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1.
Neuromuscul Disord ; 29(9): 693-697, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488384

RESUMO

We report a novel mitochondrial m.4414T>C variant in the mt-tRNAMet (MT-TM) gene in an adult patient with chronic progressive external ophthalmoplegia and myopathy whose muscle biopsy revealed focal cytochrome c oxidase (COX)-deficient and ragged red fibres. The m.4414T>C variant occurs at a strongly evolutionary conserved sequence position, disturbing a canonical base pair and disrupting the secondary and tertiary structure of the mt-tRNAMet. Definitive evidence of pathogenicity is provided by clear segregation of m.4414T>C mutant levels with COX deficiency in single muscle fibres. Interestingly, the variant is present in skeletal muscle at relatively low levels (30%) and undetectable in accessible, non-muscle tissues from the patient and her asymptomatic brother, emphasizing the continuing requirement for a diagnostic muscle biopsy as the preferred tissue for mtDNA genetic investigations of mt-tRNA variants leading to mitochondrial myopathy.

2.
Lancet Diabetes Endocrinol ; 7(9): 695-706, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31377265

RESUMO

BACKGROUND: Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T3) concentrations (Allan-Herndon-Dudley syndrome). This chronic thyrotoxicosis leads to progressive deterioration in bodyweight, tachycardia, and muscle wasting, predisposing affected individuals to substantial morbidity and mortality. Treatment that safely alleviates peripheral thyrotoxicosis and reverses cerebral hypothyroidism is not yet available. We aimed to investigate the effects of treatment with the T3 analogue Triac (3,3',5-tri-iodothyroacetic acid, or tiratricol), in patients with MCT8 deficiency. METHODS: In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 µg Triac, the daily dose was increased progressively in 350 µg increments, with the goal of attaining serum total T3 concentrations within the target range of 1·4-2·5 nmol/L. We assessed changes in several clinical and biochemical signs of hyperthyroidism between baseline and 12 months of treatment. The prespecified primary endpoint was the change in serum T3 concentrations from baseline to month 12. The co-primary endpoints were changes in concentrations of serum thyroid-stimulating hormone (TSH), free and total thyroxine (T4), and total reverse T3 from baseline to month 12. These analyses were done in patients who received at least one dose of Triac and had at least one post-baseline evaluation of serum throid function. This trial is registered with ClinicalTrials.gov, number NCT02060474. FINDINGS: Between Oct 15, 2014, and June 1, 2017, we screened 50 patients, all of whom were eligible. Of these patients, four (8%) patients decided not to participate because of travel commitments. 46 (92%) patients were therefore enrolled in the trial to receive Triac (median age 7·1 years [range 0·8-66·8]). 45 (98%) participants received Triac and had at least one follow-up measurement of thyroid function and thus were included in the analyses of the primary endpoints. Of these 45 patients, five did not complete the trial (two patients withdrew [travel burden, severe pre-existing comorbidity], one was lost to follow-up, one developed of Graves disease, and one died of sepsis). Patients required a mean dose of 38.3 µg/kg of bodyweight (range 6·4-84·3) to attain T3 concentrations within the target range. Serum T3 concentration decreased from 4·97 nmol/L (SD 1·55) at baseline to 1·82 nmol/L (0·69) at month 12 (mean decrease 3·15 nmol/L, 95% CI 2·68-3·62; p<0·0001), while serum TSH concentrations decreased from 2·91 mU/L (SD 1·68) to 1·02 mU/L (1·14; mean decrease 1·89 mU/L, 1·39-2·39; p<0·0001) and serum free T4 concentrations decreased from 9·5 pmol/L (SD 2·5) to 3·4 (1·6; mean decrease 6·1 pmol/L (5·4-6·8; p<0·0001). Additionally, serum total T4 concentrations decreased by 31·6 nmol/L (28·0-35·2; p<0·0001) and reverse T3 by 0·08 nmol/L (0·05-0·10; p<0·0001). Seven treatment-related adverse events (transiently increased perspiration or irritability) occurred in six (13%) patients. 26 serious adverse events that were considered unrelated to treatment occurred in 18 (39%) patients (mostly hospital admissions because of infections). One patient died from pulmonary sepsis leading to multi-organ failure, which was unrelated to Triac treatment. INTERPRETATION: Key features of peripheral thyrotoxicosis were alleviated in paediatric and adult patients with MCT8 deficiency who were treated with Triac. Triac seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency. FUNDING: Dutch Scientific Organization, Sherman Foundation, NeMO Foundation, Wellcome Trust, UK National Institute for Health Research Cambridge Biomedical Centre, Toulouse University Hospital, and Una Vita Rara ONLUS.

