Glutaric aciduria type 1

Last updated
Glutaric acidemia type 1
Other namesGlutaric aciduria, GA1, GAT1
Glutaric acid.png
Glutaric acid
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg

Glutaric acidemia type 1 (GA1) is an inherited disorder in which the body is unable to completely break down the amino acids lysine, hydroxylysine and tryptophan. Excessive levels of their intermediate breakdown products (glutaric acid, glutaryl-CoA, 3-hydroxyglutaric acid, glutaconic acid) can accumulate and cause damage to the brain (and also other organs [1] ), but particularly the basal ganglia, which are regions that help regulate movement. GA1 causes secondary carnitine deficiency, as glutaric acid, like other organic acids, is detoxified by carnitine. Mental retardation may occur.

Contents

GA1 is an autosomal recessive disorder caused by deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH), encoded by the GCDH gene.

Signs and symptoms

The severity of glutaric acidemia type 1 varies widely; some individuals are only mildly affected, while others suffer severe problems. GA1 can be defined as two clinical entities: GA-1 diagnosed at birth or pre-birth and managed through dietary restrictions, and GA-1 diagnosed after an encephalopathic crisis. A crisis may occur under both headings, but the care of individuals diagnosed before a crisis can be managed to avoid most or all injury.[ citation needed ]

GA1 without encephalopathic crisis

Macrocephaly

Babies with glutaric acidemia type 1 often are born with unusually large heads (macrocephaly). Macrocephaly is amongst the earliest signs of GA1. It is thus important to investigate all cases of macrocephaly of unknown origins for GCDH deficiency, [2] [3] given the importance of the early diagnosis of GA1. [4] Macrocephaly is a pivotal clinical sign of many neurological diseases. Physicians and parents should be aware of the benefits of investigating for an underlying neurological disorder, particularly a neurometabolic one, in children with head circumferences in the highest percentiles. [5]

GA1 after an encephalopathic crisis

Neuromotor aspects

Affected individuals may have difficulty moving and may experience spasms, jerking, rigidity or decreased muscle tone and muscle weakness (which may be the result of secondary carnitine deficiency). GA, in patients who have suffered a crisis, can be defined as a cerebral palsy of genetic origins.[ citation needed ][ clarification needed ]

Occupational therapy
GA1 posture2.jpg

A common way to manage striatal necrosis is to provide special seating. These special wheelchairs are designed to limit abnormal movements. However, spasticity can be worsened by constraint. Parents and caregivers can provide a more interactive occupational therapy by enabling the child to use his or her own excessive postural muscle tone to his or her own advantage (see picture; note the care with which minimal pressure is applied while ensuring safety).[ citation needed ]

The excessive tone can also be managed with hanging doorway baby exercisers and other aids to the upright stance that do not constrain the child but help him or her gradually tone down the rigidity.[ citation needed ]

Bleeding abnormalities

Some individuals with glutaric acidemia have developed bleeding in the brain or eyes that could be mistaken for the effects of child abuse.[ citation needed ]

Genetics

The condition is inherited in an autosomal recessive pattern: mutated copies of the gene GCDH must be provided by both parents to cause GA1. The GCDH gene encodes the enzyme glutaryl-CoA dehydrogenase. This enzyme is involved in degrading the amino acids lysine, hydroxylysine and tryptophan. Mutations in the GCDH gene prevent production of the enzyme or result in the production of a defective enzyme with very low residual activity, or an enzyme with relatively high residual activity but still phenotypic consequences. [6] [7] This enzyme deficiency allows glutaric acid, 3-hydroxyglutaric acid and to a lesser extent glutaconic acid to build up to abnormal levels, especially at times when the body is under stress. These intermediate breakdown products are particularly prone to affect the basal ganglia, causing many of the signs and symptoms of GA1.[ citation needed ]

GA1 occurs in approximately 1 of every 30,000 to 40,000 births. As a result of founder effect, it is much more common in the Amish community and in the Ojibway population of Canada, [8] where up to 1 in 300 newborns may be affected.

