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1.
N Engl J Med ; 387(15): 1395-1403, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36239646

RESUMO

We describe the case of identical twin boys who presented with low body weight despite excessive caloric intake. An evaluation of their fibroblasts showed elevated oxygen consumption and decreased mitochondrial membrane potential. Exome analysis revealed a de novo heterozygous variant in ATP5F1B, which encodes the ß subunit of mitochondrial ATP synthase (also called complex V). In yeast, mutations affecting the same region loosen coupling between the proton motive force and ATP synthesis, resulting in high rates of mitochondrial respiration. Expression of the mutant allele in human cell lines recapitulates this phenotype. These data support an autosomal dominant mitochondrial uncoupling syndrome with hypermetabolism. (Funded by the National Institutes of Health.).


Assuntos
Doenças Mitocondriais , ATPases Mitocondriais Próton-Translocadoras , Fosforilação Oxidativa , Consumo de Oxigênio , Humanos , Masculino , Trifosfato de Adenosina/metabolismo , Doenças em Gêmeos/genética , Doenças em Gêmeos/metabolismo , Fibroblastos/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/congênito , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , ATPases Mitocondriais Próton-Translocadoras/genética , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Mutação , Consumo de Oxigênio/genética , Consumo de Oxigênio/fisiologia , Gêmeos Monozigóticos/genética
2.
Am J Med Genet A ; : e63825, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39058293

RESUMO

Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial disorder of carbohydrate oxidation characterized by lactic acidosis and central nervous system involvement. Knowledge of the affected metabolic pathways and clinical observations suggest that early initiation of the ketogenic diet may ameliorate the metabolic and neurologic course of the disease. We present a case in which first trimester ultrasound identified structural brain abnormalities prompting a prenatal molecular diagnosis of PDCD. Ketogenic diet, thiamine, and N-acetylcysteine were initiated in the perinatal period with good response, including sustained developmental progress. This case highlights the importance of a robust neurometabolic differential diagnosis for prenatally diagnosed structural anomalies and the use of prenatal molecular testing to facilitate rapid, genetically tailored intervention.

3.
Am J Med Genet A ; : e63817, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39031459

RESUMO

Exome sequencing (ES) has emerged as an essential tool in the evaluation of neurodevelopmental disorders (NDD) of unknown etiology. Genome sequencing (GS) offers advantages over ES due to improved detection of structural, copy number, repeat number and non-coding variants. However, GS is less commonly utilized due to higher cost and more intense analysis. Here, we present nine cases of pediatric NDD that were molecularly diagnosed with GS between 2017 and 2022, following non-diagnostic ES. All individuals presented with global developmental delay or regression. Other features present in our cohort included epilepsy, white matter abnormalities, brain malformation and dysmorphic features. Two cases were diagnosed on GS due to newly described gene-disease relationship or variant reclassification (MAPK8IP3, CHD3). Additional features missed on ES that were later detected on GS were: intermediate-size deletions in three cases who underwent ES that were not validated for CNV detection, pathogenic variants within the non-protein coding genes SNORD118 and RNU7-1, pathogenic variant within the promoter region of GJB1, and a coding pathogenic variant within BCAP31 which was not sufficiently covered on ES. GS following non-diagnostic ES led to the identification of pathogenic variants in this cohort of nine cases, four of which would not have been identified by reanalysis alone.

4.
Genet Med ; 25(2): 100332, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36520152

RESUMO

PURPOSE: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities. METHODS: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells. RESULTS: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells. CONCLUSION: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities.


Assuntos
Transtornos dos Movimentos , Transtornos do Neurodesenvolvimento , Animais , Humanos , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Células HEK293 , Complexo Cetoglutarato Desidrogenase/genética , Complexo Cetoglutarato Desidrogenase/metabolismo , Transtornos do Neurodesenvolvimento/genética
5.
Genet Med ; 25(6): 100314, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36305855

RESUMO

PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.


