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1.
Artigo em Inglês | MEDLINE | ID: mdl-38464914

RESUMO

Background: L-2-hydroxyglutaric aciduria (L2HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by pathogenic variants in the L2HGDH gene which encodes mitochondrial 2-hydroxyglutarate dehydrogenase. Here, we report a case of L2HGA in a Mexican-Mayan patient with a homozygous mutation at L2HGDH gene and clinical response to vitamin supplements and levocarnitine. Case report: A 17-year-old, right-handed female patient with long-term history of seizures, developmental delay and ataxia was referred to a movement disorders specialist for the evaluation of tremor. Her brain MRI showed typical findings of L2HGA. The diagnosis was corroborated with elevated levels of 2-hydroxyglutaric acid in urine and genetic test which revealed a homozygous genetic known variant c.569C>T in exon 5 of L2HGDH gene. She was treated with levocarnitine and vitamin supplements, showing improvement in tremor and gait. Discussion: To our knowledge this is the first report of a Mexican patient with L2HGA. This case adds information about a rare condition in a different ethnic group and supports the findings of other authors which encountered symptomatic improvement with the use of flavin adenine dinucleotide (and its precursor riboflavin), and levocarnitine. Highlights: We report the first case of Mexican-Mayan patient with L2HGA showing a missense homozygous mutation in L2HGDH gene, and improvement of symptoms with vitamin supplements and levocarnitine.


Assuntos
Encefalopatias Metabólicas Congênitas , Carnitina , Tremor , Humanos , Feminino , Adolescente , Mutação/genética , Vitaminas , Oxirredutases do Álcool/genética
2.
J Biol Chem ; 300(1): 105491, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37995940

RESUMO

l-2-hydroxyglutarate dehydrogenase (L2HGDH) is a mitochondrial membrane-associated metabolic enzyme, which catalyzes the oxidation of l-2-hydroxyglutarate (l-2-HG) to 2-oxoglutarate (2-OG). Mutations in human L2HGDH lead to abnormal accumulation of l-2-HG, which causes a neurometabolic disorder named l-2-hydroxyglutaric aciduria (l-2-HGA). Here, we report the crystal structures of Drosophila melanogaster L2HGDH (dmL2HGDH) in FAD-bound form and in complex with FAD and 2-OG and show that dmL2HGDH exhibits high activity and substrate specificity for l-2-HG. dmL2HGDH consists of an FAD-binding domain and a substrate-binding domain, and the active site is located at the interface of the two domains with 2-OG binding to the re-face of the isoalloxazine moiety of FAD. Mutagenesis and activity assay confirmed the functional roles of key residues involved in the substrate binding and catalytic reaction and showed that most of the mutations of dmL2HGDH equivalent to l-2-HGA-associated mutations of human L2HGDH led to complete loss of the activity. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of L2HGDH and provide insights into the functional roles of human L2HGDH mutations in the pathogeneses of l-2-HGA.


Assuntos
Oxirredutases do Álcool , Encefalopatias Metabólicas Congênitas , Drosophila melanogaster , Modelos Moleculares , Animais , Humanos , Oxirredutases do Álcool/química , Oxirredutases do Álcool/metabolismo , Encefalopatias Metabólicas Congênitas/enzimologia , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/fisiopatologia , Drosophila melanogaster/enzimologia , Glutaratos/metabolismo , Mutação , Domínio Catalítico/genética , Especificidade por Substrato/genética , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
3.
Am J Med Genet A ; 194(2): 337-345, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37850681

RESUMO

Seizures occur in up to 59% of boys with creatine transporter deficiency (CTD). While seizure phenotypes have been previously described, electroencephalogram (EEG) findings have only been reported in several case reports. In this prospective observational study, we report seizure characteristics and EEG findings in combination with neurobehavioral and SLC6A8 pathogenic variants in twenty males with CTD. Eighteen study participants (SP) underwent video-EEG, and seven had follow-up EEG recordings. Seizures typically occurred by age of 2 years. Thirteen (65%) had non-febrile seizures, requiring anti-seizure medications in nine. Four had febrile seizures. Seizures were bilateral tonic-clonic in 7 SP and focal impaired awareness in 5 SP; often responding to 1 to 2 antiseizure medications. EEG showed slowing in 5 SP, beta activity in 6 SP, and focal/multifocal, and/or generalized epileptiform activity in 9 SP. Follow-up EEGs in 7 SP showed emergence of epileptiform activity in 1 SP, and increased activity in 2 SP. In conclusion, seizures were frequent in our cohort but tended to respond to antiseizure medications. Longitudinal follow up provided further insight into emergence of seizures and EEG abnormalities soliciting future studies with long term follow up. Biomarkers of epileptogenicity in CTD are needed to predict seizures in this population.


