Materiały źródłowe

• #1 Glutaric Acidemia, Pathogenesis and Nutritional Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8714794/

  Glutaric acidemia (GA) are heterogeneous, genetic diseases that present with specific catabolic deficiencies of amino acid or fatty acid metabolism. […] This review discusses the pathogenesis of GA and its nutritional management practices, and aims to promote understanding and management of GA. […] GA-I presents as a severe neurometabolic aciduria which is characterized by acute encephalopathic crises in early childhood. This disease is caused by an inherited deficiency of the flavoprotein Glutaryl-CoA dehydrogenase (GCDH; EC 1.3.99.7). […] Deficient GCDH activity results in an accumulation of GA, 3-OH-GA and a lesser extent glutaconic acid and glutaryl carnitine (C5DC) in body fluids and brain. […] Studies have demonstrated that accumulation of GA, 3-OH-GA and glutaryl-CoA interferes with cerebral energy metabolism.

• #2 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. It results in the accumulation of 3-hydroxyglutaric and glutaric acid. […] 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. It is still unclear what causes this selective sensitivity. Glutaric and 3-OH-glutaric acid accumulate in the brain of affected individuals, even in patients who are low excretors of glutaric acid, at levels that are one or two orders of magnitude higher than in other tissues. Glutaric acid and 3-OH glutaric acid accumulation leads to neuronal damage with loss of striatal neuron at time of sepsis/fever. This might be followed or accompanied to lymphocytic infiltration and subsequently by glial proliferation followed by atrophy. Neuronal loss happens at time of the acute event and does not progress over time.

• #3 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. […] 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 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.

• #4 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. […] 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 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.

• #5 Journal of Pediatric Sciences » Makale » Glutaric aciduria type I: A translational approach to an enigmatic disease

  https://dergipark.org.tr/tr/pub/jps/issue/19080/202100

  Glutaric aciduria type I (GA-I) is an autosomal recessively inherited disorder of L-lysine, L-tryptophan and L-hydroxylysine metabolism which is biochemically characterized by the accumulation of putatively toxic glutaric and 3-hydroxyglutaric acids, and non-toxic glutarylcarnitine due to deficient activity of glutaryl-CoA dehydrogenase. […] Evidence is increasing that some of the accumulating metabolites in GA-I patients are neurotoxic due to their interference with glutamatergic neurotransmission, inhibition of the 2-oxoglutarate dehydrogenase complex and impairment of the dicarboxylic acid shuttle between astrocytes and neurons. […] Strikingly, glutaric and 3-hydroxylgutaric acids massively accumulate in the brain of patients due to the low permeability of the blood brain barrier for dicarboxylic acids which may explain the selective neurological phenotype of GA-I.

• #6 Glutaric Acidemia, Pathogenesis and Nutritional Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8714794/

  Glutaric acidemia (GA) are heterogeneous, genetic diseases that present with specific catabolic deficiencies of amino acid or fatty acid metabolism. […] This review discusses the pathogenesis of GA and its nutritional management practices, and aims to promote understanding and management of GA. […] GA-I presents as a severe neurometabolic aciduria which is characterized by acute encephalopathic crises in early childhood. This disease is caused by an inherited deficiency of the flavoprotein Glutaryl-CoA dehydrogenase (GCDH; EC 1.3.99.7). […] Deficient GCDH activity results in an accumulation of GA, 3-OH-GA and a lesser extent glutaconic acid and glutaryl carnitine (C5DC) in body fluids and brain. […] Studies have demonstrated that accumulation of GA, 3-OH-GA and glutaryl-CoA interferes with cerebral energy metabolism.

• #7 Glutaric aciduria | MedLink Neurology

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

  It is worth noting that lysine loading, which increases the cerebral concentrations of putatively toxic glutaric and 3-hydroxyglutaric acids, has produced a clinical phenotype in young Gcdh-/–deficient mice similar to acute encephalopathic crises in infants with glutaric aciduria type I. […] An alternative mechanism has been postulated. Glutaryl-CoA inhibits the 2-oxoglutarate dehydrogenase complex, a key enzyme in the tricarboxylic acid cycle. […] These studies highlight that accumulation of toxic dicarboxylic metabolites is likely to chronically affect the brain metabolism of glutamate and glutamine.

• #8 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. It results in the accumulation of 3-hydroxyglutaric and glutaric acid. […] 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. It is still unclear what causes this selective sensitivity. Glutaric and 3-OH-glutaric acid accumulate in the brain of affected individuals, even in patients who are low excretors of glutaric acid, at levels that are one or two orders of magnitude higher than in other tissues. Glutaric acid and 3-OH glutaric acid accumulation leads to neuronal damage with loss of striatal neuron at time of sepsis/fever. This might be followed or accompanied to lymphocytic infiltration and subsequently by glial proliferation followed by atrophy. Neuronal loss happens at time of the acute event and does not progress over time.