Assuntos
Falência Hepática Aguda , Falência Hepática , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Adulto Jovem , Acetilcisteína/uso terapêutico , Falência Hepática/tratamento farmacológico , Falência Hepática/genética , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/genética , Proteínas Mitocondriais/genética , Mutação , Estudos Retrospectivos , tRNA Metiltransferases/genética
6.
Clin Chem ; 69(6): 564-582, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37099687

RESUMO

BACKGROUND: Mitochondria are cytosolic organelles within most eukaryotic cells. Mitochondria generate the majority of cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OxPhos). Pathogenic variants in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) lead to defects in OxPhos and physiological malfunctions (Nat Rev Dis Primer 2016;2:16080.). Patients with primary mitochondrial disorders (PMD) experience heterogeneous symptoms, typically in multiple organ systems, depending on the tissues affected by mitochondrial dysfunction. Because of this heterogeneity, clinical diagnosis is challenging (Annu Rev Genomics Hum Genet 2017;18:257-75.). Laboratory diagnosis of mitochondrial disease depends on a multipronged analysis that can include biochemical, histopathologic, and genetic testing. Each of these modalities has complementary strengths and limitations in diagnostic utility. CONTENT: The primary focus of this review is on diagnosis and testing strategies for primary mitochondrial diseases. We review tissue samples utilized for testing, metabolic signatures, histologic findings, and molecular testing approaches. We conclude with future perspectives on mitochondrial testing. SUMMARY: This review offers an overview of the current biochemical, histologic, and genetic approaches available for mitochondrial testing. For each we review their diagnostic utility including complementary strengths and weaknesses. We identify gaps in current testing and possible future avenues for test development.


Assuntos
Mitocôndrias , Doenças Mitocondriais , Humanos , Transporte de Elétrons , Mitocôndrias/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , DNA Mitocondrial/genética , Fosforilação Oxidativa
7.
Mol Genet Metab ; 140(1-2): 107710, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37903659

RESUMO

Iron­sulfur clusters (FeS) are one of the most primitive and ubiquitous cofactors used by various enzymes in multiple pathways. Biosynthesis of FeS is a complex multi-step process that is tightly regulated and requires multiple machineries. IBA57, along with ISCA1 and ISCA2, play a role in maturation of [4Fe-4S] clusters which are required for multiple mitochondrial enzymes including mitochondrial Complex I, Complex II, lipoic acid synthase, and aconitase. Pathogenic variants in IBA57 have been associated with multiple mitochondrial dysfunctions syndrome 3 (MMDS3) characterized by infantile to early childhood-onset psychomotor regression, optic atrophy and nonspecific dysmorphism. Here we report a female proband who had prenatal involvement including IUGR and microcephaly and developed subacute psychomotor regression at the age of 5 weeks in the setting of preceding viral infection. Brain imaging revealed cortical malformation with polymicrogyria and abnormal signal alteration in brainstem and spinal cord. Biochemical analysis revealed increased plasma glycine and hyperexcretion of multiple organic acids in urine, raising the concern for lipoic acid biosynthesis defects and mitochondrial FeS assembly defects. Molecular analysis subsequently detected compound heterozygous variants in IBA57, confirming the diagnosis of MMDS3. Although the number of MMDS3 patients are limited, certain degree of genotype-phenotype correlation has been observed. Unusual brain imaging in the proband highlights the need to include mitochondrial disorders as differential diagnoses of structural brain abnormalities. Lastly, in addition to previously known biomarkers including high blood lactate and plasma glycine levels, the increase of 2-hydroxyadipic and 2-ketoadipic acids in urine organic acid analysis, in the appropriate clinical context, should prompt an evaluation for the lipoic acid biosynthesis defects and mitochondrial FeS assembly defects.


Assuntos
Proteínas Ferro-Enxofre , Doenças Mitocondriais , Ácido Tióctico , Humanos , Pré-Escolar , Feminino , Lactente , Lisina/metabolismo , Triptofano/metabolismo , Proteínas Ferro-Enxofre/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Biomarcadores/metabolismo , Glicina/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas de Transporte/genética
8.
Genet Med ; 24(2): 319-331, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34906466