Relatives of children with GA1 can have low GCDH activity: in an early study of GA1, GCDH activity was found to be 38%, 42%, and 42% in three of the four unaffected relatives tested, a pattern consistent with the 50% level that would be expected in heterozygous carriers. [9] Those levels are close to those found in some heavily symptomatic GA1-affected children. [6]

Diagnosis

Normally, magnetic resonance imaging shows the Sylvian fissure to be operculated, but in GA1-associated encephalopathy, operculation is absent. In many jurisdictions, GA1 is included in newborn screening panels. Elevated glutarylcarnitine can be detected by mass spectrometry in a dried blood spot collected shortly after birth. After a positive screening result, confirmatory testing is performed. This includes urine organic acid analysis, looking for glutaric acid and 3-hydroxyglutaric acid. Plasma and urine acylcarnitine analysis can also be informative. Molecular analysis, including gene sequencing and copy number analysis of GCDH, can be performed to confirm the diagnosis. Molecular testing can also provide information for family planning and prenatal testing, if desired.[ citation needed ]

Treatment

Correction of secondary carnitine depletion

Like many other organic acidemias, GA1 causes carnitine depletion. [10] Whole-blood carnitine can be raised by oral supplementation. However, this does not significantly change blood concentrations of glutarylcarnitine or esterified carnitine, [4] suggesting that oral supplementation is suboptimal in raising tissue levels of carnitine. Clinical nutrition researchers have likewise concluded that oral carnitine raises plasma levels but does not affect those in muscles, where most of it is stored and used. [11]

In contrast, regular intravenous infusions of carnitine cause distinct clinical improvements: "decreased frequency of decompensations, improved growth, improved muscle strength and decreased reliance on medical foods with liberalization of protein intake." [10]

Choline increases carnitine uptake and retention. [12] Choline supplements are inexpensive, are safe (probably even in children requiring anticholinergics) and can increase exercise tolerance, truncal tone and general well-being, providing evidence of the suboptimal efficiency of carnitine supplementation alone.[ citation needed ]

Selective precursor restriction

Dietary control may help limit progression of the neurological damage.[ citation needed ]

Lysine

Lysine restriction, as well as carnitine supplementation, are considered the best predictors of a good prognosis for GA1. [13] This excludes, however, patients who already suffered an encephalopathic crisis, for whom the prognosis is more related to the treatment of their acquired disorder (striatal necrosis, frontotemporal atrophy).[ citation needed ]

Protein restriction

Vegetarian diets and, for younger children, breastfeeding [14] are common ways to limit protein intake without endangering tryptophan transport to the brain.

Tryptophan

Formulas such as XLys, XTrp Analog, XLys, XTrp Maxamaid, XLys, XTrp Maxamum or Glutarex 1 are designed to provide amino acids other than lysine and tryptophan, to help prevent protein malnutrition.[ citation needed ]

The entry of tryptophan into the brain is crucial in the proper synthesis of the neurotransmitter serotonin in the brain. One way to acutely cause depression, bulimia or anxiety in humans, in order to assess an individual's vulnerability to those disorders, is to supplement with a formula with all or most amino acids except tryptophan.[ citation needed ] Acute tryptophan depletion is a diagnostic procedure, not a treatment for GA1. The protein synthesis elicited by the amino acids leads circulating amino acids, including tryptophan, to be incorporated into proteins. Tryptophan is thus lowered in the brain as a result of the protein synthesis enhancement, causing circulating tryptophan to drop more than other amino acids. [15] A relative excess of other large neutral amino acids may also compete with tryptophan for transport across the blood–brain barrier through the large neutral amino acid transporter 1. The consequence is acute tryptophan depletion in the brain and a consequent decrease in serotonin synthesis.[ citation needed ]