• #9 Glutaric Acidemia Type 1

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

  Involvement of the striatum might be due to their abundance of receptors for glutamate. Among these, the N-methyl-D-aspartate receptor seems to play a major role in excitotoxicity mediated by 3-OH-glutaric acid or by quinolinic acid. Neuronal damage can be aggravated by production of cytokines and nitric oxide. Abnormalities of the development of blood vessels or of blood flow could contribute to striatal injury. […] A mouse model for glutaric acidemia type 1 was recently developed via targeted deletion of the glutaryl CoA dehydrogenase gene in embryonic stem cells. Mutant mice had a biochemical phenotype very similar to human patients with glutaric acidemia type 1, including elevations of glutaric and 3-OH-glutaric acid. However, they did not present the complex clinical phenotype of humans with glutaric acidemia type 1.

• #10

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

  Here, we wish to further discuss the pathophysiological mechanism of this organic aciduria. […] Blockage of Lys catabolism due to GCDH deficiency (1) leading to accumulation of GA and 3OHGA (2). GA inhibits the Krebs cycle and mitochondrial function (3) causing increased ROS (4). In the synaptic cleft, the high concentrations of GA and 3OHGA inhibit glutamate uptake (5), increasing glutamate availability. 3OHGA overstimulates AMPA and NMDA (6). This excitotoxic environment associated with changes in astrocyte function and astrogliosis leads to neuronal damage. […] 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. This excitotoxic environment activates microglia and astrocytes, leading to a pro-inflammatory state and damaging the neural tissue.

• #11 Glutaric aciduria | MedLink Neurology

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

  It is worth noting that lysine loading, which increases the cerebral concentrations of putatively toxic glutaric and 3-hydroxyglutaric acids, has produced a clinical phenotype in young Gcdh-/–deficient mice similar to acute encephalopathic crises in infants with glutaric aciduria type I. […] An alternative mechanism has been postulated. Glutaryl-CoA inhibits the 2-oxoglutarate dehydrogenase complex, a key enzyme in the tricarboxylic acid cycle. […] These studies highlight that accumulation of toxic dicarboxylic metabolites is likely to chronically affect the brain metabolism of glutamate and glutamine.

• #12 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

  Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. […] The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. […] Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. […] Bloodbrain barrier breakdown was associated with displacement of tight-junction protein Occludin. […] Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke.

• #13 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

  Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. […] The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. […] Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. […] Bloodbrain barrier breakdown was associated with displacement of tight-junction protein Occludin. […] Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke.

• #14

  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) […] Despite early diagnosis, one-third of Amish infants with glutaryl-CoA dehydrogenase deficiency developed striatal lesions that leave them permanently disabled. To better understand mechanisms of striatal degeneration, Strauss et al. (2007) retrospectively studied imaging results from 25 Amish patients homozygous for the 1296C-T mutation in GCDH (608801.0002). Asymptomatic infants had reduced glucose tracer uptake and increased blood volume throughout the gray matter, which may signify predisposition to brain injury. Striatal lesions developed in 9 children (36%): 3 had sudden motor regression during infancy, whereas 6 had insidious motor delay associated with striatal lesions of undetermined onset. Acute striatal necrosis consisted of 3 stages: (1) an acute stage within 24 hours of motor regression, characterized by cytotoxic edema within the basal ganglia, cerebral oligemia, and rapid transit of blood throughout the gray matter; (2) a subacute stage, 4 to 5 days after the onset of clinical symptoms, characterized by reduced striatal perfusion and glucose uptake, and supervening vasogenic edema; and (3) a chronic stage of striatal atrophy. Strauss et al. (2007) suggested that intravenous fluid and dextrose therapy for illnesses during the first 2 years of life was the only intervention that was clearly neuroprotective in these patients.

• #15 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

  Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. […] The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. […] Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. […] Bloodbrain barrier breakdown was associated with displacement of tight-junction protein Occludin. […] Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke.