3.
Ann Clin Transl Neurol ; 6(3): 515-524, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30911575

RESUMO

Objectives: Mitochondrial methionyl-tRNA formyltransferase (MTFMT) is required for the initiation of translation and elongation of mitochondrial protein synthesis. Pathogenic variants in MTFMT have been associated with Leigh syndrome (LS) and mitochondrial multiple respiratory chain deficiencies. We sought to elucidate the spectrum of clinical, neuroradiological and molecular genetic findings of patients with bi-allelic pathogenic variants in MTFMT. Methods: Retrospective cohort study combining new cases and previously published cases. Results: Thirty-eight patients with pathogenic variants in MTFMT were identified, including eight new cases. The median age of presentation was 14 months (range: birth to 17 years, interquartile range [IQR] 4.5 years), with developmental delay and motor symptoms being the most frequent initial manifestation. Twenty-nine percent of the patients survived into adulthood. MRI headings in MTFMT pathogenic variants included symmetrical basal ganglia changes (62%), periventricular and subcortical white matter abnormalities (55%), and brainstem lesions (48%). Isolated complex I and combined respiratory chain deficiencies were identified in 31% and 59% of the cases, respectively. Reduction of the mitochondrial complex I and complex IV subunits was identified in the fibroblasts (13/13). Sixteen pathogenic variants were identified, of which c.626C>T was the most common. Seventy-four percent of the patients were alive at their last clinical review (median 6.8 years, range: 14 months to 31 years, IQR 14.5 years). Interpretation: Patients that harbour pathogenic variants in MTFMT have a milder clinical phenotype and disease progression compared to LS caused by other nuclear defects. Fibroblasts may preclude the need for muscle biopsy, to prove causality of any novel variant.

4.
Front Genet ; 9: 400, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30369941

RESUMO

Mitochondrial disorders, characterized by clinical symptoms and/or OXPHOS deficiencies, are caused by pathogenic variants in mitochondrial genes. However, pathogenic variants in some of these genes can lead to clinical manifestations which overlap with other neuromuscular diseases, which can be caused by pathogenic variants in non-mitochondrial genes as well. Mitochondrial pathogenic variants can be found in the mitochondrial DNA (mtDNA) or in any of the 1,500 nuclear genes with a mitochondrial function. We have performed a two-step next-generation sequencing approach in a cohort of 117 patients, mostly children, in whom a mitochondrial disease-cause could likely or possibly explain the phenotype. A total of 86 patients had a mitochondrial disorder, according to established clinical and biochemical criteria. The other 31 patients had neuromuscular symptoms, where in a minority a mitochondrial genetic cause is present, but a non-mitochondrial genetic cause is more likely. All patients were screened for pathogenic variants in the mtDNA and, if excluded, analyzed by whole exome sequencing (WES). Variants were filtered for being pathogenic and compatible with an autosomal or X-linked recessive mode of inheritance in families with multiple affected siblings and/or consanguineous parents. Non-consanguineous families with a single patient were additionally screened for autosomal and X-linked dominant mutations in a predefined gene-set. We identified causative pathogenic variants in the mtDNA in 20% of the patient-cohort, and in nuclear genes in 49%, implying an overall yield of 68%. We identified pathogenic variants in mitochondrial and non-mitochondrial genes in both groups with, obviously, a higher number of mitochondrial genes affected in mitochondrial disease patients. Furthermore, we show that 31% of the disease-causing genes in the mitochondrial patient group were not included in the MitoCarta database, and therefore would have been missed with MitoCarta based gene-panels. We conclude that WES is preferable to panel-based approaches for both groups of patients, as the mitochondrial gene-list is not complete and mitochondrial symptoms can be secondary. Also, clinically and genetically heterogeneous disorders would require sequential use of multiple different gene panels. We conclude that WES is a comprehensive and unbiased approach to establish a genetic diagnosis in these patients, able to resolve multi-genic disease-causes.

5.
Orphanet J Rare Dis ; 13(1): 120, 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30025539

RESUMO

BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. CONCLUSIONS: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.