Assuntos
Encefalopatias Metabólicas Congênitas , Creatina/deficiência , Eletroencefalografia , Retardo Mental Ligado ao Cromossomo X , Masculino , Humanos , Pré-Escolar , Mutação , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Convulsões/genética , Proteínas do Tecido Nervoso , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética
4.
J Mol Biol ; 436(2): 168383, 2024 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-38070861

RESUMO

Creatine is an essential metabolite for the storage and rapid supply of energy in muscle and nerve cells. In humans, impaired metabolism, transport, and distribution of creatine throughout tissues can cause varying forms of mental disability, also known as creatine deficiency syndrome (CDS). So far, 80 mutations in the creatine transporter (SLC6A8) have been associated to CDS. To better understand the effect of human genetic variants on the physiology of SLC6A8 and their possible impact on CDS, we studied 30 missense variants including 15 variants of unknown significance, two of which are reported here for the first time. We expressed these variants in HEK293 cells and explored their subcellular localization and transport activity. We also applied computational methods to predict variant effect and estimate site-specific changes in thermodynamic stability. To explore variants that might have a differential effect on the transporter's conformers along the transport cycle, we constructed homology models of the inward facing, and outward facing conformations. In addition, we used mass-spectrometry to study proteins that interact with wild type SLC6A8 and five selected variants in HEK293 cells. In silico models of the protein complexes revealed how two variants impact the interaction interface of SLC6A8 with other proteins and how pathogenic variants lead to an enrichment of ER protein partners. Overall, our integrated analysis disambiguates the pathogenicity of 15 variants of unknown significance revealing diverse mechanisms of pathogenicity, including two previously unreported variants obtained from patients suffering from the creatine deficiency syndrome.


Assuntos
Encefalopatias Metabólicas Congênitas , Creatina , Retardo Mental Ligado ao Cromossomo X , Proteínas do Tecido Nervoso , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores , Humanos , Creatina/deficiência , Células HEK293 , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Encefalopatias Metabólicas Congênitas/genética , Análise Mutacional de DNA/métodos , Mutação de Sentido Incorreto , Biologia Computacional/métodos
5.
Mol Genet Metab ; 140(3): 107694, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37708665

RESUMO

Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, is the second most common cause of X-linked intellectual disability. Symptoms include intellectual disability, epilepsy, and behavioral disorders and are caused by reduced cerebral creatine levels. Targeted treatment with oral supplementation is available, however the treatment efficacy is still being investigated. There are clinical and theoretical indications that heterozygous females with CTD respond better to supplementation treatment than hemizygous males. Unfortunately, heterozygous females with CTD often have more subtle and uncharacteristic clinical and biochemical phenotypes, rendering diagnosis more difficult. We report a new female case who presented with learning disabilities and seizures. After determining the diagnosis with molecular genetic testing confirmed by proton magnetic resonance spectroscopy (1H-MRS), the patient was treated with supplementation treatment including creatine, arginine, and glycine. After 28 months of treatment, the patient showed prominent clinical improvement and increased creatine levels in the brain. Furthermore, we provide a review of the 32 female cases reported in the current literature including a description of phenotypes, genotypes, diagnostic approaches, and effects of supplementation treatment. Based on this, we find that supplementation treatment should be tested in heterozygous female patients with CTD, and a prospective treatment underlines the importance of diagnosing these patients. The diagnosis should be suspected in a broad clinical spectrum of female patients and can only be made by molecular genetic testing. 1H-MRS of cerebral creatine levels is essential for establishing the diagnosis in females, and especially valuable when assessing variants of unknown significance.