• #16 Endothelial Effects of 3-Hydroxyglutaric Acid: Implications for Glutaric Aciduria Type I | Pediatric Research

  https://www.nature.com/articles/pr200641

  Infants with glutaric aciduria type 1 (GA1) are subject to intracranial vascular dysfunction. Here, we demonstrate that the disease-specific metabolite 3-hydroxyglutaric acid (3-OH-GA) inhibits basal and vascular endothelial growth factor (VEGF)-induced endothelial cell migration. […] The study demonstrates that 3-OH-GA reduces endothelial chemotaxis and disturbs structural vascular integrity in vitro and in vivo. These data may provide insight in the mechanisms of 3-OH-GA-induced vasculopathic processes and suggest N-methyl-d-aspartate receptor-dependent and -independent pathways in the pathogenesis of GA1. […] The pathomechanisms in GA1 leading to neuronal death are still not understood and are presumably multifactorial. Due to structural relation of 3-OH-GA with glutamate, it has been proposed that 3-OH-GA may act via interaction with NMDA receptors, resulting in excitotoxic neuronal damage. […] Our study provides evidence that 3-OH-GA affects the expression of one of these proteins, Ve-cadherin, in tube-formation experiments and in HDMEC grown in monolayer. Ve-cadherin is the major cell-cell adhesion molecule at endothelial adherens junction. Its cytoplasmic domains contains binding sites for catenin p120 and plakoglobulin, linking Ve-cadherin to the actin and vimentin cytoskeleton network. The loss of Ve-cadherin and plakoglobulin results in abnormal assembly of endothelial cells into vascular structures during development, and disruption of endothelial cell-cell contacts, thus affecting barrier function.

• #17 Endothelial Effects of 3-Hydroxyglutaric Acid: Implications for Glutaric Aciduria Type I | Pediatric Research

  https://www.nature.com/articles/pr200641

  Infants with glutaric aciduria type 1 (GA1) are subject to intracranial vascular dysfunction. Here, we demonstrate that the disease-specific metabolite 3-hydroxyglutaric acid (3-OH-GA) inhibits basal and vascular endothelial growth factor (VEGF)-induced endothelial cell migration. […] The study demonstrates that 3-OH-GA reduces endothelial chemotaxis and disturbs structural vascular integrity in vitro and in vivo. These data may provide insight in the mechanisms of 3-OH-GA-induced vasculopathic processes and suggest N-methyl-d-aspartate receptor-dependent and -independent pathways in the pathogenesis of GA1. […] The pathomechanisms in GA1 leading to neuronal death are still not understood and are presumably multifactorial. Due to structural relation of 3-OH-GA with glutamate, it has been proposed that 3-OH-GA may act via interaction with NMDA receptors, resulting in excitotoxic neuronal damage. […] Our study provides evidence that 3-OH-GA affects the expression of one of these proteins, Ve-cadherin, in tube-formation experiments and in HDMEC grown in monolayer. Ve-cadherin is the major cell-cell adhesion molecule at endothelial adherens junction. Its cytoplasmic domains contains binding sites for catenin p120 and plakoglobulin, linking Ve-cadherin to the actin and vimentin cytoskeleton network. The loss of Ve-cadherin and plakoglobulin results in abnormal assembly of endothelial cells into vascular structures during development, and disruption of endothelial cell-cell contacts, thus affecting barrier function.

• #18 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

  Together these pathological changes suggest early filling of the venous system resulting in increased venous pressure, BBB breakdown and hemorrhage. […] The lack of valves in the cerebral venous system provides an even distribution of symmetric expansion of these structures. […] Combined with BBB weakness, increased pressure associated with shunting and early filling of the venous system likely accounts for hemorrhages in GA1. […] In the current study we have characterized metabolic stroke in a mouse model of GA1 showing initial neuronal swelling with secondary ischemia associated with impingement of brain capillaries. […] Loss of the tight-junction protein, occludin, is shown as an intrinsic weakness of the BBB exacerbated by metabolic encephalopathy.

• #19

  https://www.jci.org/articles/view/31617

  Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. […] The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. […] These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I. […] Our current findings identified developmental differences that control glutaric acid accumulation and age-dependent brain injury.

• #20 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

  Elevated levels of GA and 3-OHGA may cause neuronal damage by blocking the tricarboxylic acid cycle (TCA cycle). […] Additionally, glutaryl-CoA can inhibit the activity of the -ketoglutarate dehydrogenase complex (OGDC), which is the rate-limiting enzyme in the TCA cycle. […] 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 a Gcdh/ mouse model fed a high-lysine diet, glucose not only corrects hypoglycemia and reduces the demand for alternate substrates but also lowers brain lysine uptake, a rate-limiting step of lysine metabolism. […] The activities of lysine metabolism-related transporters and enzymes decrease with brain maturation; thus, the immature brain is more likely to be affected by amino acid metabolism disorders.

• #21

  https://www.jci.org/articles/view/31617

  These data indicate that enhanced lysine uptake in the immature brain provides increased glutaric acid accumulation and susceptibility to brain injury. […] We propose that loss of Krebs cycle intermediates through -ketoglutarate may be a primary cause of mitochondrial disruption as diagrammed in Figure 6. […] We demonstrated that blocking brain lysine uptake with homoarginine decreased glutaric acid levels, resulting in reduced brain injury and increased survival. […] These findings are likely to have clinical relevance, since elevated brain glutaric acid levels and brain injury in GA-I patients occur despite the use of low lysine diets. […] The current findings provide insight into the age-dependent mechanism, treatment, and monitoring of GA-I and offer new strategies for the prediction and prevention of brain injury.