6.
Neuroimage Clin ; 18: 231-244, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29868447

RESUMO

One of the most common mitochondrial DNA (mtDNA) mutations, the A to G transition at base pair 3243, has been linked to changes in the brain, in addition to commonly observed hearing problems, diabetes and myopathy. However, a detailed quantitative description of m.3243A>G patients' brains has not been provided so far. In this study, ultra-high field MRI at 7T and volume- and surface-based data analyses approaches were used to highlight morphology (i.e. atrophy)-, microstructure (i.e. myelin and iron concentration)- and metabolism (i.e. cerebral blood flow)-related differences between patients (N = 22) and healthy controls (N = 15). The use of quantitative MRI at 7T allowed us to detect subtle changes of biophysical processes in the brain with high accuracy and sensitivity, in addition to typically assessed lesions and atrophy. Furthermore, the effect of m.3243A>G mutation load in blood and urine epithelial cells on these MRI measures was assessed within the patient population and revealed that blood levels were most indicative of the brain's state and disease severity, based on MRI as well as on neuropsychological data. Morphometry MRI data showed a wide-spread reduction of cortical, subcortical and cerebellar gray matter volume, in addition to significantly enlarged ventricles. Moreover, surface-based analyses revealed brain area-specific changes in cortical thickness (e.g. of the auditory cortex), and in T1, T2* and cerebral blood flow as a function of mutation load, which can be linked to typically m.3243A>G-related clinical symptoms (e.g. hearing impairment). In addition, several regions linked to attentional control (e.g. middle frontal gyrus), the sensorimotor network (e.g. banks of central sulcus) and the default mode network (e.g. precuneus) were characterized by alterations in cortical thickness, T1, T2* and/or cerebral blood flow, which has not been described in previous MRI studies. Finally, several hypotheses, based either on vascular, metabolic or astroglial implications of the m.3243A>G mutation, are discussed that potentially explain the underlying pathobiology. To conclude, this is the first 7T and also the largest MRI study on this patient population that provides macroscopic brain correlates of the m.3243A>G mutation indicating potential MRI biomarkers of mitochondrial diseases and might guide future (longitudinal) studies to extensively track neuropathological and clinical changes.

7.
Mol Ther Methods Clin Dev ; 8: 152-165, 2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29687034

RESUMO

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by thymidine phosphorylase (TP) deficiency resulting in systemic accumulation of thymidine (d-Thd) and deoxyuridine (d-Urd) and characterized by early-onset neurological and gastrointestinal symptoms. Long-term effective and safe treatment is not available. Allogeneic bone marrow transplantation may improve clinical manifestations but carries disease and transplant-related risks. In this study, lentiviral vector-based hematopoietic stem cell gene therapy (HSCGT) was performed in Tymp-/-Upp1-/- mice with the human phosphoglycerate kinase (PGK) promoter driving TYMP. Supranormal blood TP activity reduced intestinal nucleoside levels significantly at low vector copy number (median, 1.3; range, 0.2-3.6). Furthermore, we covered two major issues not addressed before. First, we demonstrate aberrant morphology of brain astrocytes in areas of spongy degeneration, which was reversed by HSCGT. Second, long-term follow-up and vector integration site analysis were performed to assess safety of the therapeutic LV vectors in depth. This report confirms and supplements previous work on the efficacy of HSCGT in reducing the toxic metabolites in Tymp-/-Upp1-/- mice, using a clinically applicable gene transfer vector and a highly efficient gene transfer method, and importantly demonstrates phenotypic correction with a favorable risk profile, warranting further development toward clinical implementation.

8.
Eur J Hum Genet ; 26(4): 537-551, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29440775

RESUMO

This study aims to identify gene defects in pediatric cardiomyopathy and early-onset brain disease with oxidative phosphorylation (OXPHOS) deficiencies. We applied whole-exome sequencing in three patients with pediatric cardiomyopathy and early-onset brain disease with OXPHOS deficiencies. The brain pathology was studied by MRI analysis. In consanguineous patient 1, we identified a homozygous intronic variant (c.850-3A > G) in the QRSL1 gene, which was predicted to cause abnormal splicing. The variant segregated with the disease and affected the protein function, which was confirmed by complementation studies, restoring OXPHOS function only with wild-type QRSL1. Patient 2 was compound heterozygous for two novel affected and disease-causing variants (c.[253G > A];[938G > A]) in the MTO1 gene. In patient 3, we detected one unknown affected and disease-causing variants (c.2872C > T) and one known disease-causing variant (c.1774C > T) in the AARS2 gene. The c.1774C > T variant was present in the paternal copy of the AARS2 gene, the c.2872C > T in the maternal copy. All genes were involved in translation of mtDNA-encoded proteins. Defects in mtDNA-encoded protein translation lead to severe pediatric cardiomyopathy and brain disease with OXPHOS abnormalities. This suggests that the heart and brain are particularly sensitive to defects in mitochondrial protein synthesis during late embryonic or early postnatal development, probably due to the massive mitochondrial biogenesis occurring at that stage. If both the heart and brain are involved, the prognosis is poor with a likely fatal outcome at young age.

