Materiały źródłowe

• #1 Glutaric aciduria type 1

  https://www.nhs.uk/conditions/glutaric-aciduria/

  Glutaric aciduria type 1 (GA1) is a rare but serious inherited condition. It means the body can’t process certain amino acids („building blocks” of protein), causing a harmful build-up of substances in the blood and urine. […] The genetic cause (mutation) of GA1 is passed on by the parents, who usually don’t have any symptoms of the condition. […] The way this mutation is passed on is known as autosomal recessive inheritance. This means a baby needs to receive 2 copies of the affected gene to develop the condition 1 from their mother and 1 from their father. If the baby only receives 1 affected gene, they’ll just be a carrier of GA1.

• #2 Glutaric acidemia type I: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/glutaric-acidemia-type-i/

  Glutaric acidemia type I (also called glutaric aciduria type I) is an inherited disorder in which the body is unable to process certain proteins properly. […] Mutations in the GCDH gene cause glutaric acidemia type I. The GCDH gene provides instructions for making the enzyme glutaryl-CoA dehydrogenase. […] Mutations in the GCDH gene prevent production of the enzyme or result in the production of a defective enzyme that cannot function. […] A shortage (deficiency) of this enzyme allows lysine, hydroxylysine and tryptophan and their intermediate breakdown products to build up to abnormal levels, especially at times when the body is under stress. […] The intermediate breakdown products resulting from incomplete processing of lysine, hydroxylysine, and tryptophan can damage the brain, particularly the basal ganglia, causing the signs and symptoms of glutaric acidemia type I.

• #3 Newborn screening information for glutaric acidemia type I | Baby’s First Test | Newborn Screening | Baby Health

  https://www.babysfirsttest.org/newborn-screening/conditions/glutaric-acidemia-type-i

  Glutaric acidemia, type 1 (GA-1) is an inherited condition in which the body is unable to break down certain proteins properly. […] GA-1 occurs when your babys body either doesnt make enough or makes malfunctioning glutaryl-CoA dehydrogenase enzymes. When your babys body cannot break down these substances, harmful substances build up in the body. […] GA-1 is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for GA-1, one from each parent, in order to have the condition. The parents of a child with an autosomal recessive condition each carry one copy of the non-working gene, but they typically do not show signs and symptoms of the condition.

• #4 Diagnosis and management of glutaric aciduria type I – revised recommendations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3109243/

  Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. […] Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. […] More than 200 disease-causing mutations are known. […] The GCDH gene is localized on chromosome 19p13.2 and encodes a flavin adenine dinucleotide-dependent mitochondrial matrix protein that is involved in the degradative metabolism of L-lysine, L-hydroxylysine and L-tryptophan. […] Untreated, approximately 90% of patients will develop neurological disease during a finite period of brain development (age 3-36 months) following an acute encephalopathic crisis often precipitated by gastroenteritis, intercurrent febrile illness, immunization, or surgical intervention.

• #5

  https://omim.org/entry/231670

  A number sign (#) is used with this entry because glutaric acidemia I (GA1) is caused by homozygous or compound heterozygous mutation in the gene encoding glutaryl-CoA dehydrogenase (GCDH; 608801) on chromosome 19p13. […] Glutaric acidemia I (GA1) is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (Goodman et al., 1995). […] Caused by mutation in the glutaryl-CoA dehydrogenase gene (GCDH, 608801.0001)

• #6 Glutaric aciduria | MedLink Neurology

  https://www.medlink.com/articles/glutaric-aciduria

  Glutaric aciduria or acidemia type I is biochemically characterized by an accumulation of putatively neurotoxic glutaric and 3-hydroxyglutaric acid and nontoxic glutarylcarnitine. […] Glutaric aciduria or acidemia type I (glutaryl-CoA dehydrogenase [GCDH] deficiency) was first described in 1975 and is caused by inherited deficiency of GCDH (EC 1.3.8.6), an essential enzyme for the catabolism of lysine, hydroxylysine, and tryptophan. […] The primary defect in glutaric aciduria type I is the deficiency of GCDH, a homotetrameric, flavin adenine dinucleotidebinding enzyme that is one of a family of mitochondrial acyl-CoA dehydrogenases linked to the electron-transport chain through electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase. […] GCDH is a key enzyme in the common catabolic pathway of the amino acids L-tryptophan, L-lysine, and L-hydroxylysine.

• #7 Diagnosis and management of glutaric aciduria type I – revised recommendations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3109243/

  Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. […] Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. […] More than 200 disease-causing mutations are known. […] The GCDH gene is localized on chromosome 19p13.2 and encodes a flavin adenine dinucleotide-dependent mitochondrial matrix protein that is involved in the degradative metabolism of L-lysine, L-hydroxylysine and L-tryptophan. […] Untreated, approximately 90% of patients will develop neurological disease during a finite period of brain development (age 3-36 months) following an acute encephalopathic crisis often precipitated by gastroenteritis, intercurrent febrile illness, immunization, or surgical intervention.