Assuntos
Encefalopatias Metabólicas Congênitas , Deficiência Intelectual , Retardo Mental Ligado ao Cromossomo X , Masculino , Humanos , Feminino , Deficiência Intelectual/genética , Creatina , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas do Tecido Nervoso
6.
Acta Neurol Belg ; 123(6): 2315-2323, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37378753

RESUMO

BACKGROUND: L-2-Hydroxyglutaric aciduria (L2HGA) is a rare progressive neurometabolic disorder with variable clinical presentation including cerebellar ataxia, psychomotor retardation, seizures, macrocephaly and speech problems. In this study, we aimed at identifying the genetic cause in two unrelated families suspected with L2HGA. METHODS: Exome sequencing was performed on two patients from family 1 with suspected L2HGA. MLPA analysis was carried out on the index patient of family 2 to detect deletions/duplications in the L2HGDH gene. Sanger sequencing was carried out to validate the identified variants and to confirm segregation of the variants in the family members. RESULTS: In family 1, a novel homozygous variant c.1156C > T resulting in a nonsense mutation p.Gln386Ter was identified in the L2HGDH gene. The variant segregated with autosomal recessive inheritance in the family. In family 2, a homozygous deletion of exon 10 in the L2HGDH gene was identified in the index patient using MLPA analysis. PCR validation confirmed the presence of the deletion variant in the patient which is not present in the unaffected mother or an unrelated control. CONCLUSION: This study identified novel pathogenic variants in the L2HGDH gene in patients with L2HGA. These findings contribute to the understanding of the genetic basis of L2HGA and highlight the importance of genetic testing for diagnosis and genetic counseling of affected families.


Assuntos
Encefalopatias Metabólicas Congênitas , Feminino , Humanos , Oxirredutases do Álcool/genética , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/diagnóstico , Homozigoto , Mutação/genética , Deleção de Sequência
7.
Acta Neuropathol Commun ; 11(1): 34, 2023 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-36882863

RESUMO

Mutations in the solute carrier family 6-member 8 (Slc6a8) gene, encoding the protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with intellectual disability, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood, hindering the development of therapies. In this study, we generated an extensive transcriptomic profile of CTD showing that Cr deficiency causes perturbations of gene expression in excitatory neurons, inhibitory cells, and oligodendrocytes which result in remodeling of circuit excitability and synaptic wiring. We also identified specific alterations of parvalbumin-expressing (PV+) interneurons, exhibiting a reduction in cellular and synaptic density, and a hypofunctional electrophysiological phenotype. Mice lacking Slc6a8 only in PV+ interneurons recapitulated numerous CTD features, including cognitive deterioration, impaired cortical processing and hyperexcitability of brain circuits, demonstrating that Cr deficit in PV+ interneurons is sufficient to determine the neurological phenotype of CTD. Moreover, a pharmacological treatment targeted to restore the efficiency of PV+ synapses significantly improved cortical activity in Slc6a8 knock-out animals. Altogether, these data demonstrate that Slc6a8 is critical for the normal function of PV+ interneurons and that impairment of these cells is central in the disease pathogenesis, suggesting a novel therapeutic venue for CTD.


Assuntos
Encefalopatias Metabólicas Congênitas , Proteínas de Membrana Transportadoras , Parvalbuminas , Animais , Camundongos , Creatina , Neurônios , Proteínas de Membrana Transportadoras/genética
8.
J Vet Intern Med ; 37(2): 676-680, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36880414

RESUMO

CASE DESCRIPTION: A 9-month-old intact male domestic shorthair cat was evaluated for increasing frequency of generalized tonic-clonic seizures. CLINICAL FINDINGS: The cat was reported to have had episodes of circling between the seizures. Upon examination, the cat had bilateral inconsistent menace response but otherwise normal physical and neurological examinations. DIAGNOSTICS: Magnetic resonance imaging (MRI) of the brain identified multifocal, small, rounded intra-axial lesions within the subcortical white matter containing fluid with similar characteristics as cerebrospinal fluid. Evaluation of urine organic acids showed increased excretion of 2-hydroxyglutaric acid. An XM_023255678.2:c.397C>T nonsense variant in the L2HGDH gene encoding L-2-hydroxyglutarate dehydrogenase was identified using whole genome sequencing. TREATMENT AND OUTCOME: Levetiracetam treatment was initiated at 20 mg/kg PO q8h, but the cat died after a seizure 10 days later. CLINICAL RELEVANCE: We report the second pathogenic gene variant in L-2-hydroxyglutaric aciduria in cats and describe for the first time multicystic cerebral lesions on MRI.


