RESUMO
BACKGROUND AND PURPOSE: Pyruvate dehydrogenase complex deficiency is in up to 90% caused by pathogenic variants in the X-linked PDHA1 gene. We aimed to investigate female relatives of index patients with PDHA1-related disease to (i) describe the prevalence of female PDHA1 carriers, (ii) determine whether they had symptoms and signs, and (iii) delineate the associated phenotype. METHODS: In a national population-based study, we identified 37 patients with pathogenic variants in PDHA1. Sanger sequencing for the presence of the pathogenic variant was performed in their mothers and female relatives. The identified female carriers were clinically assessed, and their medical records were reviewed. RESULTS: The proportion carrying a de novo variant was 86%. We identified seven female PDHA1 carriers from five families. Five of them exhibited clinical features of the disease and were previously undiagnosed; all had signs of peripheral axonal neuropathy, four presented with strokelike episodes including two with Leigh-like lesions, and three had facial stigmata. CONCLUSIONS: PDHA1-related disease is underrecognized in heterozygous female carriers. Peripheral axonal neuropathy, strokelike and Leigh-like changes, and facial dysmorphism should raise suspicion of the disorder. Genetic analysis and clinical examination of potential female carriers are important for genetic counseling and have implications for treatment.
Assuntos
Heterozigoto , Piruvato Desidrogenase (Lipoamida) , Doença da Deficiência do Complexo de Piruvato Desidrogenase , Humanos , Feminino , Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Adulto , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Fenótipo , Criança , LinhagemRESUMO
BACKGROUND: Large-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset. METHODS: A retrospective multicentre study was performed in patients with clinical onset <16 years of age, diagnosed and followed in seven European mitochondrial disease centres. RESULTS: A total of 80 patients were included. The average age at disease onset and at last examination was 10 and 31 years, respectively. The median time from disease onset to death was 11.5 years. Pearson syndrome was present in 21%, Kearns-Sayre syndrome spectrum disorder in 50% and progressive external ophthalmoplegia in 29% of patients. Haematological abnormalities were the hallmark of the disease in preschool children, while the most common presentations in older patients were ptosis and external ophthalmoplegia. Skeletal muscle involvement was found in 65% and exercise intolerance in 25% of the patients. Central nervous system involvement was frequent, with variable presence of ataxia (40%), cognitive involvement (36%) and stroke-like episodes (9%). Other common features were pigmentary retinopathy (46%), short stature (42%), hearing impairment (39%), cardiac disease (39%), diabetes mellitus (25%) and renal disease (19%). CONCLUSION: Our study provides new insights into the phenotypic spectrum of childhood-onset, LMD-associated syndromes. We found a wider spectrum of more prevalent multisystem involvement compared with previous studies, most likely related to a longer time of follow-up.