• #22 Glutaric aciduria type 1 – wikidoc

  https://www.wikidoc.org/index.php/Glutaric_aciduria_type_1

  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 thus follows that collagen breakdown (and protein breakdown in general) should be prevented by all possible means. Ascorbic acid is used to prevent multiple organ failure and to lessen mortality and morbidity in intensive care units. It thus appears reasonable to include 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.

• #23 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

  Elevated levels of GA and 3-OHGA may cause neuronal damage by blocking the tricarboxylic acid cycle (TCA cycle). […] Additionally, glutaryl-CoA can inhibit the activity of the -ketoglutarate dehydrogenase complex (OGDC), which is the rate-limiting enzyme in the TCA cycle. […] 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 a Gcdh/ mouse model fed a high-lysine diet, glucose not only corrects hypoglycemia and reduces the demand for alternate substrates but also lowers brain lysine uptake, a rate-limiting step of lysine metabolism. […] The activities of lysine metabolism-related transporters and enzymes decrease with brain maturation; thus, the immature brain is more likely to be affected by amino acid metabolism disorders.

• #24 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

  Elevated levels of GA and 3-OHGA may cause neuronal damage by blocking the tricarboxylic acid cycle (TCA cycle). […] Additionally, glutaryl-CoA can inhibit the activity of the -ketoglutarate dehydrogenase complex (OGDC), which is the rate-limiting enzyme in the TCA cycle. […] 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 a Gcdh/ mouse model fed a high-lysine diet, glucose not only corrects hypoglycemia and reduces the demand for alternate substrates but also lowers brain lysine uptake, a rate-limiting step of lysine metabolism. […] The activities of lysine metabolism-related transporters and enzymes decrease with brain maturation; thus, the immature brain is more likely to be affected by amino acid metabolism disorders.

• #25

  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) […] Despite early diagnosis, one-third of Amish infants with glutaryl-CoA dehydrogenase deficiency developed striatal lesions that leave them permanently disabled. To better understand mechanisms of striatal degeneration, Strauss et al. (2007) retrospectively studied imaging results from 25 Amish patients homozygous for the 1296C-T mutation in GCDH (608801.0002). Asymptomatic infants had reduced glucose tracer uptake and increased blood volume throughout the gray matter, which may signify predisposition to brain injury. Striatal lesions developed in 9 children (36%): 3 had sudden motor regression during infancy, whereas 6 had insidious motor delay associated with striatal lesions of undetermined onset. Acute striatal necrosis consisted of 3 stages: (1) an acute stage within 24 hours of motor regression, characterized by cytotoxic edema within the basal ganglia, cerebral oligemia, and rapid transit of blood throughout the gray matter; (2) a subacute stage, 4 to 5 days after the onset of clinical symptoms, characterized by reduced striatal perfusion and glucose uptake, and supervening vasogenic edema; and (3) a chronic stage of striatal atrophy. Strauss et al. (2007) suggested that intravenous fluid and dextrose therapy for illnesses during the first 2 years of life was the only intervention that was clearly neuroprotective in these patients.

• #26 Biochemical and molecular features of Chinese patients with glutaric acidemia type 1 detected through newborn screening | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01964-5

  Glutaric acidemia type 1 (GA1) is a treatable disorder affecting cerebral organic acid metabolism caused by a defective glutaryl-CoA dehydrogenase (GCDH) gene. […] GA1 leads to the accumulation of glutaric acid (GA) and 3-hydroxyglutaric acid (3HGA) in bodily tissues, particularly in the brain. […] The most common variant was c.1244-2 AC, which had an allelic frequency of 54.55% (12/22), followed by c.1261GA (p.Ala421Thr) at 9.09% (2/22). […] The newly identified variants have not been described in human genome variation databases such as dbSNP, GnomAD, ExAC, and 1000 Genomes, or in disease-causing mutation databases such as HGMD, ClinVar, and LOVD. […] The c.1244-2 AC splice site variant destroys the canonical splice acceptor site in intron 11 of the GCDH gene and is expected to cause aberrant splicing. […] The GCDH variant spectra vary significantly between ethnicities, which may also differ among different populations in the same ethnic group. […] The novel variants identified in this study expanded the GCDH variant spectra.