RESUMO

PURPOSE: Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown. METHODS: We used exome sequencing to uncover ADD1 variants associated with intellectual disability (ID) and brain malformations. We studied ADD1 splice isoforms in mouse and human neocortex development with RNA sequencing, super resolution imaging, and immunoblotting. We investigated 4 variant ADD1 proteins and heterozygous ADD1 cells for protein expression and ADD1-ADD2 dimerization. We studied Add1 functions in vivo using Add1 knockout mice. RESULTS: We uncovered loss-of-function ADD1 variants in 4 unrelated individuals affected by ID and/or structural brain defects. Three additional de novo copy number variations covering the ADD1 locus were associated with ID and brain malformations. ADD1 is highly expressed in the neocortex and the corpus callosum, whereas ADD1 splice isoforms are dynamically expressed between cortical progenitors and postmitotic neurons. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. CONCLUSION: Our human and mouse genetics results indicate that pathogenic ADD1 variants cause corpus callosum dysgenesis, ventriculomegaly, and/or ID.


Assuntos
Hidrocefalia , Deficiência Intelectual , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Animais , Variações do Número de Cópias de DNA , Humanos , Hidrocefalia/genética , Deficiência Intelectual/genética , Camundongos , Fenótipo
9.
Mol Genet Metab ; 137(3): 230-238, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36182714

RESUMO

In this retrospective cohort study of 193 consecutive subjects with primary mitochondrial disease (PMD) seen at the Children's Hospital of Philadelphia Mitochondrial Medicine Frontier Program, we assessed prevalence, severity, and time of onset of sensorineural hearing loss (SNHL) for PMD cases with different genetic etiologies. Subjects were grouped by genetic diagnosis: mitochondrial DNA (mtDNA) pathogenic variants, single large-scale mtDNA deletions (SLSMD), or nuclear DNA (nDNA) pathogenic variants. SNHL was audiometrically confirmed in 27% of PMD subjects (20% in mtDNA pathogenic variants, 58% in SLSMD and 25% in nDNA pathogenic variants). SLSMD had the highest odds ratio for SNHL. SNHL onset was post-lingual in 79% of PMD cases, interestingly including all cases with mtDNA pathogenic variants and SLSMD, which was significantly different from PMD cases caused by nDNA pathogenic variants. SNHL onset during school age was predominant in this patient population. Regular audiologic assessment is important for PMD patients, and PMD of mtDNA etiology should be considered as a differential diagnosis in pediatric patients and young adults with post-lingual SNHL onset, particularly in the setting of multi-system clinical involvement. Pathogenic mtDNA variants and SLSMD are less likely etiologies in subjects with congenital, pre-lingual onset SNHL.


Assuntos
Perda Auditiva Neurossensorial , Doenças Mitocondriais , Adulto Jovem , Humanos , Criança , DNA Mitocondrial/genética , Estudos Retrospectivos , Doenças Mitocondriais/complicações , Doenças Mitocondriais/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/diagnóstico , Mitocôndrias/genética
10.
Mol Genet Metab ; 135(1): 93-101, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34969639

RESUMO

Mitochondrial disease diagnosis requires interrogation of both nuclear and mitochondrial (mtDNA) genomes for single-nucleotide variants (SNVs) and copy number alterations, both in the proband and often maternal relatives, together with careful phenotype correlation. We developed a comprehensive mtDNA sequencing test ('MitoGenome') using long-range PCR (LR-PCR) to amplify the full length of the mtDNA genome followed by next generation sequencing (NGS) to accurately detect SNVs and large-scale mtDNA deletions (LSMD), combined with droplet digital PCR (ddPCR) for LSMD heteroplasmy quantification. Overall, MitoGenome tests were performed on 428 samples from 394 patients with suspected or confirmed mitochondrial disease. The positive yield was 11% (43/394), including 34 patients with pathogenic or likely pathogenic SNVs (the most common being m.3243A > G in 8/34 (24%) patients), 8 patients with single LSMD, and 3 patients with multiple LSMD exceeding 10% heteroplasmy levels. Two patients with both LSMD and pathogenic SNV were detected. Overall, this LR-PCR/NGS assay provides a highly accurate and comprehensive diagnostic method for simultaneous mtDNA SNV detection at heteroplasmy levels as low as 1% and LSMD detection at heteroplasmy levels below 10%. Inclusion of maternal samples for variant classification and ddPCR to quantify LSMD heteroplasmy levels further enables accurate pathogenicity assessment and clinical correlation interpretation of mtDNA genome sequence variants and copy number alterations.


