acidemia type 1. J Inherit Metab Dis 35:431–435
Morris AAM, Hoffmann GF, Naughten ER, Monavari AA, Collins JE, Leonard JV (1999) Glutaric aciduria and suspected child abuse. Arch Dis Child 80:404–405
Morton DH, Bennett MJ, Seargeant LE, Nichter CA, Kelley RI (1991) A common cause of episodic encephalopathy an spastic paralysis in the Amish of Lancaster County, Pennsylvania. Am J Med Genet 41:89–95
Müller E, Kölker S (2004) Reduction of lysine intake while avoiding malnutrition–major goals and major problems in dietary treatment of glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27:903–910
Mushimoto Y, Fukuda S, Hasegawa Y et al (2011) Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1. Mol Genet Metab 102:343–348
Nasser M, Javaheri H, Fedorowicz Z, Noorani Z (2009) Carnitine supplementation for inborn errors of metabolism. Cochrane Database Syst Rev 2:CD006659
Naughten ER, Mayne PD, Monavari AA, Goodman SI, Sulaiman G, Croke DT (2004) Glutaric Aciduria Type I, Outcome in the Republic of Ireland. J Inherit Metab Dis 27:917–920
Neumaier-Probst E, Harting I, Seitz A, Ding C, Kölker S (2004) Neuroradiological findings in glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency). J Inherit Metab Dis 27:869–876
Oguz KK, Ozturk A, Cila A (2005) Diffusion-weighted MR imaging and MR spectroscopy in glutaric aciduria type I. Neuroradiology 47:229–234
Optimix®, Nutritional recommendations for children and adolescents, Research Institute for Child Nutrition Dortmund, Germany; URL http://www.fke-do.de/index.php; retrieved from 8th March 2016
Patay Z, Mills JC, Löbel U, Lambert A, Sablauer A, Ellison DW (2012) Cerebral neoplasms in L-2 hydroxyglutaric aciduria: 3 new cases and meta-analysis of literature data. AJNR Am J Neuroradiol 33:940–943
Pfeil J, Listl S, Hoffmann GF et al (2013) Newborn screening by tandem mass spectrometry for glutaric aciduria type 1: A cost-effectiveness analysis. Orphanet J Rare Dis 8:167
Pierson TM, Nezhad M, Tremblay MA et al (2015) Adult-onset glutaric aciduria type I presenting with white matter abnormalities and subependymal nodules. Neurogenetics 16:325–328
Prietsch V, Lindner M, Zschocke J, Nyhan WL, Hoffmann GF (2002) Emergency management of inherited metabolic diseases. J Inherit Metab Dis 25:531–546
Pusti S, Das N, Nayek K et al (2014) A treatable neurometabolic disorder: glutaric aciduria type 1. Case Rep Pediatr 2014:256356
Radha Rama Devi A, Ramesh VA, Nagarajaram HA et al (2016) Spectrum of mutations in glutaryl-coa dehydrogenase gene in glutaric aciduria type I - study from South India. Brain Dev 38:54–60
Rakocevic G, Lyons KE, Wilkinson SB, Overman JW, Pahwa R (2004) Bilateral pallidotomy for severe dystonia in an 18-month-old child with glutaric aciduria. Stereotact Funct Neurosurg 82:80–83
Renaud dl (2012) Leukoencephalopathies associated with macrocephaly. Semin Neurol 32:34–41
Rice J, Waugh MC (2009) Pilot study on trihexiphenidyl in the treatment of dystonia in children with cerebral palsy. J Child Neurol 24:176–182
Sanger TD, Bastian A, Brunstrom J et al (2007) Prospective open-label clinical trial of trihexiphenidyl in children with secondary dystonia due to cerebral palsy. J Child Neurol 22:530–537
Sauer SW, Opp S, Hoffmann GF et al (2011) Therapeutic modulation of cerebral L-lysine metabolism in a mouse model for glutaric aciduria type I. Brain 134:157–170
Schmahmann JD, Smith EE, Eichler FS, Filley CM (2008) Cerebral white matter: neuroanatomy, clinical neurology, and neurobehavioral correlates. Ann N Y Acad Sci 1142:266–309