Assuntos
Encefalopatias Metabólicas Congênitas , Doenças do Gato , Animais , Gatos , Masculino , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/veterinária , Doenças do Gato/diagnóstico , Doenças do Gato/tratamento farmacológico , Doenças do Gato/genética , Glutaratos , Imageamento por Ressonância Magnética/veterinária , Mutação de Sentido Incorreto , Convulsões/diagnóstico , Convulsões/veterinária , Oxirredutases do Álcool/metabolismo
9.
Am J Med Genet A ; 191(6): 1614-1618, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36891747

RESUMO

Ethylmalonic encephalopathy (EE) is a rare, severe, autosomal recessive condition caused by pathogenic variants in ETHE1 leading to progressive encephalopathy, hypotonia evolving to dystonia, petechiae, orthostatic acrocyanosis, diarrhea, and elevated ethylmalonic acid in urine. In this case report, we describe a patient with only mild speech and gross motor delays, subtle biochemical abnormalities, and normal brain imaging found to be homozygous for a pathogenic ETHE1 variant (c.586G>A) via whole exome sequencing. This case highlights the clinical heterogeneity of ETHE1 mutations and the utility of whole-exome sequencing in diagnosing mild cases of EE.


Assuntos
Encefalopatias Metabólicas Congênitas , Encefalopatias , Púrpura , Humanos , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Púrpura/diagnóstico , Púrpura/genética , Encéfalo/patologia , Encefalopatias/diagnóstico , Encefalopatias/genética , Encefalopatias/patologia , Proteínas Mitocondriais/genética , Proteínas de Transporte Nucleocitoplasmático/genética
10.
J Investig Med High Impact Case Rep ; 11: 23247096231154438, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36752093

RESUMO

Cerebral creatine deficiency syndromes (CCDS) are a rare group of inherited metabolic disorders (IMDs) that often present with nonspecific findings including global developmental delay (GDD), intellectual disability (ID), seizures, hypotonia, and behavioral differences. Creatine transporter (CRTR) deficiency is the most common CCDS, exhibiting X-linked inheritance and an estimated prevalence as high as 2.6% in individuals with neurodevelopmental disorders. Here, we present a 20-month-old boy with worsening failure to thrive (FTT) and GDD admitted for evaluation. He was found to have persistently low serum creatinine levels and a family history notable for a mother with learning disabilities and a maternal male cousin with GDD. Urine analyses revealed a marked elevation of creatine and elevated creatine:creatinine ratio suggestive of CRTR deficiency. Molecular genetic testing of SLC6A8 identified a maternally inherited hemizygous variant and brain magnetic resonance spectroscopy (MRS) showed diffusely diminished creatine peaks, further supporting the diagnosis of CRTR deficiency. The proband was started on creatine, arginine, and glycine supplementation and has demonstrated improved development. This case highlights that CRTR deficiency should be considered in all patients presenting with FTT and abnormal neurodevelopmental features, particularly if creatinine levels are low on serum chemistry studies. The nonspecific presentation of this condition in males and females likely has resulted in CRTR deficiency being underdiagnosed. There are existing therapies for individuals affected with CRTR deficiency and other CCDS, highlighting the importance of early diagnosis and intervention for affected individuals.


Assuntos
Encefalopatias Metabólicas Congênitas , Deficiência Intelectual , Humanos , Lactente , Masculino , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/patologia , Creatina/genética , Creatina/metabolismo , Creatinina , Insuficiência de Crescimento , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores
12.
Clin Neurol Neurosurg ; 225: 107529, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36610237

RESUMO

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare autosomal recessive disease resulted from the mutated gene L-2- hydroxyglutarate dehydrogenase (L2HGDH). We presented a female case who inherited the disease from her consanguineous relatives and suffered from cognitive impairment, seizure, and ataxia. Using cerebral magnetic resonance imaging (MRI), urine organic acid test, and high-throughput DNA sequencing, a novel homozygous missense mutation was found in the L2HGDH gene, namely c 0.847 G>A/p. G283R in exon 7. Summarizing the clinical information of the patient with L-2-HGA exhibited to be beneficial for the diagnosis of this rare disease. In summary, the pathogenic missense mutation in the case was reliably confirmed using the bioinformatics analysis.