• #27 Glutaric aciduria type I – Genomics Education Programme

  http://www.genomicseducation.hee.nhs.uk/documents/glutaric-aciduria-type-i/

  Glutaric aciduria type I (GA-I) is an autosomal recessive condition, caused by deficiency of glutaryl-CoA dehydrogenase, an enzyme involved in the catabolic pathway of lysine, hydroxylysine and tryptophan. […] GA-I is an autosomal recessive condition caused by variants in the GCDH gene. Over 200 variants have been reported, and DNA analysis requires sequencing of the whole gene due to the lack of a common variant. […] Treatment is managed by a multi-disciplinary team at specialised metabolic centres.

• #28 Glutaric aciduria type 1 – Wikipedia

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

  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. […] 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.

• #29 Glutaric Acidemia, Pathogenesis and Nutritional Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8714794/

  Because GA and 3-OH-GA are only weak neurotoxins the neurodegenerative cascade destroying the striatum in patients with GA-I involves mainly mechanisms other than excitotoxicity. […] Data from 215 patients diagnosed with GA-I showed that good correlations between genotype and biochemical phenotype, GA and 3-OH-GA concentrations in plasma and urine negatively correlate with residual GCDH activity in fibroblasts and leucocytes. […] Furthermore, the severity of the clinical phenotype usually depends on the development of an encephalopathic crisis in childhood. […] The early onset of gradual motor symptoms (69 months) and brain atrophy are poor prognostic signs, the age at symptom onset can significantly predict the severity of motor deficits and the overall outcome. […] Glutaric acidemia type II (GA-II), also known as Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), is an autosomal recessive genetic disorder of fatty acid, some amino acid and choline oxidation, caused predominately by mutations in the /-subunit of Electron Transfer Flavoprotein (ETF, encoded by ETFA, ETFB) or Electron Transfer Flavoprotein-Ubiquinone Oxidoreductase (ETF-QO, encoded by ETFDH).

• #30 Interaction of Glutaric Aciduria Type 1-Related glutaryl-CoA Dehydrogenase with Mitochondrial Matrix Proteins | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087715

  Glutaric aciduria type 1 (GA1) is an inherited neurometabolic disorder caused by mutations in the GCDH gene encoding glutaryl-CoA dehydrogenase (GCDH), which forms homo- and heteromeric complexes in the mitochondrial matrix. […] Using an affinity chromatography approach we report here for the first time on the identification of mitochondrial proteins interacting directly with GCDH. […] These data suggest that GCDH is a constituent of multimeric mitochondrial dehydrogenase complexes, and the characterization of their interrelated functions may provide new insights into the regulation of lysine oxidation and the pathophysiology of GA1. […] The inherited neurodegenerative disorder glutaric aciduria type 1 (GA1, OMIM 231670) is caused by mutations in the gene for the mitochondrial matrix enzyme glutaryl-CoA dehydrogenase (GCDH, E.C. 1.3.99.7).

• #31 Interaction of Glutaric Aciduria Type 1-Related glutaryl-CoA Dehydrogenase with Mitochondrial Matrix Proteins | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087715

  Mutations in the GCDH gene lead to formation and accumulation of the dicarboxylates glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in tissues and body fluids. […] The interaction between GCDH and DLST suggests that both consecutive enzymes function in a multienzyme complex to allow sufficiently short distance for efficient oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA. […] The other GCDH binding partner, ETFB, forms with ETFA an FAD-containing heterodimer that serves as electron acceptor for at least nine mitochondrial matrix flavoprotein dehydrogenases of fatty acid oxidation and amino acid catabolism. […] The identification of the first GCDH interacting proteins provides new insights into the functional linkage between multienzyme complexes required for efficient metabolism of glutaryl-CoA, and its role in the pathogenesis of glutaric aciduria type 1.

• #32 Interaction of Glutaric Aciduria Type 1-Related glutaryl-CoA Dehydrogenase with Mitochondrial Matrix Proteins | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087715

  Mutations in the GCDH gene lead to formation and accumulation of the dicarboxylates glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in tissues and body fluids. […] The interaction between GCDH and DLST suggests that both consecutive enzymes function in a multienzyme complex to allow sufficiently short distance for efficient oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA. […] The other GCDH binding partner, ETFB, forms with ETFA an FAD-containing heterodimer that serves as electron acceptor for at least nine mitochondrial matrix flavoprotein dehydrogenases of fatty acid oxidation and amino acid catabolism. […] The identification of the first GCDH interacting proteins provides new insights into the functional linkage between multienzyme complexes required for efficient metabolism of glutaryl-CoA, and its role in the pathogenesis of glutaric aciduria type 1.