5-Hydroxytryptophan, a precursor of serotonin that is not metabolized to glutaryl-CoA, glutaric acid and secondary metabolites, could be used as an adjunct to selective tryptophan restriction, although it has risks. However, the evidence in favour of selective tryptophan restriction remains insufficient and the consensus is evolving towards the restriction of lysine only. [13] In the Amish community, where GA1 is overrepresented, patients with GA1 typically do not receive tryptophan-free formulas, either as the sole source of amino acids or as a supplement to protein restriction.[ citation needed ]

Enhancement of precursor anabolic pathways

Lysine and hydroxylysine anabolic pathway enhancement

A possible way to prevent the build-up of metabolites is to limit lysine and hydroxylysine degradation, as lysine is one of the most abundant amino acids and tryptophan is one of the least abundant amino acids.[ citation needed ]

Interaction of GCDH deficiency with vitamin C levels

Humans lack the enzyme L-gulonolactone oxidase, which is necessary for the synthesis of ascorbic acid (vitamin C), leaving them dependent on dietary sources of this vitamin. Vitamin C is a necessary cofactor for the utilization of lysine in collagen synthesis. Collagen, the most abundant protein in the human body, requires great amounts of lysine, the most abundant amino acid in proteins. Ascorbic acid, the main hydroxyl radical quencher, works as the cofactor providing the hydroxyl radical required for collagen cross-linking; lysine thus becomes hydroxylysine.[ citation needed ]

GA1 worsens during stresses and catabolic episodes, such as fasts and infections. Endogenous catabolism of proteins could be an important route for glutaric acid production. It follows that collagen breakdown (and protein breakdown in general) should be prevented by all possible means.[ citation needed ]

Ascorbic acid is used to prevent multiple organ failure and to lessen mortality and morbidity in intensive care units. [16] It thus appears reasonable to add sufficient doses of ascorbic acid to the treatment protocol during stresses and other challenges to growth in order to stimulate collagen synthesis and thus prevent lysine breakdown.[ citation needed ]

Tryptophan anabolic pathway enhancement

The conversion of tryptophan to serotonin and other metabolites depends on vitamin B6. [17] If tryptophan catabolism has any impact on brain glutaric acid and other catabolite levels, vitamin B6 levels should be routinely assayed and normalized in the course of the treatment of GA1.[ citation needed ]

Management of intercurrent illnesses

Stress caused by infection, fever or other demands on the body may lead to worsening of the signs and symptoms, with only partial recovery.[ citation needed ]

Prognosis

A 2006 study of 279 patients found that of those with symptoms (185, 66%), 95% had suffered an encephalopathic crises, usually with following brain damage. Of the participants in the study, 49 children died and the median age of death was 6.6 years. A Kaplan–Meier analysis of the data estimated that about 50% of symptomatic people would die by the age of 25. [13] More recent studies provide an updated prognosis whereby individuals affected can, through proper dietary management and carnitine supplementation, manage the disease with a much improved prognosis. Newborn screening has allowed affected patients to avoid crises and live full lives without any injury to the brain. It is essential that patients with the disease be diagnosed at or before birth and that all variables be strictly managed in order to maintain quality of life. When suspected and in the absence of confirmed diagnosis (through genetic sequencing), it is critical that the individual maintain a diet restrictive of all proteins and that blood sugars be monitored rigorously. The WHO now considers this disease entirely manageable. [18]

Epidemiology

GA1 can be described as a metabolic disorder, a neurometabolic disease, a cerebral palsy or a basal ganglia disorder (it may also be misdiagnosed as shaken baby syndrome). Depending on the paradigm adopted, GA1 will mostly be managed with precursor restriction or with neurorehabilitation.[ citation needed ]