Assuntos
Genoma Mitocondrial , Doenças Mitocondriais , DNA Mitocondrial/genética , Genoma Mitocondrial/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mitocôndrias/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética
11.
Mol Genet Metab ; 134(1-2): 37-42, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34176718

RESUMO

Elevated citrulline and C5-OH levels are reported as part of the newborn screening of core and secondary disorders on the Recommended Uniform Screening Panel (RUSP). Additionally, some state laboratory newborn screening programs report low citrulline levels, which may be observed in proximal urea cycle disorders. We report six patients who were found on newborn screening to have low citrulline and/or elevated C5-OH levels in whom confirmatory testing showed the combination of these two abnormal analytes. Mitochondrial sequencing revealed known pathogenic variants in MT-ATP6 at high heteroplasmy levels in all cases. MT-ATP6 at these heteroplasmy levels is associated with Leigh syndrome, a progressive neurodegenerative disease. Patients were treated with supplemental citrulline and, in some cases, mitochondrial cofactor therapy. These six patients have not experienced metabolic crises or developmental regression, and early diagnosis and management may help prevent the neurological sequelae of Leigh syndrome. The affected mothers and siblings are asymptomatic or paucisymptomatic (e.g. intellectual disability, depression, migraines, obsessive-compulsive disorder, and poor balance) despite high heteroplasmy or apparent homoplasmy of the familial variant, thus expanding the clinical spectrum seen in pathogenic variants of MT-ATP6. Confirmatory plasma amino acid analysis and acylcarnitine profiling should be ordered in a patient with either low citrulline and/or elevated C5-OH, as this combination appears specific for pathogenic variants in MT-ATP6.


Assuntos
Testes Genéticos/métodos , Doença de Leigh/diagnóstico , Doença de Leigh/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Triagem Neonatal/métodos , Carnitina/sangue , Carnitina/química , Citrulina/sangue , DNA Mitocondrial/genética , Feminino , Humanos , Recém-Nascido , Masculino , Estudos Prospectivos
12.
Am J Med Genet A ; 185(8): 2519-2525, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34008913

RESUMO

Defects of mitoribosome assembly with destabilization of mitochondrial ribosomal proteins and subsequent aberrant mitochondrial translation machinery are one of the emerging categories of human mitochondrial disease. Mitochondrial translation deficiency constitutes a growing cause of combined oxidative phosphorylation deficiency and overall causes a set of clinically heterogeneous multi-systemic diseases. We present here the sixth individual with combined oxidative phosphorylation deficiency-9 (COXPD9) secondary to a likely pathogenic homozygous MRPL3 variant c.571A > C; p.(Thr191Pro). MRPL3 encodes a large mitochondrial ribosome subunit protein, impairing the mitochondrial translation and resulting in multisystem disease. Similar to previously reported individuals, this reported female proband presented with psychomotor retardation, sensorineural hearing loss, hypertrophic cardiomyopathy, failure to thrive, and lactic acidosis. Further, she has additional, previously unreported, features including Leigh syndrome, cataracts, hypotonia, scoliosis, myopathy, exercise intolerance, childhood-onset cardiomyopathy, and microcephaly. This subject is the oldest reported individual with COXPD9. This report also summarizes the clinical and molecular data of the previously reported individuals with COXPD9 to describe the full phenotypic spectrum.


Assuntos
Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação , Proteínas Ribossômicas/genética , Alelos , Substituição de Aminoácidos , Biomarcadores , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Erros Inatos do Metabolismo/tratamento farmacológico , Doenças Mitocondriais/tratamento farmacológico , Porto Rico , Irmãos
13.
Hum Mol Genet ; 27(19): 3305-3312, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29917077