• #33 Interaction of Glutaric Aciduria Type 1-Related glutaryl-CoA Dehydrogenase with Mitochondrial Matrix Proteins | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087715

  Mutations in the GCDH gene lead to formation and accumulation of the dicarboxylates glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in tissues and body fluids. […] The interaction between GCDH and DLST suggests that both consecutive enzymes function in a multienzyme complex to allow sufficiently short distance for efficient oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA. […] The other GCDH binding partner, ETFB, forms with ETFA an FAD-containing heterodimer that serves as electron acceptor for at least nine mitochondrial matrix flavoprotein dehydrogenases of fatty acid oxidation and amino acid catabolism. […] The identification of the first GCDH interacting proteins provides new insights into the functional linkage between multienzyme complexes required for efficient metabolism of glutaryl-CoA, and its role in the pathogenesis of glutaric aciduria type 1.

• #34 Glutaric aciduria type 1: Typical aspects in imaging – Edorium Journal of Radiology

  https://www.edoriumjournalofradiology.com/archive/article-full-text/100022R02HZ2022

  Glutaric aciduria type 1 is an autosomal recessive lysine and tryptophan disorder characterized by glutamic acid and other metabolic by-product accumulation. […] Pathophysiologically, GA1 is distinguished by bilateral striatal neurodegeneration caused by glutaric acid and connected metabolites accumulation, which results in vascular dysfunction with decreased cerebral blood flow as well as impairment of the blood-brain barrier. […] Primarily, the pathological presentation in GA1 is the loss of gamma-aminobutyric acid (GABA) which contains neurons along with gliosis in the basal ganglia. […] For the evaluation of GA1, brain MRI is the examination of choice. […] The main characteristic appearance is the widening of the Sylvian fissures in the frontotemporal brain region, resulting in the bat-wing appearance.

• #35 Glutaric Aciduria Type 1: Comparison between Diffusional Kurtosis Imaging and Conventional MR Imaging | American Journal of Neuroradiology

  https://www.ajnr.org/content/44/8/967

  GA-1 animal model studies show that the pathologic mechanism of brain injury is realized via cytotoxic edema, bilateral striatal neurodegeneration, neuronal swelling, and vacuole formation leading to cerebral capillary occlusion. Thus, the extracellular tortuosity, decreased membrane permeability, and cell swelling during cytotoxic edema in specific brain regions of patients with GA-1 are reflected by an increase in kurtosis metrics and FA. We found that the increase in MK, AK, and RK of the putamen, caudate head, and pallidum could be related to cell swelling, ischemic state, and an increase in the volume fraction of limited water diffusion. The cytotoxic edema reduced the extracellular volume and restriction in water motion, which gave rise to a decrease in the MD value. […] In our study, the significant correlation between the BAD score and DKI metrics, including the MK, AK, and RK in the putamen, caudate head, and pallidum, supported the hypothesis that striatum microstructural changes may contribute to a permanent motor decline and dystonia. […] Our results indicate that DKI enables the timely detection of changes in the brain tissue microstructure of patients with GA-1, which is more beneficial for the assessment of the disease severity compared with routine brain MR imaging scores.

• #36 Glutaric Aciduria Type 1: Comparison between Diffusional Kurtosis Imaging and Conventional MR Imaging | American Journal of Neuroradiology

  https://www.ajnr.org/content/44/8/967

  GA-1 animal model studies show that the pathologic mechanism of brain injury is realized via cytotoxic edema, bilateral striatal neurodegeneration, neuronal swelling, and vacuole formation leading to cerebral capillary occlusion. Thus, the extracellular tortuosity, decreased membrane permeability, and cell swelling during cytotoxic edema in specific brain regions of patients with GA-1 are reflected by an increase in kurtosis metrics and FA. We found that the increase in MK, AK, and RK of the putamen, caudate head, and pallidum could be related to cell swelling, ischemic state, and an increase in the volume fraction of limited water diffusion. The cytotoxic edema reduced the extracellular volume and restriction in water motion, which gave rise to a decrease in the MD value. […] In our study, the significant correlation between the BAD score and DKI metrics, including the MK, AK, and RK in the putamen, caudate head, and pallidum, supported the hypothesis that striatum microstructural changes may contribute to a permanent motor decline and dystonia. […] Our results indicate that DKI enables the timely detection of changes in the brain tissue microstructure of patients with GA-1, which is more beneficial for the assessment of the disease severity compared with routine brain MR imaging scores.

