Expanding Phenotypic Spectrum of Cerebral Aspartate–Glutamate Carrier Isoform 1 (AGC1) Deficiency

Pfeiffer, Brian K.; Sen, Kuntal; Kaur, Shagun; Pappas, Kara

doi:10.1055/s-0039-3400976

Cited by 16 publications

(43 citation statements)

References 10 publications

(11 reference statements)

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“…Two other patients, two siblings with the homozygous mutation p.Arg252Gln (found in the SMS at position 34, Figures 1 and 2A,C, outside the pore) exhibited similar symptoms as the previous one; and the activity of the mutated protein was dramatically reduced but not completely abolished [91]. Recently, another disease-causing mutation, p.Thr444Ile ( Figure 2B,D, at position 130), has been found in the substrate translocation pore (Table S1), but the transport activity of this AGC1 variant has not been investigated [95].…”

Section: Slc25a12 (Aspartate-glutamate Carrier 1 Agc1 Aralar) Deficsupporting

confidence: 64%

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

2020

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In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2- and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.

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Section: Slc25a12 (Aspartate-glutamate Carrier 1 Agc1 Aralar) Deficsupporting

confidence: 64%

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

2020

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“…Accumulating evidence also supports a pathogenic role of NAA deficiency in epilepsy. Severely reduced NAA was reported in patients with homozygous aspartate-glutamate carrier 1 (AGC1) mutations, which cause infantile epilepsy [ 65 , 66 , 67 , 68 ]. Based on the fact that AGC1 mediates the efflux of aspartate from neuronal mitochondria to cytoplasm, it has been proposed that the deficient function of AGC1 leads to impaired transportation of aspartate to the cytoplasm, where can be metabolized to NAA [ 69 ].…”

Section: Potential Impacts Of Decreased Brain N-acetylaspartate Anmentioning

confidence: 99%

“…Hence, the decreased aspartate in MSUD may affect oxidative phosphorylation and adenosine triphosphate production in neurons (reviewed elsewhere [ 15 ]). Furthermore, studies reported that MAS deficits are associated with infantile-onset epileptic encephalopathies [ 65 , 66 , 67 , 68 , 77 , 78 ] and autism [ 79 , 80 , 81 , 82 ]. In short, reduced aspartate levels in the CNS of MSUD patients may decrease MAS flux and contribute to neurologic symptoms in MSUD patients.…”

Section: Potential Impacts Of Decreased Brain N-acetylaspartate Anmentioning

confidence: 99%

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Jakher

Ahrens‐Nicklas

2020

IJMS

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Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), which catalyzes the irreversible catabolism of branched-chain amino acids (BCAAs). Current management of this BCAA dyshomeostasis consists of dietary restriction of BCAAs and liver transplantation, which aims to partially restore functional BCKDC activity in the periphery. These treatments improve the circulating levels of BCAAs and significantly increase survival rates in MSUD patients. However, significant cognitive and psychiatric morbidities remain. Specifically, patients are at a higher lifetime risk for cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorder. Recent literature suggests that the neurological sequelae may be due to the brain-specific roles of BCAAs. This review will focus on the derangements of BCAAs observed in the brain of MSUD patients and will explore the potential mechanisms driving neurologic dysfunction. Finally, we will discuss recent evidence that implicates the relevance of BCAA metabolism in other neurological disorders. An understanding of the role of BCAAs in the central nervous system may facilitate future identification of novel therapeutic approaches in MSUD and a broad range of neurological disorders.

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“…KD has been proved to be beneficial in patients with pharmaco-resistant epilepsy (Klepper et al, 2007;Kossoff et al, 2009;Villeneuve et al, 2009;Kessler et al, 2011) and, interestingly, in several metabolic disorders like GLUT-1 deficiency (Alter et al, 2015) and MPC-1 deficiency (Vanderperre et al, 2016). Indeed, it has also been proposed as a therapeutic diet in several neurologic diseases as Alzheimer's disease (Van der Auwera et al, 2005), amyotrophic lateral sclerosis (Zhao et al, 2006), Huntington's disease (Ruskin et al, 2011), autism (Ruskin et al, 2013), Parkinson's disease (VanItallie et al, 2005), and as previously mentioned in two patients with Aralar/AGC1 deficiency (Dahlin et al, 2015;Pfeiffer et al, 2020).…”

Section: Introductionmentioning

confidence: 90%

“…In humans, Aralar/AGC1 deficiency causes the rare disease "global cerebral hypomyelination" (OMIM #612949, also named early infantile epileptic encephalopathy 39), a neurodevelopmental disease that matches aralar-KO mice phenotype, as it is characterized by severe hypomyelination, hypotonia, neurodevelopmental arrest, and seizures (Wibom et al, 2009;Falk et al, 2014;Kavanaugh et al, 2019;Pfeiffer et al, 2020). The first patient described for Aralar/AGC1 deficiency initiated a treatment with ketogenic diet (KD) at the age of 6 and for at least 19 months.…”

Section: Introductionmentioning

confidence: 99%

βOHB Protective Pathways in Aralar-KO Neurons and Brain: An Alternative to Ketogenic Diet

et al. 2020

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Aralar/AGC1/Slc25a12, the mitochondrial aspartate-glutamate carrier expressed in neurons, is the regulatory component of the NADH malate-aspartate shuttle. AGC1 deficiency is a neuropediatric rare disease characterized by hypomyelination, hypotonia, developmental arrest, and epilepsy. We have investigated whether b-hydroxybutyrate (bOHB), the main ketone body (KB) produced in ketogenic diet (KD), is neuroprotective in aralar-knock-out (KO) neurons and mice. We report that bOHB efficiently recovers aralar-KO neurons from deficits in basal-stimulated and glutamate-stimulated respiration, effects requiring bOHB entry into the neuron, and protects from glutamate excitotoxicity. Aralar-deficient mice were fed a KD to investigate its therapeutic potential early in development, but this approach was unfeasible. Therefore, aralar-KO pups were treated without distinction of gender with daily intraperitoneal injections of bOHB during 5 d. This treatment resulted in a recovery of striatal markers of the dopaminergic system including dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratio, and vesicular monoamine transporter 2 (VMAT2) protein. Regarding postnatal myelination, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) myelin proteins were markedly increased in the cortices of bOHB-treated aralar-KO mice. Although brain Asp and NAA levels did not change by bOHB administration, a 4-d bOHB treatment to aralar-KO, but not to control, neurons led to a substantial increase in Asp (3-fold) and NAA (4-fold) levels. These results suggest that the lack of increase in brain Asp and NAA is possibly because of its active utilization by the aralar-KO brain and the likely involvement of neuronal NAA in postnatal myelination in these mice. The effectiveness of bOHB as a therapeutic treatment in AGC1 deficiency deserves further investigation.

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Expanding Phenotypic Spectrum of Cerebral Aspartate–Glutamate Carrier Isoform 1 (AGC1) Deficiency

Cited by 16 publications

References 10 publications

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

βOHB Protective Pathways in Aralar-KO Neurons and Brain: An Alternative to Ketogenic Diet

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