9.
JIMD Rep ; 38: 101-105, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28685493

RESUMO

A combination of unexplained peripheral neuropathy, hypoparathyroidism, and the inability to cope with metabolic stress could point to a rare inborn error of metabolism, such as mitochondrial trifunctional protein (MTP) deficiency.Here, we describe a 20-year-old woman who was known since childhood with axonal motor sensory polyneuropathy of unknown origin. She presented with progressive dyspnoea, and increased muscle weakness, preceded by 6 days of fever, vomiting, and diarrhoea. Laboratory testing showed rhabdomyolysis, and hypocalcaemia with low parathyroid levels. The patient was intubated because of respiratory insufficiency and a viral and bacterial pneumonia was diagnosed. She was discharged after 16 days of admission. Metabolic screening, performed at the time of rhabdomyolysis, showed increased concentrations of long-chain 3-hydroxyacyl carnitine species, together with elevated urinary excretion of 3-hydroxy dicarboxylic acids. Decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketoacyl-CoA thiolase in peripheral lymphocytes and fibroblasts confirmed a MTP deficiency. Sequence analysis of the HADHB gene showed two heterozygous variants: c.209+1G>C (splicing defect) and c.980T>C (p.Leu327Leu). When the acylcarnitine profile was repeated after the episode of rhabdomyolysis had resolved it showed no abnormalities.Our case illustrates a cluster of peripheral neuropathy, episodic rhabdomyolysis, and hypoparathyroidism in a patient with MTP deficiency caused by mutations in the HADHB gene. It stresses the importance of performing metabolic screening when patients are most symptomatic, as normal results can be found at times when no metabolic stress is present. Screening is relatively easy and timely diagnosis has important implications for treatment.

10.
J Med Genet ; 55(1): 21-27, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29101127

RESUMO

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 , Fenótipo
11.
Front Mol Neurosci ; 10: 336, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29093663

RESUMO

Mitochondrial disorders are genetically and clinically heterogeneous, mainly affecting high energy-demanding organs due to impaired oxidative phosphorylation (OXPHOS). Currently, effective treatments for OXPHOS defects, with complex I deficiency being the most prevalent, are not available. Yet, clinical practice has shown that some complex I deficient patients benefit from a high-fat or ketogenic diet, but it is unclear how these therapeutic diets influence mitochondrial function and more importantly, which complex I patients could benefit from such treatment. Dietary studies in a complex I deficient patient with exercise intolerance showed increased muscle endurance on a high-fat diet compared to a high-carbohydrate diet. We performed whole-exome sequencing to characterize the genetic defect. A pathogenic homozygous p.G212V missense mutation was identified in the TMEM126B gene, encoding an early assembly factor of complex I. A complementation study in fibroblasts confirmed that the p.G212V mutation caused the complex I deficiency. The mechanism turned out to be an incomplete assembly of the peripheral arm of complex I, leading to a decrease in the amount of mature complex I. The patient clinically improved on a high-fat diet, which was supported by the 25% increase in maximal OXPHOS capacity in TMEM126B defective fibroblast by the saturated fatty acid palmitic acid, whereas oleic acid did not have any effect in those fibroblasts. Fibroblasts of other patients with a characterized complex I gene defect were tested in the same way. Patient fibroblasts with complex I defects in NDUFS7 and NDUFAF5 responded to palmitic acid, whereas ACAD9, NDUFA12, and NDUFV2 defects were non-responding. Although the data are too limited to draw a definite conclusion on the mechanism, there is a tendency that protein defects involved in early assembly complexes, improve with palmitic acid, whereas proteins defects involved in late assembly, do not. Our data show at a clinical and biochemical level that a high fat diet can be beneficial for complex I patients and that our cell line assay will be an easy tool for the selection of patients, who might potentially benefit from this therapeutic diet.