• #8 Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

  https://www.mdpi.com/2409-515X/1/2/57

  Glutaric aciduria type I (GA-I) is caused by two pathogenic mutations in the GCDH gene which consists of 11 exons (7 kb) and is located on 19p13.2. […] More than 200 disease-causing mutations have been identified so far; most of them are private. […] The most frequent mutation in Europe is p.Arg402Trp accounting for 10%–20% of all alleles. […] Other mutations are predominantly or even exclusively found in distinct populations such as p.Ala421Val in the Amish Community as well as Southern parts of Germany and Switzerland, the original settlement area of the Amish, IVS1 + 5G > T in the Oji-Cree First Nations, p.Pro248Leu and p.Glu365Lys in Turkey, and p.Arg227Pro and p.Val400Met in Spain. […] Inherited deficiency of glutaryl-CoA dehydrogenase, a mitochondrial flavoprotein which catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA in the catabolic pathways of l-lysine, l-tryptophan and l-hydroxylysine, causes cerebral accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutarylcarnitine (C5DC).

• #9 Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

  https://www.mdpi.com/2409-515X/1/2/57

  Glutaric aciduria type I (GA-I) is caused by two pathogenic mutations in the GCDH gene which consists of 11 exons (7 kb) and is located on 19p13.2. […] More than 200 disease-causing mutations have been identified so far; most of them are private. […] The most frequent mutation in Europe is p.Arg402Trp accounting for 10%–20% of all alleles. […] Other mutations are predominantly or even exclusively found in distinct populations such as p.Ala421Val in the Amish Community as well as Southern parts of Germany and Switzerland, the original settlement area of the Amish, IVS1 + 5G > T in the Oji-Cree First Nations, p.Pro248Leu and p.Glu365Lys in Turkey, and p.Arg227Pro and p.Val400Met in Spain. […] Inherited deficiency of glutaryl-CoA dehydrogenase, a mitochondrial flavoprotein which catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA in the catabolic pathways of l-lysine, l-tryptophan and l-hydroxylysine, causes cerebral accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutarylcarnitine (C5DC).

• #10 Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

  https://www.mdpi.com/2409-515X/1/2/57

  Glutaric aciduria type I (GA-I) is caused by two pathogenic mutations in the GCDH gene which consists of 11 exons (7 kb) and is located on 19p13.2. […] More than 200 disease-causing mutations have been identified so far; most of them are private. […] The most frequent mutation in Europe is p.Arg402Trp accounting for 10%–20% of all alleles. […] Other mutations are predominantly or even exclusively found in distinct populations such as p.Ala421Val in the Amish Community as well as Southern parts of Germany and Switzerland, the original settlement area of the Amish, IVS1 + 5G > T in the Oji-Cree First Nations, p.Pro248Leu and p.Glu365Lys in Turkey, and p.Arg227Pro and p.Val400Met in Spain. […] Inherited deficiency of glutaryl-CoA dehydrogenase, a mitochondrial flavoprotein which catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA in the catabolic pathways of l-lysine, l-tryptophan and l-hydroxylysine, causes cerebral accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutarylcarnitine (C5DC).

• #11 Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

  https://www.mdpi.com/2409-515X/1/2/57

  Glutaric aciduria type I (GA-I) is caused by two pathogenic mutations in the GCDH gene which consists of 11 exons (7 kb) and is located on 19p13.2. […] More than 200 disease-causing mutations have been identified so far; most of them are private. […] The most frequent mutation in Europe is p.Arg402Trp accounting for 10%–20% of all alleles. […] Other mutations are predominantly or even exclusively found in distinct populations such as p.Ala421Val in the Amish Community as well as Southern parts of Germany and Switzerland, the original settlement area of the Amish, IVS1 + 5G > T in the Oji-Cree First Nations, p.Pro248Leu and p.Glu365Lys in Turkey, and p.Arg227Pro and p.Val400Met in Spain. […] Inherited deficiency of glutaryl-CoA dehydrogenase, a mitochondrial flavoprotein which catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA in the catabolic pathways of l-lysine, l-tryptophan and l-hydroxylysine, causes cerebral accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutarylcarnitine (C5DC).

• #12 Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

  https://www.mdpi.com/2409-515X/1/2/57

  Glutaric aciduria type I (GA-I) is caused by two pathogenic mutations in the GCDH gene which consists of 11 exons (7 kb) and is located on 19p13.2. […] More than 200 disease-causing mutations have been identified so far; most of them are private. […] The most frequent mutation in Europe is p.Arg402Trp accounting for 10%–20% of all alleles. […] Other mutations are predominantly or even exclusively found in distinct populations such as p.Ala421Val in the Amish Community as well as Southern parts of Germany and Switzerland, the original settlement area of the Amish, IVS1 + 5G > T in the Oji-Cree First Nations, p.Pro248Leu and p.Glu365Lys in Turkey, and p.Arg227Pro and p.Val400Met in Spain. […] Inherited deficiency of glutaryl-CoA dehydrogenase, a mitochondrial flavoprotein which catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA in the catabolic pathways of l-lysine, l-tryptophan and l-hydroxylysine, causes cerebral accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutarylcarnitine (C5DC).