RESUMO

Leigh syndrome is a frequent, heterogeneous pediatric presentation of mitochondrial oxidative phosphorylation (OXPHOS) disease, manifesting with psychomotor retardation and necrotizing lesions in brain deep gray matter. OXPHOS occurs at the inner mitochondrial membrane through the integrated activity of five protein complexes, of which complex V (CV) functions in a dimeric form to directly generate adenosine triphosphate (ATP). Mutations in several different structural CV subunits cause Leigh syndrome; however, dimerization defects have not been associated with human disease. We report four Leigh syndrome subjects from three unrelated Ashkenazi Jewish families harboring a homozygous splice-site mutation (c.87 + 1G>C) in a novel CV subunit disease gene, USMG5. The Ashkenazi population allele frequency is 0.57%. This mutation produces two USMG5 transcripts, wild-type and lacking exon 3. Fibroblasts from two Leigh syndrome probands had reduced wild-type USMG5 mRNA expression and undetectable protein. The mutation did not alter monomeric CV expression, but reduced both CV dimer expression and ATP synthesis rate. Rescue with wild-type USMG5 cDNA in proband fibroblasts restored USMG5 protein, increased CV dimerization and enhanced ATP production rate. These data demonstrate that a recurrent USMG5 splice-site founder mutation in the Ashkenazi Jewish population causes autosomal recessive Leigh syndrome by reduction of CV dimerization and ATP synthesis.


Assuntos
Doença de Leigh/genética , Mitocôndrias/genética , Doenças Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Trifosfato de Adenosina/biossíntese , Criança , Pré-Escolar , Dimerização , Éxons/genética , Efeito Fundador , Frequência do Gene , Haplótipos , Humanos , Lactente , Recém-Nascido , Judeus/genética , Doença de Leigh/metabolismo , Doença de Leigh/patologia , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Mutação , Fosforilação Oxidativa , Sítios de Splice de RNA/genética , Sequenciamento do Exoma
14.
Am J Med Genet A ; 182(2): 365-373, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31825167

RESUMO

Pearson syndrome (PS) is a multisystem mitochondrial respiratory chain disorder typically characterized by sideroblastic anemia and exocrine pancreatic insufficiency. PS is caused by a single large-scale mitochondrial DNA (mtDNA) deletion. PS classically presents in the first year of life and may be fatal in infancy. Children who survive PS may progress to develop Kearns-Sayre syndrome later in life. The full phenotypic spectrum and prognosis of the condition continue to evolve. Here we report five new patients with PS with unique clinical presentations, including four patients with onset later than previously reported in the literature, and one patient with prenatal onset of symptoms. The timing and unique features of these presentations support an expanded phenotypic spectrum of single large-scale mtDNA deletion syndromes (SLSMDS) and reinforce the importance of including SLSMDS in the differential for children with complex multisystem presentations.


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , DNA Mitocondrial/genética , Síndrome de Kearns-Sayre/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Doenças Musculares/genética , Anemia Sideroblástica/genética , Anemia Sideroblástica/fisiopatologia , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea/fisiopatologia , Insuficiência Pancreática Exócrina/genética , Insuficiência Pancreática Exócrina/fisiopatologia , Feminino , Deleção de Genes , Humanos , Lactente , Síndrome de Kearns-Sayre/fisiopatologia , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Masculino , Mitocôndrias/genética , Doenças Mitocondriais/patologia , Doenças Mitocondriais/fisiopatologia , Doenças Musculares/fisiopatologia , Fenótipo , Deleção de Sequência/genética
15.
Curr Opin Pediatr ; 32(6): 707-718, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33105273

RESUMO

PURPOSE OF REVIEW: Primary mitochondrial disease is a highly heterogeneous but collectively common inherited metabolic disorder, affecting at least one in 4300 individuals. Therapeutic management of mitochondrial disease typically involves empiric prescription of enzymatic cofactors, antioxidants, and amino acid and other nutrient supplements, based on biochemical reasoning, historical experience, and consensus expert opinion. As the field continues to rapidly advance, we review here the preclinical and clinical evidence, and specific dosing guidelines, for common mitochondrial medicine therapies to guide practitioners in their prescribing practices. RECENT FINDINGS: Since publication of Mitochondrial Medicine Society guidelines for mitochondrial medicine therapies management in 2009, data has emerged to support consideration for using additional therapeutic agents and discontinuation of several previously used agents. Preclinical animal modeling data have indicated a lack of efficacy for vitamin C as an antioxidant for primary mitochondrial disease, but provided strong evidence for vitamin E and N-acetylcysteine. Clinical data have suggested L-carnitine may accelerate atherosclerotic disease. Long-term follow up on L-arginine use as prophylaxis against or acute treatment for metabolic strokes has provided more data supporting its clinical use in individuals with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome and Leigh syndrome. Further, several precision therapies have been developed for specific molecular causes and/or shared clinical phenotypes of primary mitochondrial disease. SUMMARY: We provide a comprehensive update on mitochondrial medicine therapies based on current evidence and our single-center clinical experience to support or refute their use, and provide detailed dosing guidelines, for the clinical management of mitochondrial disease. The overarching goal of empiric mitochondrial medicines is to utilize therapies with favorable benefit-to-risk profiles that may stabilize and enhance residual metabolic function to improve cellular resiliency and slow clinical disease progression and/or prevent acute decompensation.