13.
PLoS Genet ; 13(5): e1006809, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28542170

RESUMO

Integrator is an RNA polymerase II (RNAPII)-associated complex that was recently identified to have a broad role in both RNA processing and transcription regulation. Importantly, its role in human development and disease is so far largely unexplored. Here, we provide evidence that biallelic Integrator Complex Subunit 1 (INTS1) and Subunit 8 (INTS8) gene mutations are associated with rare recessive human neurodevelopmental syndromes. Three unrelated individuals of Dutch ancestry showed the same homozygous truncating INTS1 mutation. Three siblings harboured compound heterozygous INTS8 mutations. Shared features by these six individuals are severe neurodevelopmental delay and a distinctive appearance. The INTS8 family in addition presented with neuronal migration defects (periventricular nodular heterotopia). We show that the first INTS8 mutation, a nine base-pair deletion, leads to a protein that disrupts INT complex stability, while the second missense mutation introduces an alternative splice site leading to an unstable messenger. Cells from patients with INTS8 mutations show increased levels of unprocessed UsnRNA, compatible with the INT function in the 3'-end maturation of UsnRNA, and display significant disruptions in gene expression and RNA processing. Finally, the introduction of the INTS8 deletion mutation in P19 cells using genome editing alters gene expression throughout the course of retinoic acid-induced neural differentiation. Altogether, our results confirm the essential role of Integrator to transcriptome integrity and point to the requirement of the Integrator complex in human brain development.


Assuntos
Deficiências do Desenvolvimento/genética , Deleção de Genes , Mutação de Sentido Incorreto , Subunidades Proteicas/genética , RNA Mensageiro/metabolismo , Adulto , Processamento Alternativo , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Criança , Deficiências do Desenvolvimento/diagnóstico , Feminino , Fibroblastos/metabolismo , Células HEK293 , Células HeLa , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , Subunidades Proteicas/metabolismo , RNA Mensageiro/genética , Síndrome , Transcriptoma , Proteína Wnt1
14.
Front Cell Neurosci ; 11: 31, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28261062

RESUMO

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive metabolic disorder caused by thymidine phosphorylase (TP) enzyme deficiency. The lack of TP results in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd). In these patients, clinical features include mental regression, ophthalmoplegia, and fatal gastrointestinal complications. The accumulation of nucleosides also causes imbalances in mitochondrial DNA (mtDNA) deoxyribonucleoside triphosphates (dNTPs), which may play a direct or indirect role in the mtDNA depletion/deletion abnormalities, although the exact underlying mechanism remains unknown. The available therapeutic approaches include dialysis and enzyme replacement therapy, both can only transiently reverse the biochemical imbalance. Allogeneic hematopoietic stem cell transplantation is shown to be able to restore normal enzyme activity and improve clinical manifestations in MNGIE patients. However, transplant related complications and disease progression result in a high mortality rate. New therapeutic approaches, such as adeno-associated viral vector and hematopoietic stem cell gene therapy have been tested in Tymp-/-Upp1-/- mice, a murine model for MNGIE. This review provides background information on disease manifestations of MNGIE with a focus on current management and treatment options. It also outlines the pre-clinical approaches toward future treatment of the disease.

15.
Am J Physiol Regul Integr Comp Physiol ; 312(5): R689-R701, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28179228

RESUMO

Muscle weakness and exercise intolerance negatively affect the quality of life of patients with mitochondrial myopathy. Short-term dietary nitrate supplementation has been shown to improve exercise performance and reduce oxygen cost of exercise in healthy humans and trained athletes. We investigated whether 1 wk of dietary inorganic nitrate supplementation decreases the oxygen cost of exercise and improves mitochondrial function in patients with mitochondrial myopathy. Ten patients with mitochondrial myopathy (40 ± 5 yr, maximal whole body oxygen uptake = 21.2 ± 3.2 ml·min-1·kg body wt-1, maximal work load = 122 ± 26 W) received 8.5 mg·kg body wt-1·day-1 inorganic nitrate (~7 mmol) for 8 days. Whole body oxygen consumption at 50% of the maximal work load, in vivo skeletal muscle oxidative capacity (evaluated from postexercise phosphocreatine recovery using 31P-magnetic resonance spectroscopy), and ex vivo mitochondrial oxidative capacity in permeabilized skinned muscle fibers (measured with high-resolution respirometry) were determined before and after nitrate supplementation. Despite a sixfold increase in plasma nitrate levels, nitrate supplementation did not affect whole body oxygen cost during submaximal exercise. Additionally, no beneficial effects of nitrate were found on in vivo or ex vivo muscle mitochondrial oxidative capacity. This is the first time that the therapeutic potential of dietary nitrate for patients with mitochondrial myopathy was evaluated. We conclude that 1 wk of dietary nitrate supplementation does not reduce oxygen cost of exercise or improve mitochondrial function in the group of patients tested.