• #13 A review of patients with glutaric aciduria type 1 at Inkosi Albert Luthuli Central Hospital, Durban, South Africa

  http://www.scielo.org.za/scielo.php?script=sci_arttext&pid=S0256-95742017000300017

  A higher carrier rate of the A293T mutation has been previously described in patients of black indigenous ancestry in the SA population. Heterozygosity for the A293T mutation was found in 1 of 36 unrelated black SA newborns, giving a predicted prevalence rate for GA1 of 1/5 184 in this population. All patients in our cohort were of black African indigenous ancestry. […] GA1 has a high prevalence in SA.

• #14 Glutaric aciduria type 1 – Wikipedia

  https://en.wikipedia.org/wiki/Glutaric_aciduria_type_1

  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. […] GA1 is an autosomal recessive disorder caused by deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH), encoded by the GCDH gene. […] The condition is inherited in an autosomal recessive pattern: mutated copies of the gene GCDH must be provided by both parents to cause GA1. […] 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. […] 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. […] 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, where up to 1 in 300 newborns may be affected.

• #15 Glutaric Acidemia Type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2556991/

  Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder of lysine, hydroxylysine, and tryptophan metabolism caused by deficiency of glutaryl-CoA dehydrogenase. […] This disorder can be diagnosed by expanded newborn screening by MS/MS and here we will review what can be expected from early diagnosis as compared to clinical diagnosis. […] GA-1 is caused by heterogenous mutations in the glutaryl-CoA dehydrogenase gene. […] More than 63 different mutations, including missense, nonsense and intronic variants, have been reported in patients with GA-1. […] There is correlation between residual enzyme activity and biochemical phenotype, i.e. urinary excretion of glutaric acid. […] However, there is no association between phenotype and severity of the genetic lesion, since siblings within the same family and with the same mutation and genetic background can have discordant phenotypes.

• #16 Diagnosis and management of glutaric aciduria type I – revised recommendations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3109243/

  Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. […] Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. […] More than 200 disease-causing mutations are known. […] The GCDH gene is localized on chromosome 19p13.2 and encodes a flavin adenine dinucleotide-dependent mitochondrial matrix protein that is involved in the degradative metabolism of L-lysine, L-hydroxylysine and L-tryptophan. […] Untreated, approximately 90% of patients will develop neurological disease during a finite period of brain development (age 3-36 months) following an acute encephalopathic crisis often precipitated by gastroenteritis, intercurrent febrile illness, immunization, or surgical intervention.

• #17 Glutaric aciduria | MedLink Neurology

  https://www.medlink.com/articles/glutaric-aciduria

  Glutaric aciduria or acidemia type I is biochemically characterized by an accumulation of putatively neurotoxic glutaric and 3-hydroxyglutaric acid and nontoxic glutarylcarnitine. […] Glutaric aciduria or acidemia type I (glutaryl-CoA dehydrogenase [GCDH] deficiency) was first described in 1975 and is caused by inherited deficiency of GCDH (EC 1.3.8.6), an essential enzyme for the catabolism of lysine, hydroxylysine, and tryptophan. […] The primary defect in glutaric aciduria type I is the deficiency of GCDH, a homotetrameric, flavin adenine dinucleotidebinding enzyme that is one of a family of mitochondrial acyl-CoA dehydrogenases linked to the electron-transport chain through electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase. […] GCDH is a key enzyme in the common catabolic pathway of the amino acids L-tryptophan, L-lysine, and L-hydroxylysine.

• #18 Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

  https://www.mdpi.com/2409-515X/1/2/57

  Glutaric aciduria type I (GA-I) is caused by two pathogenic mutations in the GCDH gene which consists of 11 exons (7 kb) and is located on 19p13.2. […] More than 200 disease-causing mutations have been identified so far; most of them are private. […] The most frequent mutation in Europe is p.Arg402Trp accounting for 10%–20% of all alleles. […] Other mutations are predominantly or even exclusively found in distinct populations such as p.Ala421Val in the Amish Community as well as Southern parts of Germany and Switzerland, the original settlement area of the Amish, IVS1 + 5G > T in the Oji-Cree First Nations, p.Pro248Leu and p.Glu365Lys in Turkey, and p.Arg227Pro and p.Val400Met in Spain. […] Inherited deficiency of glutaryl-CoA dehydrogenase, a mitochondrial flavoprotein which catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA in the catabolic pathways of l-lysine, l-tryptophan and l-hydroxylysine, causes cerebral accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutarylcarnitine (C5DC).