So-called "orphan diseases", such as GA1, can be adopted into wider groups of diseases (such as carnitine deficiency diseases, cerebral palsies of diverse origins, basal ganglia disorders, and others); Morton at al. (2003b) emphasize that acute striatal necrosis is a distinctive pathologic feature of at least 20 other disorders of very different etiologies, including, HIV encephalopathy–AIDS dementia complex, pneumococcal meningitis, hypoadrenal crisis, methylmalonic acidemia, propionic acidemia, middle cerebral artery occlusion, hypertensive vasculopathy, acute Mycoplasma pneumoniae infection, 3-nitropropionic acid intoxication, late-onset familial dystonia, cerebrovascular abrupt and severe neonatal asphyxia ("selective neuronal necrosis").[ citation needed ]

In a cohort of 279 patients who had been reported to have GA1, 185 were symptomatic (two-thirds); being symptomatic was seen as an indication of low treatment efficacy. Screening of those known to be at high risk, neonatal population screening and a diagnosis of macrocephaly are the ways to identify bearers of the GCDH mutation who are not frankly symptomatic. Macrocephaly remains the main sign of GA1 for those who have no relatives with GA1 and have not been included in a population screening program. GA1 is considered a treatable disease. [13] Two-thirds of the patients who have GA1 encephalopathy will receive little benefit from the treatment for GA1 but can benefit from treatments given to victims of middle cerebral artery occlusion, AIDS dementia and other basal ganglia disorders: brain implants, stem cell neurorestoration, growth factors, monoaminergic agents, and many other neurorehabilitation strategies.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Lysine</span> Amino acid

Lysine is an α-amino acid that is a precursor to many proteins. It contains an α-amino group, an α-carboxylic acid group, and a side chain lysyl, classifying it as a basic, charged, aliphatic amino acid. It is encoded by the codons AAA and AAG. Like almost all other amino acids, the α-carbon is chiral and lysine may refer to either enantiomer or a racemic mixture of both. For the purpose of this article, lysine will refer to the biologically active enantiomer L-lysine, where the α-carbon is in the S configuration.

<span class="mw-page-title-main">Macrocephaly</span> Abnormally large head size

Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to determine whether the syndrome is accompanied by particular disorders. Those with benign or familial macrocephaly are considered to have megalencephaly.

<span class="mw-page-title-main">Methylmalonic acidemias</span> Medical condition

Methylmalonic acidemias, also called methylmalonic acidurias, are a group of inherited metabolic disorders, that prevent the body from properly breaking down proteins and fats. This leads to a buildup of a toxic level of methylmalonic acid in body liquids and tissues. Due to the disturbed branched-chain amino acids (BCAA) metabolism, they are among the classical organic acidemias.

Propionic acidemia, also known as propionic aciduria or propionyl-CoA carboxylase deficiency, is a rare autosomal recessive metabolic disorder, classified as a branched-chain organic acidemia.

Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or due to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are often referred to as congenital metabolic diseases or inherited metabolic disorders. Another term used to describe these disorders is "enzymopathies". This term was created following the study of biodynamic enzymology, a science based on the study of the enzymes and their products. Finally, inborn errors of metabolism were studied for the first time by British physician Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene–one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism, was published in 1923.

<span class="mw-page-title-main">Isovaleric acidemia</span> Medical condition disrupting normal metabolism

Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

<span class="mw-page-title-main">Maple syrup urine disease</span> Autosomal recessive metabolic disorder

Maple syrup urine disease (MSUD) is a rare, inherited metabolic disorder that affects the body’s ability to metabolize amino acids due to a deficiency in the activity of the branched-chain alpha-ketoacid dehydrogenase (BCKAD) complex. It particularly affects the metabolism of amino acids- leucine, isoleucine, and valine. With MSUD, the body is not able to properly break down these amino acids, therefore leading to the amino acids to build up in urine and become toxic. The condition gets its name from the distinctive sweet odor of affected infants' urine and earwax due to the buildup of these amino acids.

<span class="mw-page-title-main">Beta-ketothiolase deficiency</span> Medical condition

Beta-ketothiolase deficiency is a rare, autosomal recessive metabolic disorder in which the body cannot properly process the amino acid isoleucine or the products of lipid breakdown. Along with SCOT deficiency, it belongs to a group of disorders called ketone utilisation disorders.