Assuntos
Síndrome de Kearns-Sayre , Doenças Musculares , Oftalmoplegia Externa Progressiva Crônica , Pré-Escolar , Humanos , Criança , Idoso , DNA Mitocondrial/genética , Síndrome de Kearns-Sayre/epidemiologia , Síndrome de Kearns-Sayre/genética , Oftalmoplegia Externa Progressiva Crônica/epidemiologia , Oftalmoplegia Externa Progressiva Crônica/genética , Doenças Musculares/genética , Progressão da DoençaRESUMO
The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiologia , Chaperonas Moleculares/genética , Chaperonas Moleculares/fisiologia , Doenças Musculares/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Alelos , Animais , Caenorhabditis elegans , Feminino , Variação Genética , Humanos , Mutação com Perda de Função , Masculino , Músculo Esquelético/patologia , Miofibrilas , Miosinas , Sarcômeros/metabolismo , Análise de Sequência de RNA , Transgenes , Sequenciamento do Exoma , Adulto JovemRESUMO
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/genéticaRESUMO
The vast clinical and radiological spectrum of pyruvate dehydrogenase complex (PDHc) deficiency continues to pose challenges both in diagnostics and disease monitoring. Prompt diagnosis is important to enable early initiation of ketogenic diet. The patients were recruited from an ongoing population-based study in Sweden. All patients with a genetically confirmed diagnosis who had been investigated with an MRI of the brain were included. Repeated investigations were assessed to study the evolution of the MRI changes. Sixty-two MRI investigations had been performed in 34 patients (23 females). The genetic cause was mutations in PDHA1 in 29, PDHX and DLAT in 2 each, and PDHB in 1. The lesions were prenatal developmental in 16, prenatal clastic in 18, and postnatal clastic in 15 individuals. Leigh-like lesions with predominant involvement of globus pallidus were present in 12, while leukoencephalopathy was present in 6 and stroke-like lesions in 3 individuals. A combination of prenatal developmental and clastic lesions was present in 15 individuals. In addition, one male with PDHA1 also had postnatal clastic lesions. The most common lesions found in our study were agenesis or hypoplasia of corpus callosum, ventriculomegaly, or Leigh-like lesions. Furthermore, we describe a broad spectrum of other MRI changes that include leukoencephalopathy and stroke-like lesions. We argue that a novel important clue, suggesting the possibility of PDHc deficiency on MRI scans, is the simultaneous presence of multiple lesions on MRI that have occurred during different phases of brain development.
Assuntos
Leucoencefalopatias , Doença da Deficiência do Complexo de Piruvato Desidrogenase , Acidente Vascular Cerebral , Encéfalo/patologia , Feminino , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética , Masculino , Gravidez , Piruvato Desidrogenase (Lipoamida)/genética , Complexo Piruvato Desidrogenase/genética , Complexo Piruvato Desidrogenase/metabolismo , Acidente Vascular Cerebral/patologiaRESUMO
Mitochondrial trifunctional protein (MTP) is involved in long-chain fatty acid ß-oxidation (lcFAO). Deficiency of one or more of the enzyme activities as catalyzed by MTP causes generalized MTP deficiency (MTPD), long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), or long-chain ketoacyl-CoA thiolase deficiency (LCKATD). When genetic variants result in thermo-sensitive enzymes, increased body temperature (e.g. fever) can reduce enzyme activity and be a risk factor for clinical decompensation. This is the first description of five patients with a thermo-sensitive MTP deficiency. Clinical and genetic information was obtained from clinical files. Measurement of LCHAD and LCKAT activities, lcFAO-flux studies and palmitate loading tests were performed in skin fibroblasts cultured at 37°C and 40°C. In all patients (four MTPD, one LCKATD), disease manifested during childhood (manifestation age: 2-10 years) with myopathic symptoms triggered by fever or exercise. In four patients, signs of retinopathy or neuropathy were present. Plasma long-chain acylcarnitines were normal or slightly increased. HADHB variants were identified (at age: 6-18 years) by whole exome sequencing or gene panel analyses. At 37°C, LCHAD and LCKAT activities were mildly impaired and lcFAO-fluxes were normal. Remarkably, enzyme activities and lcFAO-fluxes were markedly diminished at 40°C. Preventive (dietary) measures improved symptoms for most. In conclusion, all patients with thermo-sensitive MTP deficiency had a long diagnostic trajectory and both genetic and enzymatic testing were required for diagnosis. The frequent absence of characteristic acylcarnitine abnormalities poses a risk for a diagnostic delay. Given the positive treatment effects, upfront genetic screening may be beneficial to enhance early recognition.