Assuntos
Encefalopatias Metabólicas Congênitas , Mutação de Sentido Incorreto , Humanos , Feminino , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Imageamento por Ressonância Magnética , Homozigoto , Mutação , Oxirredutases do Álcool/genética
13.
Sci Rep ; 12(1): 16083, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36167967

RESUMO

Nitisinone (NIT) produces inevitable but varying degree of tyrosinaemia. However, the understanding of the dynamic adaptive relationships within the tyrosine catabolic pathway has not been investigated fully. The objective of the study was to assess the contribution of protein intake, serum NIT (sNIT) and tyrosine pathway metabolites to nitisinone-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24-h urine collected during SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), tyrosine (TYR), phenylalanine (PHE), hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine. Total body water (TBW) metabolites were derived using 60% body weight. 24-h urine and TBW metabolites were summed to obtain combined values. All statistical analyses were post-hoc. 307 serum and 24-h urine sampling points were analysed. Serum TYR from V2 to V6, ranging from 478 to 1983 µmol/L were stratified (number of sampling points in brackets) into groups < 701 (47), 701-900 (105), 901-1100 (96) and > 1100 (59) µmol/L. The majority of sampling points had values greater than 900 µmol/L. sPHE increased with increasing sTYR (p < 0.001). Tyrosine, HPPA and HPLA in serum and TBW all increased with rising sTYR (p < 0.001), while HPLA/TYR ratio decreased (p < 0.0001). During NIT therapy, adaptive response to minimise TYR formation was demonstrated. Decreased conversion of HPPA to HPLA, relative to TYR, seems to be most influential in determining the degree of tyrosinaemia.


Assuntos
Alcaptonúria , Encefalopatias Metabólicas Congênitas , Tirosinemias , Alcaptonúria/tratamento farmacológico , Cicloexanonas/uso terapêutico , Ácido Homogentísico , Humanos , Nitrobenzoatos/uso terapêutico , Fenilalanina , Fenilpropionatos , Tirosina/metabolismo , Tirosinemias/tratamento farmacológico
14.
Am J Med Genet A ; 188(9): 2707-2711, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35785415

RESUMO

D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare neurometabolic disease with two main subtypes, caused by either inactivating variants in D2HGDH (type I) or germline gain of function variants in IDH2 (type II), that result in accumulation of the same toxic metabolite, D-2-hydroxyglutarate. The main clinical features of both are neurologic, including developmental delay, hypotonia, and seizures. Dilated cardiomyopathy is a unique feature thus far only reported in type II. As somatic variants in IDH2 are frequently identified in several different types of cancer, including acute myeloid leukemia (AML), a link between cancer and this metabolic disease has been proposed; however, there is no reported cancer in patients with either type of D-2-HGA. Murine models have demonstrated how D-2-hydroxyglutarate alters metabolism and epigenetics, a potential mechanism by which this metabolite may cause cancer and cardiomyopathy. Here, we report the first case of both AML and dilated cardiomyopathy in a pediatric patient with D-2-HGA type I, who was treated with an anthracycline-free regimen. This report may expand the clinical spectrum of this rare metabolic disease and provide insight on long-term surveillance and care. However, this case is complicated by the presence of a complex chromosomal rearrangement resulting in a 25.5 Mb duplication of 1q41 and a 2.38 Mb deletion of 2q37.3. Thus, the direct causal relationship between D-2-HGA and leukemogenesis or cardiomyopathy warrants further scrutiny.


Assuntos
Encefalopatias Metabólicas Congênitas , Cardiomiopatias , Cardiomiopatia Dilatada , Leucemia Mieloide Aguda , Doenças Metabólicas , Anormalidades Urogenitais , Animais , Encefalopatias Metabólicas Congênitas/complicações , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Cardiomiopatias/complicações , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Criança , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Camundongos , Doenças Raras
15.
Clin Chim Acta ; 532: 29-36, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35588794

RESUMO

Cerebral creatine deficiency syndromes (CCDSs) are a group of rare mendelian disorders mainly characterized by intellectual disability, movement anomaly, behavior disorder and seizures. SLC6A8, GAMT, and GATM are known genes responsible for CCDS. In this study, seven pediatric patients with developmental delay were recruited and submitted to a series of clinical evaluation, laboratory testing, and genetic analysis. The clinical manifestations and core biochemical indications of each child were basically consistent with the diagnosis of CCDS. Genetic diagnosis determined that all patients were positive for SLC6A8 or GAMT variation. A total of 12 variants were identified in this cohort, including six novel ones. The frequency of these variants, the Revel scores and the conservatism of the affected amino acids support their pathogenicity. Our findings expanded the mutation spectrum of CCDS disorders, and provided solid evidence for the counseling to affected families.