• #19 Glutaric aciduria | MedLink Neurology

  https://www.medlink.com/articles/glutaric-aciduria

  GCDH deficiency results in an insufficient flux of glutaryl-CoA to crotonyl-CoA resulting in an accumulation of upstream metabolites, especially glutaryl-CoA, which is subsequently converted to glutaric acid and 3-hydroxyglutaric acid. […] Postmortem examinations in patients showed that intracerebral concentrations of glutaric and 3-hydroxyglutaric acids exceed plasma concentrations by 10- to 1000-fold. […] It has been shown that the cerebral susceptibility to L-lysine is modulated by three factors: gender, genetic background, and lysine dosage. […] Previous studies have provided evidence that neurodegeneration in glutaric aciduria type I might be caused by excitotoxic cell damage. […] An alternative mechanism has been postulated. Glutaryl-CoA inhibits the 2-oxoglutarate dehydrogenase complex, a key enzyme in the tricarboxylic acid cycle. […] Although most studies investigated the mechanism underlying striatal injury, the mechanism of the increasingly observed extrastriatal abnormalities has remained virtually unclear.

• #20 Glutaric aciduria | MedLink Neurology

  https://www.medlink.com/articles/glutaric-aciduria

  Glutaric aciduria or acidemia type I is biochemically characterized by an accumulation of putatively neurotoxic glutaric and 3-hydroxyglutaric acid and nontoxic glutarylcarnitine. […] Glutaric aciduria or acidemia type I (glutaryl-CoA dehydrogenase [GCDH] deficiency) was first described in 1975 and is caused by inherited deficiency of GCDH (EC 1.3.8.6), an essential enzyme for the catabolism of lysine, hydroxylysine, and tryptophan. […] The primary defect in glutaric aciduria type I is the deficiency of GCDH, a homotetrameric, flavin adenine dinucleotidebinding enzyme that is one of a family of mitochondrial acyl-CoA dehydrogenases linked to the electron-transport chain through electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase. […] GCDH is a key enzyme in the common catabolic pathway of the amino acids L-tryptophan, L-lysine, and L-hydroxylysine.

• #21 Impact of newborn screening and quality of therapy on the neurological outcome in glutaric aciduria type 1: a meta-analysis | Genetics in Medicine

  https://www.nature.com/articles/s41436-020-00971-4

  Glutaric aciduria type 1 (GA1, OMIM 231670) is a rare disorder of L-lysine, L-hydroxylysine, and L-tryptophan metabolism caused by inherited deficiency of glutaryl-CoA dehydrogenase (EC 1.3.8.6) resulting in accumulation of glutaryl-CoA and its dicarboxylic derivatives, glutaric acid (GA), 3-hydroxyglutaric acid (3OHGA), glutaconic acid, and glutarylcarnitine in body tissues, especially in the brain. […] The majority of untreated individuals present with a complex movement disorder (MD) with predominant dystonia mostly between the age of 3 and 36 months due to bilateral striatal damage. […] This prognostically relevant event mostly manifests acutely with an acute encephalopathic crisis, precipitated by catabolism and usually resulting in a severe MD with concomitantly increased morbidity and mortality, or insidiously without clinically apparent crisis, often resulting in a less severe MD compared with the acute manifestation.

• #22 Glutaric aciduria | MedLink Neurology

  https://www.medlink.com/articles/glutaric-aciduria

  GCDH deficiency results in an insufficient flux of glutaryl-CoA to crotonyl-CoA resulting in an accumulation of upstream metabolites, especially glutaryl-CoA, which is subsequently converted to glutaric acid and 3-hydroxyglutaric acid. […] Postmortem examinations in patients showed that intracerebral concentrations of glutaric and 3-hydroxyglutaric acids exceed plasma concentrations by 10- to 1000-fold. […] It has been shown that the cerebral susceptibility to L-lysine is modulated by three factors: gender, genetic background, and lysine dosage. […] Previous studies have provided evidence that neurodegeneration in glutaric aciduria type I might be caused by excitotoxic cell damage. […] An alternative mechanism has been postulated. Glutaryl-CoA inhibits the 2-oxoglutarate dehydrogenase complex, a key enzyme in the tricarboxylic acid cycle. […] Although most studies investigated the mechanism underlying striatal injury, the mechanism of the increasingly observed extrastriatal abnormalities has remained virtually unclear.

• #23

  https://journals.lww.com/aomd/fulltext/2022/05010/role_of_glutaric_aciduria_type_1_in_movement.12.aspx

  Glutaric aciduria type 1 (OMIM#231670) was characterized as complex dystonia (predominant dystonia in a complex phenotypic presentation). […] Glutaryl-CoA dehydrogenase is encountered in presynaptic neuronal mitochondria, and its deficiency causes the accumulation of GA and 3-OHGA (GA-3OHGA). […] These two compounds get trapped inside the cerebral tissue due to low dicarboxylate transport efflux. […] They can cause mitochondrial dysfunction, inhibiting the Krebs cycle and blocking the respiratory chain; this contributes to the production of reactive oxygen species. […] Moreover, GA-3OHGA can increase glutamate release in the synaptic membrane, stimulate glutamate receptors, and decrease glutamate uptake. […] An interesting fact about this disease is that the lesions occur in specific areas of the brain. […] Garbade et al. reported the neuroradiological patterns of patients with glutaric aciduria type 1 using statistical models.