<span class="mw-page-title-main">Carnitine palmitoyltransferase II deficiency</span> Medical condition

Carnitine palmitoyltransferase II deficiency, sometimes shortened to CPT-II or CPT2, is an autosomal recessively inherited genetic metabolic disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported into the mitochondria for utilization as an energy source. The disorder presents in one of three clinical forms: lethal neonatal, severe infantile hepatocardiomuscular and myopathic.

Glutaric acidemia type 2 is an autosomal recessive metabolic disorder that is characterised by defects in the ability of the body to use proteins and fats for energy. Incompletely processed proteins and fats can build up, leading to a dangerous chemical imbalance called acidosis. It is a metabolic myopathy, categorized under fatty acid metabolism disorder as that is the bioenergetic system that it affects the most. It also affects choline metabolism.

<span class="mw-page-title-main">Malonic aciduria</span> Medical condition

Malonic aciduria or malonyl-CoA decarboxylase deficiency (MCD) is an autosomal-recessive metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-CoA decarboxylase. This enzyme breaks down Malonyl-CoA into acetyl-CoA and carbon dioxide.

<span class="mw-page-title-main">Glutaryl-CoA dehydrogenase</span> Protein-coding gene in the species Homo sapiens

Glutaryl-CoA dehydrogenase (GCDH) is an enzyme encoded by the GCDH gene on chromosome 19. The protein belongs to the acyl-CoA dehydrogenase family (ACD). It catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and carbon dioxide in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. The enzyme exists in the mitochondrial matrix as a homotetramer of 45-kD subunits. Mutations in this gene result in the metabolic disorder glutaric aciduria type 1, which is also known as glutaric acidemia type I. Alternative splicing of this gene results in multiple transcript variants.

<span class="mw-page-title-main">Electron-transferring-flavoprotein dehydrogenase</span> Protein family

Electron-transferring-flavoprotein dehydrogenase is an enzyme that transfers electrons from electron-transferring flavoprotein in the mitochondrial matrix, to the ubiquinone pool in the inner mitochondrial membrane. It is part of the electron transport chain. The enzyme is found in both prokaryotes and eukaryotes and contains a flavin and FE-S cluster. In humans, it is encoded by the ETFDH gene. Deficiency in ETF dehydrogenase causes the human genetic disease multiple acyl-CoA dehydrogenase deficiency.

Organic acidemia is a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present.

<span class="mw-page-title-main">ETFA</span> Protein-coding gene in humans

The human ETFA gene encodes the Electron-transfer-flavoprotein, alpha subunit, also known as ETF-α. Together with Electron-transfer-flavoprotein, beta subunit, encoded by the 'ETFB' gene, it forms the heterodimeric electron transfer flavoprotein (ETF). The native ETF protein contains one molecule of FAD and one molecule of AMP, respectively.

<span class="mw-page-title-main">ETFB</span> Protein-coding gene in humans

The human ETFB gene encodes the Electron-transfer-flavoprotein, beta subunit, also known as ETF-β. Together with Electron-transfer-flavoprotein, alpha subunit, encoded by the 'ETFA' gene, it forms the heterodimeric Electron transfer flavoprotein (ETF). The native ETF protein contains one molecule of FAD and one molecule of AMP, respectively.

<span class="mw-page-title-main">Alpha-aminoadipic semialdehyde synthase</span> Protein-coding gene in the species Homo sapiens

Alpha-aminoadipic semialdehyde synthase is an enzyme encoded by the AASS gene in humans and is involved in their major lysine degradation pathway. It is similar to the separate enzymes coded for by the LYS1 and LYS9 genes in yeast, and related to, although not similar in structure, the bifunctional enzyme found in plants. In humans, mutations in the AASS gene, and the corresponding alpha-aminoadipic semialdehyde synthase enzyme are associated with familial hyperlysinemia. This rare disease is inherited in an autosomal recessive pattern and patients often have no clinical symptoms.