Assuntos
Encefalopatias Metabólicas Congênitas , Guanidinoacetato N-Metiltransferase , Deficiência Intelectual , Proteínas do Tecido Nervoso , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Criança , Creatina/deficiência , Guanidinoacetato N-Metiltransferase/genética , Humanos , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Síndrome
16.
Nat Cell Biol ; 24(4): 526-537, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35418624

RESUMO

D-2-Hydroxyglutarate (D-2HG) is an α-ketoglutarate-derived mitochondrial metabolite that causes D-2-hydroxyglutaric aciduria, a devastating developmental disorder. How D-2HG adversely affects mitochondria is largely unknown. Here, we report that in Caenorhabditis elegans, loss of the D-2HG dehydrogenase DHGD-1 causes D-2HG accumulation and mitochondrial damage. The excess D-2HG leads to a build-up of 3-hydroxypropionate (3-HP), a toxic metabolite in mitochondrial propionate oxidation, by inhibiting the 3-HP dehydrogenase HPHD-1. We demonstrate that 3-HP binds the MICOS subunit MIC60 (encoded by immt-1) and inhibits its membrane-binding and membrane-shaping activities. We further reveal that dietary and gut bacteria affect mitochondrial health by modulating the host production of 3-HP. These findings identify a feedback loop that links the toxic effects of D-2HG and 3-HP on mitochondria, thus providing important mechanistic insights into human diseases related to D-2HG and 3-HP.


Assuntos
Encefalopatias Metabólicas Congênitas , Propionatos , Encefalopatias Metabólicas Congênitas/metabolismo , Retroalimentação , Glutaratos/metabolismo , Humanos , Isocitrato Desidrogenase/metabolismo , Mitocôndrias/metabolismo , Oxirredutases , Propionatos/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-35165146

RESUMO

Ethylmalonic encephalopathy (MIM #602473) is a rare autosomal recessive metabolic condition caused by biallelic variants in ETHE1 (MIM #608451), characterized by global developmental delay, infantile hypotonia, seizures, and microvascular damage. The microvascular changes result in a pattern of relapsing spontaneous diffuse petechiae and purpura, positional acrocyanosis, and pedal edema, hemorrhagic suffusions of mucous membranes, and chronic diarrhea. Here, we describe an instructive case in which ethylmalonic encephalopathy masqueraded as meningococcal septicemia and shock. Ultrarapid whole-genome testing (time to result 60 h) and prompt biochemical analysis facilitated accurate diagnosis and counseling with rapid implementation of precision treatment for the metabolic crisis related to this condition. This case provides a timely reminder to consider rare genetic diagnoses when atypical features of more common conditions are present, with an early referral to ensure prompt biochemical and genomic diagnosis.


Assuntos
Púrpura , Sepse , Encefalopatias Metabólicas Congênitas , Humanos , Proteínas Mitocondriais/genética , Proteínas de Transporte Nucleocitoplasmático/genética , Púrpura/diagnóstico , Púrpura/genética , Púrpura/metabolismo
18.
Biosensors (Basel) ; 12(2)2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35200327

RESUMO

D-2-hydroxyglutaric acid (D2HG) is overproduced as a result of the D-2-hydroxyglutaric aciduria and relevant cancers, caused by gene mutation. Accurate analysis of D2HG could help rapid diagnosis of these diseases and allow for timely treatment. In this work, a D-2-hydroxyglutarate dehydrogenase from Ralstonia solanacearum (RsD2HGDH) is cloned and recombinantly expressed. This enzyme features the direct electron transfer to chemical electron mediators (such as methylene blue (MB)) in the absence of additional coenzymes. Therefore, NAD+, a natural electron acceptor for the commercial D2HGDH and usually known for being unstable and difficult for immobilization can be avoided in the preparation of biosensors. The RsD2HGDH and MB are co-immobilized on a two-dimensional material, Ti3C2 MXene, followed by drop-coating on the gold screen-printed electrode (AuSPE) to construct a compact and portable biosensor. The D2HG in samples can be catalyzed by RsD2HGDH, where the current change is measured by chronoamperometry at -0.23 V. The biosensor shows a D2HG detection range of 0.5 to 120 µM (R2 = 0.9974) with a sensitivity of 22.26 µA mM-1 cm-2 and a detection limit of 0.1 µM (S/N = 3). The biosensor retains 72.52% performance of its incipient state after 30 days of storage. The samples of D2HG-containing fetal bovine serum and artificial urine were analyzed with the recovery of 99.56% to 106.83% and 97.30% to 102.47% further indicating the great application potential of our portable D2HG biosensor.