• #37 Glutaric Aciduria Type 1: Comparison between Diffusional Kurtosis Imaging and Conventional MR Imaging | American Journal of Neuroradiology

  https://www.ajnr.org/content/44/8/967

  GA-1 animal model studies show that the pathologic mechanism of brain injury is realized via cytotoxic edema, bilateral striatal neurodegeneration, neuronal swelling, and vacuole formation leading to cerebral capillary occlusion. Thus, the extracellular tortuosity, decreased membrane permeability, and cell swelling during cytotoxic edema in specific brain regions of patients with GA-1 are reflected by an increase in kurtosis metrics and FA. We found that the increase in MK, AK, and RK of the putamen, caudate head, and pallidum could be related to cell swelling, ischemic state, and an increase in the volume fraction of limited water diffusion. The cytotoxic edema reduced the extracellular volume and restriction in water motion, which gave rise to a decrease in the MD value. […] In our study, the significant correlation between the BAD score and DKI metrics, including the MK, AK, and RK in the putamen, caudate head, and pallidum, supported the hypothesis that striatum microstructural changes may contribute to a permanent motor decline and dystonia. […] Our results indicate that DKI enables the timely detection of changes in the brain tissue microstructure of patients with GA-1, which is more beneficial for the assessment of the disease severity compared with routine brain MR imaging scores.

• #38 Journal of Pediatric Sciences » Makale » Glutaric aciduria type I: A translational approach to an enigmatic disease

  https://dergipark.org.tr/tr/pub/jps/issue/19080/202100

  Current therapeutic concepts aim to reduce the cerebral concentrations of neurotoxic metabolites by modulating lysine influx to the brain and stimulating the formation of non-toxic glutarylcarnitine. […] Sauer SW, Okun JG, Fricker G, et al: Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency.

• #39 Glutaric aciduria type 1 as a cause of dystonic cerebral palsy | Saudi Medical Journal

  https://smj.org.sa/content/36/11/1354

  Glutaric aciduria type 1 (GA1) is an inherited inborn error of metabolism caused by a deficiency of the enzyme glutaryl Co-A dehydrogenase (GCDH). […] This mitochondrial enzyme is involved in the metabolism of lysine, hydroxylysine, and tryptophan. Its deficiency lead to accumulation of glutaric and 3-hydroxyglutaric acids, which are toxic to the brain and cause striatal injury. […] The diagnosis of GA1 was confirmed in our patients based on the presence of elevated urinary 3-hydroxyglutaric acid, high serum glutarylcarnitine, and identification of the homozygous nonsense mutation (c.482GA;p.R161Q) in GCDH gene. […] Aggressive treatment of the intercurrent infections of patients with GA1 is important in order to prevent complications. The goal is to prevent catabolism by providing high-energy intake with an extra 20% of caloric requirements through carbohydrates and lipids. […] In conclusion, this case report alerts pediatricians to consider GA1 as an important differential diagnosis of dystonic CP. Early treatment of GA1 prevents long-term neurologic disabilities.

• #40 SciELO Brazil – Clinical and Nutritional Evolution of 24 Patients with Glutaric Aciduria Type 1 in Follow-up at a Center Specialized in Inborn Errors of Metabolism in Chile Clinical and Nutritional Evolution of 24 Patients with Glutaric Aciduria Type 1 i

  https://www.scielo.br/j/jiems/a/KrsSb6gkkbJNwrR6thgbsxx/

  It has been demonstrated that L-carnitine supplementation is important in the treatment of GA-1 since it contributes to preventing carnitine deficiency and in combination with actual nutritional management recommendations appears to improve neurological outcome. […] The clinical presentation of GA-1 is varied and the absence of AEC does not guarantee neurological indemnity. […] The presentation form of insidious start was prevalent in the analyzed population and the association of symptoms: Macrocephaly, developmental delay and/or regression, abnormal movements should increase diagnostic suspicion of AG-1.

• #41

  https://journals.lww.com/annalsofian/fulltext/2012/15010/glutaric_aciduria_type_i__a_treatable.9.aspx

  Diagnosis of GA-I should be considered whenever a child has include macrocephaly, acute encephalopathy, basal ganglia injury, white matter disease, movement disorders, subdural and retinal hemorrhage and isolated elevation of GA, 3-OH-GA and glutarylcarnitine in body fluids. […] Timely diagnosis and start of treatment, i.e. before an acute encephalopathic crisis, is likely to result in a better outcome than diagnosis and start of treatment after the onset of neurological disease. It is one of the treatable neurometabolic disorder and, if managed appropriately, favorable prognosis can be given.

• #42 Glutaric Acidemia, Pathogenesis and Nutritional Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8714794/

  Glutaric acidemia (GA) are heterogeneous, genetic diseases that present with specific catabolic deficiencies of amino acid or fatty acid metabolism. […] This review discusses the pathogenesis of GA and its nutritional management practices, and aims to promote understanding and management of GA. […] GA-I presents as a severe neurometabolic aciduria which is characterized by acute encephalopathic crises in early childhood. This disease is caused by an inherited deficiency of the flavoprotein Glutaryl-CoA dehydrogenase (GCDH; EC 1.3.99.7). […] Deficient GCDH activity results in an accumulation of GA, 3-OH-GA and a lesser extent glutaconic acid and glutaryl carnitine (C5DC) in body fluids and brain. […] Studies have demonstrated that accumulation of GA, 3-OH-GA and glutaryl-CoA interferes with cerebral energy metabolism.