• #24

  https://journals.lww.com/aomd/fulltext/2022/05010/role_of_glutaric_aciduria_type_1_in_movement.12.aspx

  Glutaric aciduria type 1 (OMIM#231670) was characterized as complex dystonia (predominant dystonia in a complex phenotypic presentation). […] Glutaryl-CoA dehydrogenase is encountered in presynaptic neuronal mitochondria, and its deficiency causes the accumulation of GA and 3-OHGA (GA-3OHGA). […] These two compounds get trapped inside the cerebral tissue due to low dicarboxylate transport efflux. […] They can cause mitochondrial dysfunction, inhibiting the Krebs cycle and blocking the respiratory chain; this contributes to the production of reactive oxygen species. […] Moreover, GA-3OHGA can increase glutamate release in the synaptic membrane, stimulate glutamate receptors, and decrease glutamate uptake. […] An interesting fact about this disease is that the lesions occur in specific areas of the brain. […] Garbade et al. reported the neuroradiological patterns of patients with glutaric aciduria type 1 using statistical models.

• #25

  https://journals.lww.com/aomd/fulltext/2022/05010/role_of_glutaric_aciduria_type_1_in_movement.12.aspx

  Glutaric aciduria type 1 (OMIM#231670) was characterized as complex dystonia (predominant dystonia in a complex phenotypic presentation). […] Glutaryl-CoA dehydrogenase is encountered in presynaptic neuronal mitochondria, and its deficiency causes the accumulation of GA and 3-OHGA (GA-3OHGA). […] These two compounds get trapped inside the cerebral tissue due to low dicarboxylate transport efflux. […] They can cause mitochondrial dysfunction, inhibiting the Krebs cycle and blocking the respiratory chain; this contributes to the production of reactive oxygen species. […] Moreover, GA-3OHGA can increase glutamate release in the synaptic membrane, stimulate glutamate receptors, and decrease glutamate uptake. […] An interesting fact about this disease is that the lesions occur in specific areas of the brain. […] Garbade et al. reported the neuroradiological patterns of patients with glutaric aciduria type 1 using statistical models.

• #26 Glutaric aciduria | MedLink Neurology

  https://www.medlink.com/articles/glutaric-aciduria

  GCDH deficiency results in an insufficient flux of glutaryl-CoA to crotonyl-CoA resulting in an accumulation of upstream metabolites, especially glutaryl-CoA, which is subsequently converted to glutaric acid and 3-hydroxyglutaric acid. […] Postmortem examinations in patients showed that intracerebral concentrations of glutaric and 3-hydroxyglutaric acids exceed plasma concentrations by 10- to 1000-fold. […] It has been shown that the cerebral susceptibility to L-lysine is modulated by three factors: gender, genetic background, and lysine dosage. […] Previous studies have provided evidence that neurodegeneration in glutaric aciduria type I might be caused by excitotoxic cell damage. […] An alternative mechanism has been postulated. Glutaryl-CoA inhibits the 2-oxoglutarate dehydrogenase complex, a key enzyme in the tricarboxylic acid cycle. […] Although most studies investigated the mechanism underlying striatal injury, the mechanism of the increasingly observed extrastriatal abnormalities has remained virtually unclear.

• #27 Glutaric aciduria | MedLink Neurology

  https://www.medlink.com/articles/glutaric-aciduria

  GCDH deficiency results in an insufficient flux of glutaryl-CoA to crotonyl-CoA resulting in an accumulation of upstream metabolites, especially glutaryl-CoA, which is subsequently converted to glutaric acid and 3-hydroxyglutaric acid. […] Postmortem examinations in patients showed that intracerebral concentrations of glutaric and 3-hydroxyglutaric acids exceed plasma concentrations by 10- to 1000-fold. […] It has been shown that the cerebral susceptibility to L-lysine is modulated by three factors: gender, genetic background, and lysine dosage. […] Previous studies have provided evidence that neurodegeneration in glutaric aciduria type I might be caused by excitotoxic cell damage. […] An alternative mechanism has been postulated. Glutaryl-CoA inhibits the 2-oxoglutarate dehydrogenase complex, a key enzyme in the tricarboxylic acid cycle. […] Although most studies investigated the mechanism underlying striatal injury, the mechanism of the increasingly observed extrastriatal abnormalities has remained virtually unclear.

• #28 Audiological and otologic manifestations of glutaric aciduria type I | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-01571-w

  The presence of 3-OH-GA in GA-1 patients may lead to increased vulnerability of endothelial structures and subsequent vascular dysfunction. […] Like other toxic metabolic diseases affecting the auditory system, the pathophysiology of hearing loss is still unclear. […] However, it is anticipated that oxidase and neurotoxic substance accumulation in the cochlea or the rest of the auditory system causes hearing loss. […] We found that a high percent of patients with GA-1 encountered slight to moderate sensorineural hearing loss in this study. […] The inclusion of the 4 common deafness-associated genes in the genetic tests offers strong evidence to preclude hearing loss caused by the popular deafness-related gene variants in the Taiwanese population. […] The hearing impairment of children with GA-1 was not structural or caused by infections related to the peripheral or central auditory organs.