<span class="mw-page-title-main">ETFDH</span> Protein-coding gene in humans

Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial is an enzyme that in humans is encoded by the ETFDH gene. This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain.

Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. However, the methylmalonic acid levels exceed those of malonic acid. CMAMMA is not only an organic aciduria but also a defect of mitochondrial fatty acid synthesis (mtFASII). Some researchers have hypothesized that CMAMMA might be one of the most common forms of methylmalonic acidemia, and possibly one of the most common inborn errors of metabolism. Due to being infrequently diagnosed, it most often goes undetected.

References

  1. ↑ Chow, S. L.; Rohan, C.; Morris, A. A. M.; Morris, A. A. M. (2003). "Case Report: Rhabdomyolysis in Glutaric Aciduria Type I". Journal of Inherited Metabolic Disease. 26 (7): 711–712. doi:10.1023/b:boli.0000005635.89043.8a. PMID   14707521. S2CID   11882529.
  2. ↑ Mahfoud Hawilou, Antonieta; Domínguez Méndez, Carmen Luisa; Rizzo, Cristiano; Ribes Rubio, Antonia (2004). "Macrocefalia in utero como manifestación clínica de aciduria glutárica tipo I. Informe de una nueva mutación" [In Utero Macrocephaly as Clinical Manifestation of Glutaric Aciduria Type I. Report of a Novel Mutation]. Revista de Neurología (in Spanish). 39 (10): 939–942. doi:10.33588/rn.3910.2004258. PMID   15573311.
  3. ↑ Martínez Granero, MA; Garcia Pérez, A; Martínez-Pardo, M; Parra, E (2005). "Macrocefalia como forma de presentación de la aciduria glutárica tipo 1. Importancia de un diagnóstico precoz" [Macrocephaly the first manifestation of glutaric aciduria type I: the importance of early diagnosis]. Neurología. 20 (5): 255–260. PMID   15954035.
  4. 1 2 Strauss, Kevin A.; Puffenberger, Erik G.; Robinson, Donna L.; Morton, D. Holmes (15 August 2003). "Type I glutaric aciduria, part 1: Natural history of 77 patients". American Journal of Medical Genetics. 121C (1): 38–52. doi:10.1002/ajmg.c.20007. PMID   12888985. S2CID   23370609.
  5. ↑ Accogli A, Geraldo AF, Piccolo G, Riva A, Scala M, Balagura G, Salpietro V, Madia F, Maghnie M, Zara F, Striano P, Tortora D, Severino M and Capra V (2022) Diagnostic Approach to Macrocephaly in Children. Frontiers in Pediatrics 9:794069. doi:10.3389/fped.2021.794069
  6. 1 2 Christensen E, Aracil A, Vilaseca MA, Busquets C, Ribes A, Pineda M (1998). "Glutaric aciduria type I with high residual glutaryl-CoA dehydrogenase activity". Dev Med Child Neurol. 40 (12): 840–2. doi: 10.1111/j.1469-8749.1998.tb12362.x . PMID   9881681.
  7. ↑ Christensen, E.; Ribes, A.; Merinero, B.; Zschocke, J. (2004). "Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency". Journal of Inherited Metabolic Disease. 27 (6): 861–868. doi:10.1023/B:BOLI.0000045770.93429.3c. PMID   15505393. S2CID   24612304.
  8. ↑ Larson, Austin; Goodman, Steve (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "Glutaric Acidemia Type 1", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   31536184 , retrieved 2022-01-08{{citation}}: More than one of |editor2-first= and |editor-first2= specified (help); More than one of |editor2-last= and |editor-last2= specified (help); More than one of |editor3-first= and |editor-first3= specified (help); More than one of |editor3-last= and |editor-last3= specified (help); More than one of |editor4-first= and |editor-first4= specified (help); More than one of |editor4-last= and |editor-last4= specified (help)