• #43 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

  Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. […] The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. […] Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. […] Bloodbrain barrier breakdown was associated with displacement of tight-junction protein Occludin. […] Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke.

• #44 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

  Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. […] The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. […] Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. […] Bloodbrain barrier breakdown was associated with displacement of tight-junction protein Occludin. […] Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke.

• #45

  https://www.jci.org/articles/view/31617

  Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. […] The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. […] These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I. […] Our current findings identified developmental differences that control glutaric acid accumulation and age-dependent brain injury.

• #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

  Consequently, glucose administration may prevent and reduce striatal injury in human GA1 encephalopathy. […] We also explored whether appropriate concentrations of leucine, tyrosine, arginine, homoarginine and glucose have neuroprotective effects on GA1 model cells by assessing nuclear morphology, apoptosis, the intracellular levels of ATP and the reduced form of nicotinamide adenine dinucleotide (NADH), and the expression levels of key enzymes involved in the apoptosis pathway and the TCA cycle. […] The findings revealed that GCDH gene silencing can cause impairment of energy generation, and lysine treatment of these cells can aggravate this effect. […] Furthermore, the intracellular levels of NADH and ATP observed in GA1 model cells were significantly increased through leucine, tyrosine, arginine, homoarginine or glucose treatment, although they could not be fully restored to a normal state.

• #47 Interaction of Glutaric Aciduria Type 1-Related glutaryl-CoA Dehydrogenase with Mitochondrial Matrix Proteins | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087715

  Glutaric aciduria type 1 (GA1) is an inherited neurometabolic disorder caused by mutations in the GCDH gene encoding glutaryl-CoA dehydrogenase (GCDH), which forms homo- and heteromeric complexes in the mitochondrial matrix. […] Using an affinity chromatography approach we report here for the first time on the identification of mitochondrial proteins interacting directly with GCDH. […] These data suggest that GCDH is a constituent of multimeric mitochondrial dehydrogenase complexes, and the characterization of their interrelated functions may provide new insights into the regulation of lysine oxidation and the pathophysiology of GA1. […] The inherited neurodegenerative disorder glutaric aciduria type 1 (GA1, OMIM 231670) is caused by mutations in the gene for the mitochondrial matrix enzyme glutaryl-CoA dehydrogenase (GCDH, E.C. 1.3.99.7).

• #48 Interaction of Glutaric Aciduria Type 1-Related glutaryl-CoA Dehydrogenase with Mitochondrial Matrix Proteins | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087715

  Mutations in the GCDH gene lead to formation and accumulation of the dicarboxylates glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in tissues and body fluids. […] The interaction between GCDH and DLST suggests that both consecutive enzymes function in a multienzyme complex to allow sufficiently short distance for efficient oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA. […] The other GCDH binding partner, ETFB, forms with ETFA an FAD-containing heterodimer that serves as electron acceptor for at least nine mitochondrial matrix flavoprotein dehydrogenases of fatty acid oxidation and amino acid catabolism. […] The identification of the first GCDH interacting proteins provides new insights into the functional linkage between multienzyme complexes required for efficient metabolism of glutaryl-CoA, and its role in the pathogenesis of glutaric aciduria type 1.

• #49 Glutaric Aciduria Type 1: Comparison between Diffusional Kurtosis Imaging and Conventional MR Imaging | American Journal of Neuroradiology

  https://www.ajnr.org/content/44/8/967

  GA-1 animal model studies show that the pathologic mechanism of brain injury is realized via cytotoxic edema, bilateral striatal neurodegeneration, neuronal swelling, and vacuole formation leading to cerebral capillary occlusion. Thus, the extracellular tortuosity, decreased membrane permeability, and cell swelling during cytotoxic edema in specific brain regions of patients with GA-1 are reflected by an increase in kurtosis metrics and FA. We found that the increase in MK, AK, and RK of the putamen, caudate head, and pallidum could be related to cell swelling, ischemic state, and an increase in the volume fraction of limited water diffusion. The cytotoxic edema reduced the extracellular volume and restriction in water motion, which gave rise to a decrease in the MD value. […] In our study, the significant correlation between the BAD score and DKI metrics, including the MK, AK, and RK in the putamen, caudate head, and pallidum, supported the hypothesis that striatum microstructural changes may contribute to a permanent motor decline and dystonia. […] Our results indicate that DKI enables the timely detection of changes in the brain tissue microstructure of patients with GA-1, which is more beneficial for the assessment of the disease severity compared with routine brain MR imaging scores.

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