• #29 Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/2051-5960-2-13

  The current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke. […] These findings are consistent with a recent report showing that brain injury in children with GA1 was also associated with enlargement of the vein of Galen. […] The lack of valves in the cerebral venous system provides an even distribution of symmetric expansion of these structures. […] The combination of vessel impingement, shunting and weakened blood-brain barrier likely results in hemorrhages. […] The mechanism underlying a specific BBB weakness in GA1, however, has been elusive. […] These data are consistent with our current findings that VEGF is increased and occludin is partially disrupted at baseline in the brain of Gcdh / mice and may account as a possible mechanism of BBB weakness in GA1.

• #30 Glutaric aciduria | MedLink Neurology

  https://www.medlink.com/articles/glutaric-aciduria

  GCDH deficiency results in an insufficient flux of glutaryl-CoA to crotonyl-CoA resulting in an accumulation of upstream metabolites, especially glutaryl-CoA, which is subsequently converted to glutaric acid and 3-hydroxyglutaric acid. […] Postmortem examinations in patients showed that intracerebral concentrations of glutaric and 3-hydroxyglutaric acids exceed plasma concentrations by 10- to 1000-fold. […] It has been shown that the cerebral susceptibility to L-lysine is modulated by three factors: gender, genetic background, and lysine dosage. […] Previous studies have provided evidence that neurodegeneration in glutaric aciduria type I might be caused by excitotoxic cell damage. […] An alternative mechanism has been postulated. Glutaryl-CoA inhibits the 2-oxoglutarate dehydrogenase complex, a key enzyme in the tricarboxylic acid cycle. […] Although most studies investigated the mechanism underlying striatal injury, the mechanism of the increasingly observed extrastriatal abnormalities has remained virtually unclear.

• #31 Glutaric aciduria | MedLink Neurology

  https://www.medlink.com/articles/glutaric-aciduria

  GCDH deficiency results in an insufficient flux of glutaryl-CoA to crotonyl-CoA resulting in an accumulation of upstream metabolites, especially glutaryl-CoA, which is subsequently converted to glutaric acid and 3-hydroxyglutaric acid. […] Postmortem examinations in patients showed that intracerebral concentrations of glutaric and 3-hydroxyglutaric acids exceed plasma concentrations by 10- to 1000-fold. […] It has been shown that the cerebral susceptibility to L-lysine is modulated by three factors: gender, genetic background, and lysine dosage. […] Previous studies have provided evidence that neurodegeneration in glutaric aciduria type I might be caused by excitotoxic cell damage. […] An alternative mechanism has been postulated. Glutaryl-CoA inhibits the 2-oxoglutarate dehydrogenase complex, a key enzyme in the tricarboxylic acid cycle. […] Although most studies investigated the mechanism underlying striatal injury, the mechanism of the increasingly observed extrastriatal abnormalities has remained virtually unclear.

• #32 Glutaric aciduria type 1 | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/glutaric-aciduria-type-1?embed_domain=hackmd.io%25252F%252540yIPUAFeCSL2JsU8smR5nJQ%25252Fbnjhjgjghjghjgh&lang=us

  Glutaric aciduria type I is caused by an inherited deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH). This leads to accumulation of glutaric acid and 3-hydroxyglutaric acid in the brain and body fluids, including urine (hence the name glutaric aciduria). […] Definitive diagnosis of glutaric aciduria type 1 can be established by DNA-based analysis, looking for mutations in the GCDH gene on chromosome 19. […] Glutaric aciduria type 1 is rare organic aciduria, with an estimated prevalence of 1 in 100,000 newborns. It is inherited in an autosomal recessive manner, and hence consanguineous marriages are a risk factor.

• #33

  https://link.springer.com/article/10.1007/s11011-018-0357-5

  Glutaric aciduria type 1 is a neurometabolic disorder, caused by riboflavin-dependent glutaryl-CoA dehydrogenase deficiency. […] As a result of its deficiency accumulation of the putatively neurotoxic metabolites (glutaric and 3-hydroxyglutaric acid, GA and 3-OH-GA) in body tissues, especially within the brain is observed. […] Glutaric aciduria type 1 (GA1) is caused by riboflavin-dependent glutaryl-CoA dehydrogenase (GCDH) deficiency, encoded by the GCDH gene (localized on chromosome 19p13.2). […] The estimated incidence of GA1 is 1 in 110,000 newborns. […] The prevalence however may be higher in the specific ethnic groups. […] The manifestation of glutaric aciduria type 1 is known to be variable. […] Most cases are diagnosed with acute type, based on neurological sequelae after encephalopathic crises.

• #34 Glutaric aciduria type 1 – Wikipedia

  https://en.wikipedia.org/wiki/Glutaric_aciduria_type_1

  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. […] GA1 is an autosomal recessive disorder caused by deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH), encoded by the GCDH gene. […] The condition is inherited in an autosomal recessive pattern: mutated copies of the gene GCDH must be provided by both parents to cause GA1. […] 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. […] 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. […] 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, where up to 1 in 300 newborns may be affected.