Schulze-Bergkamen A, Okun JG, Spiekerkötter U et al (2005) Quantitative acylcarnitine profiling in peripheral blood mononuclear cells using in vitro loading with palmitic and 2-Oxoadipic acids: biochemical confirmation of fatty acid oxidation and organic acid disorders. Pediatr Res 58:873–880
Seccombe DW, James L, Booth F (1986) L-Carnitine treatment in glutaric aciduria type I. Neurology 36:264–267
Shigematsu Y, Hata I, Tanaka Y, Tajima G, Sakura N, Naito E, Yorifuri T (2005) Stable-isotope dilution gas chromatography–mass spectrometric measurement of 3-hydroxyglutaric acid, glutaric acid and related metabolites in body fluids of patients with glutaric aciduria type 1 found in newborn screening. J Chromatogr B Analyt Technol Biomed Life Sci 823:7–12
Singh P, Goraya JS, Ahluwalia A, Saggar K (2011) Teaching NeuroImages: Glutaric aciduria type 1 (glutaryl-CoA dehydrogenase deficiency). Neurology 77:e6
Smith WE, Millington DS, Koeberl DD, Lesser PS (2001) Glutaric academia, type I, missed by newborn screening in an infant with dystonia following promethazine administration. Pediatrics 107:1184–1187
Souci WS, Fachmann W, Kraut H (2008) Die Zusammensetzung der Lebensmittel, Nährwert-Tabellen. Wissenschaftliche Verlagsgesellschaft, 7. Auflage, ISBN-13: 978–3804750388
Strauss KA, Puffenberger EG, Robinson dl, Morton DH (2003) Type I glutaric aciduria, part 1: Natural history of 77 patients. Am J Med Genet 121C:38–52
Strauss KA, Lazovic J, Wintermark M, Morton DH (2007) Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency. Brain 130:1905–1920
Strauss KA, Brumbaugh J, Duffy A et al (2011) Safety, efficacy and physiological actions of a lysine-free, arginine-rich formula to treat glutaryl-CoA dehydrogenase deficiency: Focus on cerebral amino acid influx. Mol Genet Metab 104:93–106
Thies B, Meyer-Schwesinger C, Lamp J et al (2013) Acute renal proximal tubule alterations during induced metabolic crises in a mouse model of glutaric aciduria type 1. Biochim Biophys Acta 1832:1463–1472
Thomason MJ, Lord J, Bain MD, Chalmers RA, Littlejohns P, Addison GM, Wilcox AH, Seymour CA (1998) A systematic review of evidence for the appropriateness of neonatal screening programmes for inborn errors of metabolism. J Public Health Med 20:331–343
Tortorelli S, Hahn SH, Cowan TM, Brewster TG, Rinaldo P, Matern D (2005) The urinary excretion of glutarylcarnitine is an informative tool in the biochemical diagnosis of glutaric aciduria type I. Mol Genet Metab 84:137–143
Treacy EP, Lee-Chong A, Roche G, Lynch B, Ryan S, Goodman SI (2003) Profound neurological presentation resulting from homozygosity for a mild glutaryl-CoA dehydrogenase mutation with a minimal biochemical phenotype. J Inherit Metab Dis 26:72–74
Twomey EL, Naughten ER, Donoghue VB, Ryan S (2003) Neuroimaging findings in glutaric aciduria type I. Pediatr Radiol 33:823–830
Van der Watt G, Owen EP, Berman P et al (2010) Glutaric aciduria type 1 in South Africa-high incidence of glutaryl-CoA dehydrogenase deficiency in black South Africans. Mol Genet Metab 101:178–182
Van Rijn M, Bekhof J, Dijkstra T, Smit PG, Moddermam P, van Spronsen FJ (2003) A different approach to breast-feeding of the infant with phenylketonuria. Eur J Pediatr 162:323–326
Vester ME, Bilo RA, Karst WA et al (2015) Subdural hematomas: Glutaric aciduria type 1 or abusive head trauma? A systematic review. Forensic Sci Med Pathol 11:405–415