  9. ↑ Whelan, DT; Hill, R; Ryan, ED; Spate, M (January 1979). "L-Glutaric acidemia: investigation of a patient and his family". Pediatrics. 63 (1): 88–93. doi:10.1542/peds.63.1.88. PMID   440804. S2CID   41194171.
  10. 1 2 Winter, S. C. (2003). "Treatment of carnitine deficiency". Journal of Inherited Metabolic Disease. 26 (2): 171–180. doi:10.1023/a:1024433100257. PMID   12889658. S2CID   5563622.
  11. ↑ Brass, Eric P (August 2000). "Supplemental carnitine and exercise". The American Journal of Clinical Nutrition. 72 (2): 618S–623S. doi: 10.1093/ajcn/72.2.618S . PMID   10919968.
  12. ↑ Daily, James W.; Sachan, Dileep S. (July 1995). "Choline Supplementation Alters Carnitine Homeostasis in Humans and Guinea Pigs". The Journal of Nutrition. 125 (7): 1938–1944. doi:10.1093/jn/125.7.1938. PMID   7616311.
  13. 1 2 3 4 Kölker, Stefan; Garbade, Sven F; Greenberg, Cheryl R; Leonard, James V; Saudubray, Jean-Marie; Ribes, Antonia; Kalkanoglu, H Serap; Lund, Allan M; Merinero, Begoña; Wajner, Moacir; Troncoso, Mónica; Williams, Monique; Walter, John H; Campistol, Jaume; MartÍ-Herrero, Milagros; Caswill, Melissa; Burlina, Alberto B; Lagler, Florian; Maier, Esther M; Schwahn, Bernd; Tokatli, Aysegul; Dursun, Ali; Coskun, Turgay; Chalmers, Ronald A; Koeller, David M; Zschocke, Johannes; Christensen, Ernst; Burgard, Peter; Hoffmann, Georg F (June 2006). "Natural History, Outcome, and Treatment Efficacy in Children and Adults with Glutaryl-CoA Dehydrogenase Deficiency". Pediatric Research. 59 (6): 840–847. doi: 10.1203/01.pdr.0000219387.79887.86 . PMID   16641220.
  14. ↑ Gokcay, G.; Baykal, T.; Gokdemir, Y.; Demirkol, M. (April 2006). "Breast feeding in organic acidaemias". Journal of Inherited Metabolic Disease. 29 (2–3): 304–310. doi:10.1007/s10545-005-0255-y. PMID   16763892. S2CID   3147346.
  15. ↑ Young SN (1993). "The use of diet and dietary components in the study of factors controlling affect in humans: a review". J Psychiatry Neurosci. 18 (5): 235–44. PMC   1188544 . PMID   8297922.
  16. ↑ Lovat, R.; Preiser, J. C. (2003). "Antioxidant therapy in intensive care". Current Opinion in Critical Care. 9 (4): 266–270. doi:10.1097/00075198-200308000-00003. PMID   12883280. S2CID   19893545.
  17. ↑ Hartvig, P.; Lindner, K. J.; Bjurling, P.; Långström, B.; Tedroff, J. (June 1995). "Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography". Journal of Neural Transmission. 102 (2): 91–97. doi:10.1007/BF01276505. PMID   8748674. S2CID   39796582.
  18. ↑ Boy, Nikolas; Mühlhausen, Chris; Maier, Esther M.; Heringer, Jana; Assmann, Birgit; Burgard, Peter; Dixon, Marjorie; Fleissner, Sandra; Greenberg, Cheryl R.; Harting, Inga; Hoffmann, Georg F.; Karall, Daniela; Koeller, David M.; Krawinkel, Michael B.; Okun, Jürgen G.; Opladen, Thomas; Posset, Roland; Sahm, Katja; Zschocke, Johannes; Kölker, Stefan (16 November 2016). "Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision". Journal of Inherited Metabolic Disease. 40 (1): 75–101. doi:10.1007/s10545-016-9999-9. PMID   27853989. S2CID   6316667.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.