Assuntos
Exercício , Mitocôndrias Musculares/metabolismo , Miopatias Mitocondriais/tratamento farmacológico , Miopatias Mitocondriais/fisiopatologia , Nitratos/administração & dosagem , Consumo de Oxigênio/efeitos dos fármacos , Administração Oral , Adulto , Idoso , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
16.
J Pediatr ; 182: 371-374.e2, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28081892

RESUMO

Whole-exome sequencing identified multiple genetic causes in 2 infants with heterogeneous disease. Three gene defects in the first patient explained all symptoms, but manifestations were overlapping (blended phenotype). Two gene defects in the second patient explained nonoverlapping symptoms (composite phenotype). Whole-exome sequencing rapidly and comprehensively resolves heterogeneous genetic disease.


Assuntos
Anormalidades Congênitas/genética , Doenças Genéticas Inatas/diagnóstico , Mutação , Análise de Sequência de DNA/métodos , Amidoidrolases/genética , Hidrolases de Éster Carboxílico/genética , Anormalidades Congênitas/diagnóstico , Exoma/genética , Testes Genéticos/métodos , Genômica , Genótipo , Humanos , Lactente , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos , Testes de Mutagenicidade , Fenótipo , Receptores de Peptídeos/genética , Sensibilidade e Especificidade , Índice de Gravidade de Doença
17.
J Med Genet ; 54(2): 73-83, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27450679

RESUMO

BACKGROUND: Severe, disease-causing germline mitochondrial (mt)DNA mutations are maternally inherited or arise de novo. Strategies to prevent transmission are generally available, but depend on recurrence risks, ranging from high/unpredictable for many familial mtDNA point mutations to very low for sporadic, large-scale single mtDNA deletions. Comprehensive data are lacking for de novo mtDNA point mutations, often leading to misconceptions and incorrect counselling regarding recurrence risk and reproductive options. We aim to study the relevance and recurrence risk of apparently de novo mtDNA point mutations. METHODS: Systematic study of prenatal diagnosis (PND) and recurrence of mtDNA point mutations in families with de novo cases, including new and published data. 'De novo' based on the absence of the mutation in multiple (postmitotic) maternal tissues is preferred, but mutations absent in maternal blood only were also included. RESULTS: In our series of 105 index patients (33 children and 72 adults) with (likely) pathogenic mtDNA point mutations, the de novo frequency was 24.6%, the majority being paediatric. PND was performed in subsequent pregnancies of mothers of four de novo cases. A fifth mother opted for preimplantation genetic diagnosis because of a coexisting Mendelian genetic disorder. The mtDNA mutation was absent in all four prenatal samples and all 11 oocytes/embryos tested. A literature survey revealed 137 de novo cases, but PND was only performed for 9 (including 1 unpublished) mothers. In one, recurrence occurred in two subsequent pregnancies, presumably due to germline mosaicism. CONCLUSIONS: De novo mtDNA point mutations are a common cause of mtDNA disease. Recurrence risk is low. This is relevant for genetic counselling, particularly for reproductive options. PND can be offered for reassurance.


Assuntos
DNA Mitocondrial/genética , Doenças Genéticas Inatas/diagnóstico , Herança Materna/genética , Diagnóstico Pré-Natal , Adulto , Criança , Feminino , Aconselhamento Genético , Humanos , Masculino , Oócitos/metabolismo , Mutação Puntual/genética , Gravidez , Diagnóstico Pré-Implantação
18.
Front Neurol ; 7: 203, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27899912