Assuntos
Erros Inatos do Metabolismo Lipídico , Miopatias Mitocondriais , Doenças Musculares , 3-Hidroxiacil-CoA Desidrogenases , Adolescente , Cardiomiopatias , Criança , Pré-Escolar , Coenzima A , Diagnóstico Tardio , Ácidos Graxos/metabolismo , Humanos , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Proteína Mitocondrial Trifuncional/deficiência , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Doenças do Sistema Nervoso , RabdomióliseRESUMO
BACKGROUND: CLN3 disease is a neurodegenerative condition presenting in the first decade of life typically leading to death in the third decade. The earliest symptom is rapidly progressive visual impairment followed by intellectual and motor impairments, epilepsy and behavioural disturbances. There are limited data on how the condition affects the family system or the role of family resilience in paediatric neurodegenerative diseases. METHODS: Semi-structured interviews were conducted with eight parents (five mothers and three fathers) of five children with CLN3. Interview questions focused on the experience of having a child with CLN3, its impact on the family system as well as the concept of family resilience. Data were analysed via thematic analysis. RESULTS: The thematic analysis resulted in four main themes. The theme 'recurring losses' included the feeling of losing a healthy child, the child's loss of abilities and loss of relationships. The theme 'disruption to the family system' included that siblings could be 'side-lined', the potential negative impact on romantic relationships and difficulties finding time to oneself. The theme 'Society is not developed for a progressive disease' highlighted the difficulties parents faced with respect to contacts with the health and/or social insurance system. The paediatric health care system was seen as supportive, but the adult health care system was not seen as fit for the purpose. Regarding family resilience, parents felt that the disease forced them to reconsider what was important in life. Several parents described that they learned to value small moments of joy and create deep connections through involvement in family routines and rituals. CONCLUSIONS: CLN3 places a very significant burden on the family system including parental feelings of loss, impact on family relationships and lack of understanding within the health/social insurance systems. The concept of family resilience may be useful in understanding the experiences of families affected by paediatric neurodegenerative conditions.
Assuntos
Lipofuscinoses Ceroides Neuronais , Resiliência Psicológica , Adulto , Criança , Saúde da Família , Feminino , Humanos , Glicoproteínas de Membrana , Chaperonas Moleculares , Mães , Pais , Pesquisa QualitativaRESUMO
The aim of this study was to compare the value of serum biomarkers, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), with histological analysis of muscle in the diagnosis of mitochondrial disease. We collected 194 serum samples from patients with a suspected or known mitochondrial disease. Biomarkers were analyzed blinded using enzyme-labeled immunosorbent assay. Clinical data were collected using a structured questionnaire. Only 39% of patients with genetically verified mitochondrial disease had mitochondrial pathology in their muscle histology. In contrast, biomarkers were elevated in 62% of patients with genetically verified mitochondrial disease. Those with both biomarkers elevated had a muscle manifesting disorder and a defect affecting mitochondrial DNA expression. If at least one of the biomarkers was induced and the patient had a myopathic disease, a mitochondrial DNA expression disease was the cause with 94% probability. Among patients with biomarker analysis and muscle biopsy taken <12 months apart, a mitochondrial disorder would have been identified in 70% with analysis of FGF21 and GDF15 compared to 50% of patients whom could have been identified with muscle biopsy alone. Muscle findings were nondiagnostic in 72% (children) and 45% (adults). Induction of FGF21 and GDF15 suggest a mitochondrial etiology as an underlying cause of a muscle manifesting disease. Normal biomarker values do not, however, rule out a mitochondrial disorder, especially if the disease does not manifest in muscle. We suggest that FGF21 and GDF15 together should be first-line diagnostic investigations in mitochondrial disease complementing muscle biopsy.