Assuntos
Técnicas Biossensoriais , Encefalopatias Metabólicas Congênitas , Técnicas Biossensoriais/métodos , Eletrodos , Glutaratos , Ouro , Humanos
19.
Brain Dev ; 44(4): 271-280, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34974949

RESUMO

INTRODUCTION: Cerebral creatine deficiency syndromes (CCDS) are a group of potentially treatable neurometabolic disorders. The clinical, genetic profile and follow up outcome of Indian CCDS patients is presented. MATERIALS AND METHODS: This was a retrospective cohort of CCDS patients seen over six-years. Diagnosis was based either on low creatine peak on proton magnetic resonance spectroscopy (MRS) and/or genetic evaluation. RESULTS: Thirteen patients were eligible [8 creatine transporter deficiency (CTD), 4 guanidinoacetate methyltransferase (GAMT) deficiency and 1 could not be classified]. The mean (±SD) age at diagnosis was 7.2(±5.0) years. Clinical manifestations included intellectual disability (ID) with significant expressive speech delay in all. Most had significant behavior issues (8/13) and/or autism (8/13). All had history of convulsive seizures (11/13 had epilepsy; 2 patients only had febrile seizures) and 2/13 had movement disorder. Constipation was the commonest non-neurological manifestation (5/13 patients). Cranial MRI was normal in all CTD patients but showed globus pallidus hyperintensity in all four with GAMT deficiency. MRS performed in 11/13 patients, revealed abnormally low creatine peak. A causative genetic variant (novel mutation in nine) was identified in 12 patients. Three GAMT deficiency and one CTD patient reported neurodevelopmental improvement and good seizure control after creatine supplementation. CONCLUSION: Intellectual disability, disproportionate speech delay, autism, and epilepsy, were common in our CCDS patients. A normal structural neuroimaging with easily controlled febrile and/or afebrile seizures differentiated CTD from GAMT deficiency patients who had abnormal neuroimaging and often difficult to control epilepsy and movement disorder.


Assuntos
Encefalopatias Metabólicas Congênitas/diagnóstico , Creatina/deficiência , Guanidinoacetato N-Metiltransferase/deficiência , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Transtornos dos Movimentos/congênito , Transtornos do Neurodesenvolvimento/diagnóstico , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Encefalopatias Metabólicas Congênitas/complicações , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/fisiopatologia , Criança , Pré-Escolar , Creatina/genética , Feminino , Seguimentos , Guanidinoacetato N-Metiltransferase/genética , Humanos , Índia , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Retardo Mental Ligado ao Cromossomo X/complicações , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Transtornos dos Movimentos/complicações , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/fisiopatologia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Estudos Retrospectivos
20.
Mol Genet Metab ; 135(1): 15-26, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34972654

RESUMO

Creatine deficiency syndromes (CDS) are inherited metabolic disorders caused by mutations in GATM, GAMT and SLC6A8 and mainly affect central nervous system (CNS). AGAT- and GAMT-deficient patients lack the functional brain endogenous creatine (Cr) synthesis pathway but express the Cr transporter SLC6A8 at blood-brain barrier (BBB), and can thus be treated by oral supplementation of high doses of Cr. For Cr transporter deficiency (SLC6A8 deficiency or CTD), current treatment strategies benefit one-third of patients. However, as their phenotype is not completely reversed, and for the other two-thirds of CTD patients, the development of novel more effective therapies is needed. This article aims to review the current knowledge on Cr metabolism and CDS clinical aspects, highlighting their current treatment possibilities and the most recent research perspectives on CDS potential therapeutics designed, in particular, to bring new options for the treatment of CTD.


Assuntos
Encefalopatias Metabólicas Congênitas , Retardo Mental Ligado ao Cromossomo X , Encéfalo/metabolismo , Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Encefalopatias Metabólicas Congênitas/genética , Creatina , Guanidinoacetato N-Metiltransferase , Humanos , Retardo Mental Ligado ao Cromossomo X/tratamento farmacológico , Retardo Mental Ligado ao Cromossomo X/genética , Síndrome
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