RESUMO

In establishing a genetic diagnosis in heterogeneous neurological disease, clinical characterization and whole exome sequencing (WES) go hand-in-hand. Clinical data are essential, not only to guide WES variant selection and define the clinical severity of a genetic defect but also to identify other patients with defects in the same gene. In an infant patient with sensorineural hearing loss, psychomotor retardation, and epilepsy, WES resulted in identification of a novel homozygous CLPP frameshift mutation (c.21delA). Based on the gene defect and clinical symptoms, the diagnosis Perrault syndrome type 3 (PRLTS3) was established. The patient's brain-MRI revealed specific abnormalities of the subcortical and deep cerebral white matter and the middle blade of the corpus callosum, which was used to identify similar patients in the Amsterdam brain-MRI database, containing over 3000 unclassified leukoencephalopathy cases. In three unrelated patients with similar MRI abnormalities the CLPP gene was sequenced, and in two of them novel missense mutations were identified together with a large deletion that covered part of the CLPP gene on the other allele. The severe neurological and MRI abnormalities in these young patients were due to the drastic impact of the CLPP mutations, correlating with the variation in clinical manifestations among previously reported patients. Our data show that similarity in brain-MRI patterns can be used to identify novel PRLTS3 patients, especially during early disease stages, when only part of the disease manifestations are present. This seems especially applicable to the severely affected cases in which CLPP function is drastically affected and MRI abnormalities are pronounced.

19.
Eur J Hum Genet ; 24(4): 619-22, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26197978

RESUMO

Autosomal recessive cerebellar ataxia (ARCA) is a group of neurological disorders characterized by degeneration or abnormal development of the cerebellum and spinal cord. ARCA is clinically and genetically highly heterogeneous, with over 20 genes involved. Exome sequencing of a girl with ARCA from non-consanguineous Dutch parents revealed two pathogenic variants c.37G>C; p.D13H and c.946A>T; p.K316* in CWF19L1, a gene with an unknown function, recently reported to cause ARCA in a Turkish family. Sanger sequencing showed that the c.37G>C variant was inherited from the father and the c.946A>T variant from the mother. Pathogenicity was based on the damaging effect on protein function as the c.37G>C variant changed the highly conserved, negatively charged aspartic acid to the positively charged histidine and the c.946A>T variant introduced a premature stop codon. In addition, 27 patients with ARCA were tested for pathogenic variants in CWF19L1, however, no pathogenic variants were identified. Our data confirm CWF19L1 as a novel but rare gene causing ARCA.


Assuntos
Proteínas de Ciclo Celular/genética , Ataxia Cerebelar/genética , Genes Recessivos , Mutação de Sentido Incorreto , Adulto , Ataxia Cerebelar/diagnóstico , Criança , Códon de Terminação , Feminino , Humanos , Masculino , Linhagem
20.
Acta Neuropathol Commun ; 3: 65, 2015 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-26510925

RESUMO

INTRODUCTION: Muscle stem cells termed satellite cells are essential for muscle regeneration. A central question in many neuromuscular disorders is why satellite cells are unable to prevent progressive muscle wasting. We have analyzed muscle fiber pathology and the satellite cell response in Pompe disease, a metabolic myopathy caused by acid alpha-glucosidase deficiency and lysosomal glycogen accumulation. Pathology included muscle fiber vacuolization, loss of cross striation, and immune cell infiltration. RESULTS: The total number of Pax7-positive satellite cells in muscle biopsies from infantile, childhood onset and adult patients (with different ages and disease severities) were indistinguishable from controls, indicating that the satellite cell pool is not exhausted in Pompe disease. Pax7/Ki67 double stainings showed low levels of satellite cell proliferation similar to controls, while MyoD and Myogenin stainings showed undetectable satellite cell differentiation. Muscle regenerative activity monitored with expression of embryonic Myosin Heavy Chain was weak in the rapidly progressing classic infantile form and undetectable in the more slowly progressive childhood and adult onset disease including in severely affected patients. CONCLUSIONS: These results imply that ongoing muscle wasting in Pompe disease may be explained by insufficient satellite cell activation and muscle regeneration. The preservation of the satellite cell pool may offer a venue for the development of novel treatment strategies directed towards the activation of endogenous satellite cells.


Assuntos
Doença de Depósito de Glicogênio Tipo II/patologia , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Músculo Esquelético/fisiologia , Regeneração/fisiologia , Células Satélites de Músculo Esquelético/patologia , Adolescente , Adulto , Idade de Início , Antígenos CD/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Antígeno Ki-67/metabolismo , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/patologia , Fator de Transcrição PAX7/metabolismo , Adulto Jovem
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