Assuntos
Doenças Mitocondriais , Humanos , Doenças Mitocondriais/tratamento farmacológico , Guias de Prática Clínica como Assunto
16.
Hum Mutat ; 40(5): 499-515, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30763462

RESUMO

Mitochondrial complex V (CV) generates cellular energy as adenosine triphosphate (ATP). Mitochondrial disease caused by the m.8993T>G pathogenic variant in the CV subunit gene MT-ATP6 was among the first described human mitochondrial DNA diseases. Due to a lack of clinically available functional assays, validating the definitive pathogenicity of additional MT-ATP6 variants remains challenging. We reviewed all reportedMT-ATP6 disease cases ( n = 218) to date, to assess for MT-ATP6 variants, heteroplasmy levels, and inheritance correlation with clinical presentation and biochemical findings. We further describe the clinical and biochemical features of a new cohort of 14 kindreds with MT-ATP6 variants of uncertain significance. Despite extensive overlap in the heteroplasmy levels of MT-ATP6 variant carriers with and without a wide range of clinical symptoms, previously reported symptomatic subjects had significantly higher heteroplasmy load (p = 2.2 x 10-16 ). Pathogenic MT-ATP6 variants resulted in diverse biochemical features. The most common findings were reduced ATP synthesis rate, preserved ATP hydrolysis capacity, and abnormally increased mitochondrial membrane potential. However, no single biochemical feature was universally observed. Extensive heterogeneity exists among both clinical and biochemical features of distinct MT-ATP6 variants. Improved mechanistic understanding and development of consistent biochemical diagnostic analyses are needed to permit accurate pathogenicity assessment of variants of uncertain significance in MT-ATP6.


Assuntos
Predisposição Genética para Doença , Variação Genética , Doenças Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Alelos , Animais , Biomarcadores , Estudos de Coortes , Testes Diagnósticos de Rotina , Estudos de Associação Genética , Testes Genéticos , Genótipo , Humanos , Padrões de Herança , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Mutação , Fenótipo
18.
J Inherit Metab Dis ; 42(1): 140-146, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30740726

RESUMO

BACKGROUND: Glutamate formiminotransferase deficiency (FTCD deficiency) or formiminoglutamic aciduria is the second most common of the known inherited disorders of folate metabolism. Initial case reports suggested that patients may have severe intellectual disability and megaloblastic anemia. However, these cases were obtained from screening cohorts of patients with developmental delay. Subsequently, patients with milder clinical phenotypes have been reported. The full phenotypic spectrum of this disorder remains unknown. METHODS: In many states, FTCD deficiency can be incidentally detected on tandem mass spectrometry-based newborn screening of dried blood spots. In this work, we report the outcomes of infants identified to have FTCD deficiency through newborn screening. RESULTS: During the study period, 18 patients were identified to have FTCD deficiency and were referred and evaluated at one of the two participating metabolic centers. The overall rate of FTCD deficiency detected through the New Jersey screening program over the study time period was 1:58,982. At a mean age of 56 months at last follow-up: 3/18 (16%) had developmental delays requiring individualized education plans, no patients had profound intellectual disability; 4/16 (25%) had mild self-limited anemia, no patients had profound anemia. CONCLUSIONS: These data suggest that the majority of individuals with FTCD deficiency detected by newborn screening are asymptomatic.

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