Vester ME, Visser G, Wijburg F, van Spronsen FJ, Williams M, van Rijn RR (2016) Occurrence of subdural hematomas in Dutch glutaric aciduria type 1 patients. Eur J Pediatr 175:1001–1006
Viau K, Ernst SL, Vanzo RJ et al (2012) Glutaric acidemia type 1: Outcomes before and after expanded newborn screening. Mol Genet Metab 106:430–438
Vilarinho L, Rocha H, Sousa C et al (2010) Four years of expanded newborn screening in Portugal with tandem mass spectrometry. J Inherit Metab Dis 33:S133–S138
Vom Dahl, S, Lammert, F, Ullrich, K, et al. Hrsg. (2014). Inherited metabolic diseases in Adults. Springer-Verlag; ISBN 978-3-642-45188-1
Walter JH (2003) L-Carnitine in inborn errors of metabolism: What is the evidence? J Inherit Metab Dis 26:181–188
Wang Q, Li X, Ding Y et al (2014) Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1. Brain Dev 36:813–822
Watson AR (2000) Non-compliance and transfer from paediatric to adult transplant unit. Pediatr Nephrol 14:469–472
Watson MS, Mann MY, Lloyd-Puryear MA et al (2006) Newborn screening: toward a uniform screening panel and system–executive summary. Pediatrics 117:S315–S319
Wechsler Preschool and Primary Scale of Intelligence (WPPSI) (2006) ,3rd edn
Wechsler Intelligence Scale for Children (WISC IV) (2007) ,4th edn
Wilcken B, Wiley V, Hammond J, Kl C (2003) Screening newborns for inborn errors of metabolism by tandem mass spectrometry. N Engl J Med 348:2304–2312
Woelfle J, Kreft B, Emons D, Haverkamp F (1996) Subdural hematoma and glutaric aciduria type I. Pediatr Radiol 26:779–781
World Health Organization (2007) Protein and amino acid requirements in human nutrition. Report of a joint WHO/FAO/UNU expert consultation. WHO Technical Report Series 935. World Health Organization, Geneva
Yang L, Yin H, Yang R et al (2011) Diagnosis, treatment and outcome of glutaric aciduria type I in Zhejiang Province, China. Med Sci Monit 17:H55–H59
Yannicelli S, Rohr F, Warman FL (1994) Nutrition support for glutaric acidemia type I. J Am Diet Assoc 94:183–191
Young-Lin N, Shalev S, Glenn OA et al (2013) Teaching neuroimages: infant with glutaric aciduria type 1 presenting with infantile spasms and hypsarrhythmia. Neurology 81:e182–e183
Zaki OK, Elabd HS, Ragheb SG et al (2014) Demographic and clinical features of glutaric acidemia type 1; a high frequency among isolates in Upper Egypt. Egypt J Med Hum Gen 15:187–192
Zeltner NA, Landolt MA, Baumgartner MR et al (2016) Living with intoxication-type inborn errors of metabolism: a qualitative analysis of interviews with paediatric patients and their parents. JIMD Rep. doi:10.1007/8904_2016_545
Zielonka M, Braun K, Bengel A et al (2015) Severe acute subdural hemorrhage in a patient with glutaric aciduria type I after minor head trauma: A case report. J Child Neurol 30:1065–1069
Zinnanti WJ, Lazovic J, Housman C, LaNoue K, O’Callaghan JP, Simpson I, Woontner M, Goodman SI, Connor JR, Jacobs RE, Cheng KC (2007) Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. J Clin Invest 117:3258–3270
Zschocke J, Quak E, Guldberg P, Hoffmann GF (2000) Mutation analysis in glutaric aciduria type I. J Med Genet 37:177–181
Zschocke J, Baumgartner MR, Morava E, Patterson MC, Peters V, Rahman S (2016) Recommendations and guidelines in the JIMD: suggested procedures and avoidance of conflicts of interest. J Inherit Metab Dis 39:327–329
Acknowledgments
This second guideline revision was supported by the German Society of Paediatrics (Deutsche Gesellschaft für Kinder- und Jugendmedizin, DGKJ).