• #35 Glutaric_aciduria_type_1

  https://www.chemeurope.com/en/encyclopedia/Glutaric_aciduria_type_1.html

  Glutaric acidemia type 1 (or „Glutaric Aciduria”, „GA1”, or „GAT1”) is an inherited disorder in which the body is unable to breakdown completely the amino acids lysine, hydroxylysine and tryptophan. […] 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. […] The condition is inherited in an autosomal recessive pattern: mutated copies of the gene GCDH must be provided by both parents to cause glutaric acidemia type 1. […] 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. […] GA1 occurs in approximately 1 of every 30,000 to 40,000 births. It is much more common in the Amish community and in the Ojibway population of Canada, where up to 1 in 300 newborns may be affected.

• #36 Glutaric aciduria type 1 – Wikipedia

  https://en.wikipedia.org/wiki/Glutaric_aciduria_type_1

  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. […] GA1 is an autosomal recessive disorder caused by deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH), encoded by the GCDH gene. […] The condition is inherited in an autosomal recessive pattern: mutated copies of the gene GCDH must be provided by both parents to cause GA1. […] 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. […] 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. […] 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, where up to 1 in 300 newborns may be affected.

• #37 What is glutaric aciduria type 1?

  https://www.medicalnewstoday.com/articles/glutaric-aciduria-type-1

  GA1 is the result of a change in the GCDH gene. This gene is responsible for producing the glutaryl-CoA dehydrogenase (GCDH) enzyme. When this enzyme is nonfunctional or deficient, the body cannot fully break down the amino acids lysine, hydroxylysine, and tryptophan. […] Typically, the body breaks down these amino acids into glutaric acid and converts that acid into energy. However, in people with GA1, a deficiency in the GCDH enzyme results in a harmful buildup of glutaric acid in the brain and body. […] GA1 is an autosomal recessive condition. This means that in order to inherit the condition, a person must receive two GCDH gene variations one from each parent. […] GA1 occurs in roughly 1 in 100,000 people in the overall population. However, it is more prevalent in certain groups, including: the Old Order Amish community in Pennsylvania, the Oji-Cree First Nations in Canada, the Irish Traveler community in Ireland, the Lumbee population in North Carolina, the Xhosa community in South Africa.

• #38 What is glutaric aciduria type 1?

  https://www.medicalnewstoday.com/articles/glutaric-aciduria-type-1

  GA1 is the result of a change in the GCDH gene. This gene is responsible for producing the glutaryl-CoA dehydrogenase (GCDH) enzyme. When this enzyme is nonfunctional or deficient, the body cannot fully break down the amino acids lysine, hydroxylysine, and tryptophan. […] Typically, the body breaks down these amino acids into glutaric acid and converts that acid into energy. However, in people with GA1, a deficiency in the GCDH enzyme results in a harmful buildup of glutaric acid in the brain and body. […] GA1 is an autosomal recessive condition. This means that in order to inherit the condition, a person must receive two GCDH gene variations one from each parent. […] GA1 occurs in roughly 1 in 100,000 people in the overall population. However, it is more prevalent in certain groups, including: the Old Order Amish community in Pennsylvania, the Oji-Cree First Nations in Canada, the Irish Traveler community in Ireland, the Lumbee population in North Carolina, the Xhosa community in South Africa.

• #39 What is glutaric aciduria type 1?

  https://www.medicalnewstoday.com/articles/glutaric-aciduria-type-1

  GA1 is the result of a change in the GCDH gene. This gene is responsible for producing the glutaryl-CoA dehydrogenase (GCDH) enzyme. When this enzyme is nonfunctional or deficient, the body cannot fully break down the amino acids lysine, hydroxylysine, and tryptophan. […] Typically, the body breaks down these amino acids into glutaric acid and converts that acid into energy. However, in people with GA1, a deficiency in the GCDH enzyme results in a harmful buildup of glutaric acid in the brain and body. […] GA1 is an autosomal recessive condition. This means that in order to inherit the condition, a person must receive two GCDH gene variations one from each parent. […] GA1 occurs in roughly 1 in 100,000 people in the overall population. However, it is more prevalent in certain groups, including: the Old Order Amish community in Pennsylvania, the Oji-Cree First Nations in Canada, the Irish Traveler community in Ireland, the Lumbee population in North Carolina, the Xhosa community in South Africa.

• #40 Glutaric aciduria type 1 | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/glutaric-aciduria-type-1?embed_domain=hackmd.io%25252F%252540yIPUAFeCSL2JsU8smR5nJQ%25252Fbnjhjgjghjghjgh&lang=us

  Glutaric aciduria type I is caused by an inherited deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH). This leads to accumulation of glutaric acid and 3-hydroxyglutaric acid in the brain and body fluids, including urine (hence the name glutaric aciduria). […] Definitive diagnosis of glutaric aciduria type 1 can be established by DNA-based analysis, looking for mutations in the GCDH gene on chromosome 19. […] Glutaric aciduria type 1 is rare organic aciduria, with an estimated prevalence of 1 in 100,000 newborns. It is inherited in an autosomal recessive manner, and hence consanguineous marriages are a risk factor.