Assuntos
DNA Mitocondrial/genética , Fatores de Crescimento de Fibroblastos/genética , Fator 15 de Diferenciação de Crescimento/genética , Doenças Mitocondriais/genética , Adolescente , Adulto , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/sangue , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Adulto JovemRESUMO
IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
Assuntos
Mutação com Ganho de Função , Estudos de Associação Genética , Genótipo , Helicase IFIH1 Induzida por Interferon/genética , Fenótipo , Alelos , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Helicase IFIH1 Induzida por Interferon/química , Masculino , Modelos Moleculares , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Variants in POLG are one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition. METHODS: A multinational, retrospective study using data from 155 patients with POLG variants recruited from seven European countries. RESULTS: We describe the spectrum of clinical features associated with POLG variants in the largest known cohort of patients. While clinical features clearly form a continuum, stratifying patients simply according to age of onset-onset prior to age 12 years; onset between 12 and 40 years and onset after the age of 40 years, permitted us to identify clear phenotypic and prognostic differences. Prior to 12 years of age, liver involvement (87%), seizures (84%), and feeding difficulties (84%) were the major features. For those with onset between 12 and 40 years, ataxia (90%), peripheral neuropathy (84%), and seizures (71%) predominated, while for those with onset over 40 years, ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) were the major clinical features. The earlier the onset the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis. CONCLUSION: Based on our data, we propose a simplified POLG disease classification, which can be used to guide diagnostic investigations and predict disease course.
Assuntos
DNA Polimerase gama/genética , Predisposição Genética para Doença/genética , Doenças Mitocondriais/classificação , Doenças Mitocondriais/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/mortalidade , Mutação , Estudos Retrospectivos , Análise de Sobrevida , Adulto JovemRESUMO
Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC, which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant lacking the PROSC homolog (ΔYggS) is pyridoxine sensitive; complementation with human PROSC restored growth whereas hPROSC encoding p.Leu175Pro, p.Arg241Gln, and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells, which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Although the mechanism involved is not fully understood, our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions.
Assuntos
Epilepsia/genética , Epilepsia/metabolismo , Homeostase/genética , Mutação , Proteínas/genética , Fosfato de Piridoxal/metabolismo , Vitamina B 6/metabolismo , Adolescente , Carnosina/análogos & derivados , Carnosina/metabolismo , Células Cultivadas , Criança , Pré-Escolar , Exoma/genética , Feminino , Fibroblastos , Homozigoto , Humanos , Lactente , Masculino , Linhagem , Prolina/metabolismo , Vitamina B 6/sangueRESUMO
Exome sequencing has recently identified mutations in the gene TANGO2 (transport and Golgi organization 2) as a cause of developmental delay associated with recurrent crises involving rhabdomyolysis, cardiac arrhythmias, and metabolic derangements. The disease is not well understood, in part as the cellular function and subcellular localization of the TANGO2 protein remain unknown. Furthermore, the clinical syndrome with its heterogeneity of symptoms, signs, and laboratory findings is still being defined. Here, we describe 11 new cases of TANGO2-related disease, confirming and further expanding the previously described clinical phenotype. Patients were homozygous or compound heterozygous for previously described exonic deletions or new frameshift, splice site, and missense mutations. All patients showed developmental delay with ataxia, dysarthria, intellectual disability, or signs of spastic diplegia. Of importance, we identify two subjects (aged 12 and 17 years) who have never experienced any overt episode of the catabolism-induced metabolic crises typical for the disease. Mitochondrial complex II activity was mildly reduced in patients investigated in association with crises but normal in other patients. In one deceased patient, post-mortem autopsy revealed heterotopic neurons in the cerebral white matter, indicating a possible role for TANGO2 in neuronal migration. Furthermore, we have addressed the subcellular localization of several alternative isoforms of TANGO2, none of which were mitochondrial but instead appeared to have a primarily cytoplasmic localization. Previously described aberrations in Golgi morphology were not observed in cultured skin fibroblasts.
Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/deficiência , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Deficiências do Desenvolvimento/genética , Metabolismo Energético/genética , Deficiência Intelectual/genética , Mitocôndrias/genética , Adolescente , Translocador Nuclear Receptor Aril Hidrocarboneto/fisiologia , Ataxia/genética , Paralisia Cerebral/genética , Criança , Pré-Escolar , Disartria/genética , Exoma , Éxons , Feminino , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Sequenciamento do ExomaRESUMO
BACKGROUND: Leigh syndrome is a phenotypically and genetically heterogeneous mitochondrial disorder. While some genetic defects are associated with well-described phenotypes, phenotype-genotype correlations in Leigh syndrome are not fully explored. OBJECTIVE: We aimed to identify phenotype-genotype correlations in Leigh syndrome in a large cohort of systematically evaluated patients. METHODS: We studied 96 patients with genetically confirmed Leigh syndrome diagnosed and followed in eight European centres specialising in mitochondrial diseases. RESULTS: We found that ataxia, ophthalmoplegia and cardiomyopathy were more prevalent among patients with mitochondrial DNA defects. Patients with mutations in MT-ND and NDUF genes with complex I deficiency shared common phenotypic features, such as early development of central nervous system disease, followed by high occurrence of cardiac and ocular manifestations. The cerebral cortex was affected in patients with NDUF mutations significantly more often than the rest of the cohort. Patients with the m.8993T>G mutation in MT-ATP6 gene had more severe clinical and radiological manifestations and poorer disease outcome compared with patients with the m.8993T>C mutation. CONCLUSION: Our study provides new insights into phenotype-genotype correlations in Leigh syndrome and particularly in patients with complex I deficiency and with defects in the mitochondrial ATP synthase.
Assuntos
Estudos de Associação Genética , Doença de Leigh/genética , Núcleo Celular/metabolismo , DNA/genética , DNA Mitocondrial/genética , Feminino , Seguimentos , Humanos , Lactente , Masculino , Mutação/genética , FenótipoRESUMO
Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions, and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate, and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein, we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. Ann Neurol 2017;82:317-330.
Assuntos
Deficiência de Tiamina/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Proteínas de Membrana Transportadoras/genética , Proteínas de Transporte da Membrana Mitocondrial , Mutação , Prognóstico , Taxa de Sobrevida , Deficiência de Tiamina/mortalidade , Adulto JovemRESUMO
OBJECTIVE: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. METHODS: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. RESULTS: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. INTERPRETATION: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.
Assuntos
Hidrolases de Éster Carboxílico/genética , Surdocegueira/diagnóstico por imagem , Surdocegueira/genética , Progressão da Doença , Distonia/diagnóstico por imagem , Distonia/genética , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Mutação/genética , Atrofia Óptica/diagnóstico por imagem , Atrofia Óptica/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Surdocegueira/terapia , Distonia/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/terapia , Masculino , Atrofia Óptica/terapia , Adulto JovemRESUMO
OBJECTIVE: Epilepsy is common in individuals with mutations in POLG, the gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma. Early recognition and aggressive seizure management are crucial for patient survival. Disruption of the blood-brain barrier (BBB) is implicated in various neurological disorders including epilepsy. The aim of this study was to assess whether POLG-related disease is associated with BBB dysfunction and what clinical implications this has for patients. METHODS: Our retrospective study used data from 83 patients with pathogenic POLG mutations from 4 countries--Norway, Sweden, Finland, and the United Kingdom. Data were collected using a structured questionnaire. We used the presence of raised cerebrospinal fluid (CSF) protein and a raised CSF/serum ratio of albumin (Q-alb) to evaluate the integrity of the blood-CSF barrier. RESULTS: Raised CSF protein was found in 70% of patients (n = 58/83) and appeared to be associated with the most severe phenotypes. In those in whom it was measured, the Q-alb ratio was markedly elevated (n = 18). The majority of those with epilepsy (n = 50/66, 76%) had raised CSF protein, and this preceded seizure debut in 75% (n = 15/20). The median survival time from symptom onset for those with raised CSF protein was decreased (13 months) compared to those with normal CSF protein (32 months). SIGNIFICANCE: Our results indicate that there is disruption of the BBB in POLG-related disease, as evidenced by a raised CSF protein and Q-alb ratio. We also find that raised CSF protein is a common finding in patients with POLG disease. Our data suggest that the presence of BBB dysfunction predicts a poorer outcome, and elevated CSF protein may therefore be an additional biomarker both for early diagnosis and to identify those at high risk of developing epilepsy.