Coauthors summarized as additional individual contributors are: Diana Ballhausen (Centre des maladies moléculaires, CHUV-Clinique Infantile, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland); Alberto B. Burlina (Division of Inherited Metabolic Diseases, University Hospital, Padova, Italy); Ralph Fingerhut (University Children`s Hospital, Zürich, Switzerland); Angeles García-Cazorla (Neurology and Metabolism Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues de Llobregat, E-08950 Barcelona, Spain); Berthold Koletzko (Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University of Munich, University of Munich Medical Centre, Munich, Germany); Martin Lindner (Division of Metabolic Diseases, University Children’s Hospital Frankfurt, Frankfurt, Germany); Sabine Scholl-Bürgi (Clinic for Paediatrics I, Inherited Metabolic Disorders, Medical, University of Innsbruck, Innsbruck, Austria) and Stephan vom Dahl (Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, University of Düesseldorf, Düsseldorf, Germany).
We thank Avihu Boneh, Alessandro P. Burlina, Ernst Christensen, Marinus Duran, Stephen I. Goodman, Mårten Kyllermann, James V. Leonard, Edith Müller, Eileen R. Naughten, and Bridget Wilcken for their contributions to the initial guideline development and first revision of guideline recommendations (Kölker et al. 2007b, 2011).
Additionally, we thank Mrs. Mirjam Kallmes as a representative of a support group for individuals with GA-I for her valuable input at the GDG meeting.
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The process for the second guideline revision was financially supported by the German Society of Paediatrics (Deutsche Gesellschaft für Kinder- und Jugendmedizin, DGKJ) and logistically supported by the University Hospital Heidelberg, Germany. The guideline process has not been influenced by the financing organisations.
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Consideration of conflicts of interests followed a recently recommended procedure (Zschocke et al. 2016). All authors declare that the answers to all other questions on the JIMD competing interest form are “NO”. The authors confirm independence from sponsors. The GDG did not accept direct funding from medical product companies or company foundations. Nikolas Boy, Chris Mühlhausen, Jana Heringer, Brigit Assmann, Diana Ballhausen, Alberto B. Burlina, Marjorie Dixon, Ralph Fingerhut, Angeles García-Cazorla, Cheryl R. Greenberg, Inga Harting, Berthold Koletzko, Martin Lindner, Jürgen G. Okun, Thomas Opladen, Roland Posset, Katja Sahm, Sabine Scholl-Bürgi, Stephan vom Dahl and Johannes Zschocke declare that they have no conflict of interest. Four members (Peter Burgard, Sandra Fleissner, Stefan Kölker, Michael Krawinkel) were consultants for a pharmaceutical company; five members (Peter Burgard, Sandra Fleissner, Georg F. Hoffmann, Stefan Kölker, Esther M. Maier) gave presentations during meetings organized by a pharmaceutical company; three members (Peter Burgard, Daniela Karall, Michael Krawinkel) received financial funding for research; one member (David M. Koeller) acted as an expert witness. No serious conflict of interest was declared. The content of this article has not been influenced by the sponsors.
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Communicated by: Jerry Vockley
References to electronic databases: Glutaric aciduria type I: OMIM no. 231670. Glutaryl-CoA dehydrogenase: EC 1.3.8.6
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Boy, N., Mühlhausen, C., Maier, E.M. et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis 40, 75–101 (2017). https://doi.org/10.1007/s10545-016-9999-9
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DOI: https://doi.org/10.1007/s10545-016-9999-9