• #41 Glutaric Acidemia Type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2556991/

  Therefore, non-genetic factors, among which fever, infections and fasting, play an important role in precipitating neuronal damage in glutaric acidemia type 1. […] The combined worldwide frequency of GA-1 based on newborn screening by MS/MS of 2.5 million children is 1:100,000 infants. […] Patients with glutaric acidemia type 1 are more vulnerable to striatal damage resulting in a severe dystonic movement disorder between 6 and 18 months of age. […] Glutaric acid and 3-OH glutaric acid accumulation leads to neuronal damage with loss of striatal neuron at time of sepsis/fever. […] Neuronal loss happens at time of the acute event and does not progress over time. […] Abnormalities of the development of blood vessels or of blood flow could contribute to striatal injury.

• #42 Glutaric Acidemia Type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2556991/

  Therefore, non-genetic factors, among which fever, infections and fasting, play an important role in precipitating neuronal damage in glutaric acidemia type 1. […] The combined worldwide frequency of GA-1 based on newborn screening by MS/MS of 2.5 million children is 1:100,000 infants. […] Patients with glutaric acidemia type 1 are more vulnerable to striatal damage resulting in a severe dystonic movement disorder between 6 and 18 months of age. […] Glutaric acid and 3-OH glutaric acid accumulation leads to neuronal damage with loss of striatal neuron at time of sepsis/fever. […] Neuronal loss happens at time of the acute event and does not progress over time. […] Abnormalities of the development of blood vessels or of blood flow could contribute to striatal injury.

• #43 Diagnosis and management of glutaric aciduria type I – revised recommendations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3109243/

  The characteristic neurological sequela of these crises is acute bilateral striatal injury and, subsequently, a complex movement disorder. […] Glutaric aciduria type I has been widely considered a disorder for which newborn screening should be offered. […] Timely diagnosis and start of treatment, i.e., before irreversible neurological symptoms occur, results in a better outcome than start of treatment after the onset of neurological disease. […] The aim of newborn and high-risk screening is to reduce the incidence of neurological disease. […] The use of a diet based on lysine intake combined with lysine-free, tryptophan-reduced AA supplements to maintain adequate total protein intake has been associated with the most favorable neurologic outcome and normal growth in some studies. […] The metabolic management during and after any surgical interventions should be based on recommendations for metabolic treatment and should be supervised by a metabolic specialist.

• #44 Glutaric Acidemia Type 1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2556991/

  Therefore, non-genetic factors, among which fever, infections and fasting, play an important role in precipitating neuronal damage in glutaric acidemia type 1. […] The combined worldwide frequency of GA-1 based on newborn screening by MS/MS of 2.5 million children is 1:100,000 infants. […] Patients with glutaric acidemia type 1 are more vulnerable to striatal damage resulting in a severe dystonic movement disorder between 6 and 18 months of age. […] Glutaric acid and 3-OH glutaric acid accumulation leads to neuronal damage with loss of striatal neuron at time of sepsis/fever. […] Neuronal loss happens at time of the acute event and does not progress over time. […] Abnormalities of the development of blood vessels or of blood flow could contribute to striatal injury.

• #45 Mechanistic Effects of Amino Acids and Glucose in a Novel Glutaric Aciduria Type 1 Cell Model | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110181

  Appropriate therapy for GA1 includes dietary restriction and control, carnitine/riboflavin supplementation and emergency treatment. […] Dietary restriction and control are especially crucial for reducing GA-producing substrates and minimizing the risk of adverse neurological outcomes. […] The metabolic crises observed in GA1 patients always cause hypoglycemia, which in turn results in amino acid uptake and altered gluconeogenesis function in the liver. […] In the immature brain, a reduced glucose level causes elevated consumption of alternate energy substrates, such as ketone bodies, and therefore increases the breakdown of ketogenic amino acids such as lysine and branched-chain amino acids (BCAAs). […] Consequently, glucose administration may prevent and reduce striatal injury in human GA1 encephalopathy.

• #46 Mechanistic Effects of Amino Acids and Glucose in a Novel Glutaric Aciduria Type 1 Cell Model | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110181

  Appropriate therapy for GA1 includes dietary restriction and control, carnitine/riboflavin supplementation and emergency treatment. […] Dietary restriction and control are especially crucial for reducing GA-producing substrates and minimizing the risk of adverse neurological outcomes. […] The metabolic crises observed in GA1 patients always cause hypoglycemia, which in turn results in amino acid uptake and altered gluconeogenesis function in the liver. […] In the immature brain, a reduced glucose level causes elevated consumption of alternate energy substrates, such as ketone bodies, and therefore increases the breakdown of ketogenic amino acids such as lysine and branched-chain amino acids (BCAAs). […] Consequently, glucose administration may prevent and reduce striatal injury in human GA1 encephalopathy.

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