Assuntos
Barreira Hematoencefálica/fisiopatologia , Proteínas do Líquido Cefalorraquidiano/metabolismo , DNA Polimerase gama/genética , Epilepsia , Mutação/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Epilepsia/líquido cefalorraquidiano , Epilepsia/diagnóstico , Epilepsia/genética , Feminino , Humanos , Lactente , Recém-Nascido , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BackgroundDiagnosing mitochondrial disease (MD) is a challenge. In addition to genetic analyses, clinical practice is to perform invasive procedures such as muscle biopsy for biochemical and histochemical analyses. Blood cell respirometry is rapid and noninvasive. Our aim was to explore its possible role in diagnosing MD.MethodsBlood samples were collected from 113 pediatric patients, for whom MD was a differential diagnosis. A respiratory analysis model based on ratios (independent of mitochondrial specific content) was derived from a group of healthy controls and tested on the patients. The diagnostic accuracy of platelet respirometry was evaluated against routine diagnostic investigation.ResultsMD prevalence in the cohort was 16%. A ratio based on the respiratory response to adenosine diphosphate in the presence of complex I substrates had 96% specificity for disease and a positive likelihood ratio of 5.3. None of the individual ratios had sensitivity above 50%, but a combined model had 72% sensitivity.ConclusionNormal findings of platelet respirometry are not able to rule out MD, but pathological results make the diagnosis more likely and could strengthen the clinical decision to perform further invasive analyses. Our results encourage further study into the role of blood respirometry as an adjunct diagnostic tool for MD.
Assuntos
Plaquetas/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/sangue , Doenças Mitocondriais/diagnóstico , Consumo de Oxigênio , Biópsia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Ácido Láctico/sangue , Masculino , Oxigênio/química , Prevalência , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: Our aime was to study the short- and long-term effects of ketogenic diet on the disease course and disease-related outcomes in patients with pyruvate dehydrogenase complex deficiency, the metabolic factors implicated in treatment outcomes, and potential safety and compliance issues. METHODS: Pediatric patients diagnosed with pyruvate dehydrogenase complex deficiency in Sweden and treated with ketogenic diet were evaluated. Study assessments at specific time points included developmental and neurocognitive testing, patient log books, and investigator and parental questionnaires. A systematic literature review was also performed. RESULTS: Nineteen patients were assessed, the majority having prenatal disease onset. Patients were treated with ketogenic diet for a median of 2.9 years. All patients alive at the time of data registration at a median age of 6 years. The treatment had a positive effect mainly in the areas of epilepsy, ataxia, sleep disturbance, speech/language development, social functioning, and frequency of hospitalizations. It was also safe-except in one patient who discontinued because of acute pancreatitis. The median plasma concentration of ketone bodies (3-hydroxybutyric acid) was 3.3 mmol/l. Poor dietary compliance was associated with relapsing ataxia and stagnation of motor and neurocognitive development. Results of neurocognitive testing are reported for 12 of 19 patients. CONCLUSION: Ketogenic diet was an effective and safe treatment for the majority of patients. Treatment effect was mainly determined by disease phenotype and attainment and maintenance of ketosis.
Assuntos
Doença da Deficiência do Complexo de Piruvato Desidrogenase/dietoterapia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Dieta Cetogênica/métodos , Epilepsia/sangue , Epilepsia/dietoterapia , Feminino , Humanos , Lactente , Recém-Nascido , Corpos Cetônicos/sangue , Cetose/sangue , Cetose/dietoterapia , Estudos Longitudinais , Masculino , Testes de Estado Mental e Demência , Atividade Motora/fisiologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/sangue , Suécia , Resultado do TratamentoRESUMO
Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid.