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1.
J Pediatr ; 2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34788681

RESUMO

OBJECTIVE: To investigate the determinants of quality of life (QoL) in children with inborn errors of metabolism with restricted diet (IEMRDs) using a single theory-based multidimensional model. STUDY DESIGN: In this multicenter cross-sectional study, data from children with IEMRDs (except phenylketonuria) aged 8 to 17 years and their parents were collected from January 2015 to December 2017. Measurements included a child's self-reported QoL, self-rated behavioral problems and anxiety, and parental anxiety. Based on hypotheses from a literature-built theoretical model linking demographic, clinical, family environment and psychosocial characteristics to QoL either directly or indirectly, associations of these factors with a child's self-rated QoL were examined using a structural equation modeling (SEM) approach. RESULTS: A total of 312 children (mean [SD] age, 12.2 [2.6] years; 160 [51%] boys) were included. Higher trait anxiety and behavioral problems in children were the most important factors associated with poorer QoL (standardized path coefficients = -0.71 and -0.23, respectively). Additionally, higher parent trait anxiety, younger age at diagnosis, and having a disease requiring an emergency diet were associated with poorer QoL in these children. The final model fit the data closely according to conventional goodness-of-fit statistics and explained 86% of QoL variance. CONCLUSIONS: Psychosocial factors appear to be major determinants of QoL impairment in children with IEMRDs. These factors should be particularly addressed in clinical practice as part of the global treatment plan for a child with IEMRD. Future studies based on longitudinal design should consider coping strategies when exploring potential predictive factors of QoL.

2.
Doc Ophthalmol ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491492

RESUMO

INTRODUCTION: Transcobalamin (TC) transports cobalamin (vitamin B12) from plasma into cells. Its congenital deficiency is a rare autosomal recessive disorder due to mutations in the TCN2 gene. It causes intracellular cobalamin depletion with early onset in the first months of life, failure to thrive with pallor due to megaloblastic anemia. It can be associated with pancytopenia, gastrointestinal symptoms with vomiting, diarrhea, and neurological complications with myelopathy. Aggressive vitamin B12 parenteral therapy must be instituted early and continuously. Retinopathy and maculopathy are rarely associated with this condition. SUBJECT: We report the electrophysiological results of one TC-deficient patient diagnosed at the age of 4 months immediately and continuosly treated by hydroxocobalamin IM. Her visual function was followed by eight ophthalmological assessments, eight flash-ERG, six EOG, one mf-ERG, and seven P-ERG recordings over a 10-year period, between the age of 2y 9 m and 12y 6 m. RESULTS: Her ophthalmological assessment including visual acuity, fundi, optical coherent tomography (OCT), and retinal nerve fiber layer (RNFL) remained normal. From the age of 2y 9 m to 5y, dark-adapted and light-adapted flash-ERGs, EOGs and pattern-ERG were normal. From the age of 6y 4 m to 12y 6 m, dark-adapted flash-ERGs and EOGs remained normal. Cone a-wave amplitudes remained normal, whereas cone b-wave and flicker-response amplitudes were decreased. At the age of 12y 6 m, mf-ERG N1P1 amplitudes on the central 30° were decreased. From the age of 7y 4 m to 12y 6 m, P-ERG P50 amplitudes were decreased with no N95. COMMENTS: While clinical and anatomical assessments remained normal over a 10-year period, patient's electrophysiological results suggested the progressive onset of a subclinical retinopathy of inner-cone dystrophy type, and a subclinical maculopathy on the central 30° including the ganglion cell layer deficiency on the central 15°, despite continuous intramuscular treatment, RPE and scotopic system remaining normal. The origins of such subclinical retinopathy and maculopathy are unknown and independent of early disease identification and aggressive intramuscular hydroxocobalamin therapy.

3.
Eur Respir J ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503986

RESUMO

INTRODUCTION: Pulmonary alveolar proteinosis related to mutations in the methionine tRNA synthetase (MARS1) gene is a severe, early-onset disease that results in death before the age of 2 years in one-third of patients. It is associated with a liver disease, growth failure and systemic inflammation. As methionine supplementation in yeast models restored normal enzymatic activity of the synthetase, we studied the tolerance, safety and efficacy of daily oral methionine supplementation in patients with severe and early disease. METHODS: Four patients received methionine supplementation and were followed for respiratory, hepatic, growth, and inflammation-related outcomes. Their course was compared to those of historical controls. Reactive oxygen species (ROS) production by patient monocytes before and after methionine supplementation was also studied. RESULTS: Methionine supplementation was associated with respiratory improvement, clearance of the extracellular lipoproteinaceous material, and discontinuation of whole-lung lavage in all patients. The three patients who required oxygen or non-invasive ventilation could be weaned off within 60 days. Liver dysfunction, inflammation, and growth delay also improved or resolved. At a cellular level, methionine supplementation normalised the production of reactive oxygen species by peripheral monocytes. CONCLUSION: Methionine supplementation was associated with important improvements in children with pulmonary alveolar proteinosis related to mutations in the MARS1 gene. This study paves the way for similar strategies for other tRNA synthetase deficiencies.

4.
Mol Genet Metab ; 134(1-2): 156-163, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34556413

RESUMO

Acyl CoA Dehydrogenase 9 (ACAD9) is a member of the family of flavoenzymes that catalyze the dehydrogenation of acyl-CoAs to 2,3 enoyl-CoAs in mitochondrial fatty acid oxidation (FAO). Inborn errors of metabolism of all family members, including ACAD9, have been described in humans, and represent significant causes of morbidity and mortality particularly in children. ACAD9 deficiency leads to a combined defect in fatty acid oxidation and oxidative phosphorylation (OXPHOS) due to a dual role in the pathways. In addition to its function in mitochondrial FAO, ACAD9 has a second function as one of 14 factors responsible for assembly of complex I of the electron transport chain (ETC). Considerable controversy remains over the relative role of these two functions in normal physiology and the disparate clinical findings described in patients with ACAD9 deficiency. To better understand the normal function of ACAD9 and the pathophysiology of its deficiency, several knock out mouse models were developed. Homozygous total body knock out appeared to be lethal as no ACAD9 animals were obtained. Cre-lox technology was then used to generate tissue-specific deletion of the gene. Cardiac-specific ACAD9 deficient animals had severe neonatal cardiomyopathy and died by 17 days of age. They had severe mitochondrial dysfunction in vitro. Muscle-specific mutants were viable but exhibited muscle weakness. Additional studies of heart muscle from the cardiac specific deficient animals were used to examine the evolutionarily conserved signaling Intermediate in toll pathway (ECSIT) protein, a known binding partner of ACAD9 in the electron chain complex I assembly pathway. As expected, ECSIT levels were significantly reduced in the absence of ACAD9 protein, consistent with the demonstrated impairment of the complex I assembly. The various ACAD9 deficient animals should serve as useful models for development of novel therapeutics for this disorder.

5.
Biomedicines ; 9(8)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34440194

RESUMO

Mitochondrial proteins carrying iron-sulfur (Fe-S) clusters are involved in essential cellular pathways such as oxidative phosphorylation, lipoic acid synthesis, and iron metabolism. NFU1, BOLA3, IBA57, ISCA2, and ISCA1 are involved in the last steps of the maturation of mitochondrial [4Fe-4S]-containing proteins. Since 2011, mutations in their genes leading to five multiple mitochondrial dysfunction syndromes (MMDS types 1 to 5) were reported. The aim of this systematic review is to describe all reported MMDS-patients. Their clinical, biological, and radiological data and associated genotype will be compared to each other. Despite certain specific clinical elements such as pulmonary hypertension or dilated cardiomyopathy in MMDS type 1 or 2, respectively, nearly all of the patients with MMDS presented with severe and early onset leukoencephalopathy. Diagnosis could be suggested by high lactate, pyruvate, and glycine levels in body fluids. Genetic analysis including large gene panels (Next Generation Sequencing) or whole exome sequencing is needed to confirm diagnosis.

6.
Science ; 373(6555): 662-673, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34353949

RESUMO

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive Phe in Pair -/- and Pah R408W/R408W mice and improved the Phe tolerance of these mice.


Assuntos
Fenilalanina Hidroxilase/metabolismo , Fenilalanina/metabolismo , Fenilcetonúrias/genética , RNA Longo não Codificante/genética , Acetilgalactosamina , Animais , Biopterina/análogos & derivados , Biopterina/metabolismo , Biopterina/uso terapêutico , Dieta , Modelos Animais de Doenças , Feminino , Hepatócitos/metabolismo , Humanos , Fígado/embriologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Conformação de Ácido Nucleico , Fenilalanina/administração & dosagem , Fenilalanina Hidroxilase/deficiência , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/tratamento farmacológico , Fenilcetonúrias/metabolismo , Ligação Proteica , RNA Longo não Codificante/química , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/uso terapêutico
7.
Mol Genet Metab ; 133(4): 397-399, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34140212

RESUMO

PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 µg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.

8.
Mol Genet Metab ; 133(2): 222-229, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33972171

RESUMO

BACKGROUND AND PURPOSE: Mitochondrial aminoacyl-tRNA synthetases-encoded by ARS2 genes-are evolutionarily conserved enzymes that catalyse the attachment of amino acids to their cognate tRNAs, ensuring the accuracy of the mitochondrial translation process. ARS2 gene mutations are associated with a wide range of clinical presentations affecting the CNS. METHODS: Two senior neuroradiologists analysed brain MRI of 25 patients (age range: 3 d-25 yrs.; 11 males; 14 females) with biallelic pathogenic variants of 11 ARS2 genes in a retrospective study conducted between 2002 and 2019. RESULTS: Though several combinations of brain MRI anomalies were highly suggestive of specific aetiologies (DARS2, EARS2, AARS2 and RARS2 mutations), our study detected no MRI pattern common to all patients. Stroke-like lesions were associated with pathogenic SARS2 and FARS2 variants. We also report early onset cerebellar atrophy and calcifications in AARS2 mutations, early white matter involvement in RARS2 mutations, and absent involvement of thalami in EARS2 mutations. Finally, our findings show that normal brain MRI results do not exclude the presence of ARS2 mutations: 5 patients with normal MRI images were carriers of pathogenic IARS2, YARS2, and FARS2 variants. CONCLUSION: Our study extends the spectrum of brain MRI anomalies associated with pathogenic ARS2 variants and suggests ARS2 mutations are largely underdiagnosed.


Assuntos
Alanina-tRNA Ligase/genética , Arginina-tRNA Ligase/genética , Aspartato-tRNA Ligase/genética , Encéfalo/diagnóstico por imagem , Proteínas Mitocondriais/genética , Fenilalanina-tRNA Ligase/genética , Adolescente , Adulto , Aminoacil-tRNA Sintetases/classificação , Aminoacil-tRNA Sintetases/genética , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Variação Genética , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Mutação/genética , Fenótipo , Adulto Jovem
9.
Lancet Diabetes Endocrinol ; 9(7): 427-435, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34023005

RESUMO

BACKGROUND: Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1. METHODS: We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only). FINDINGS: 315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7-28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age <28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment. INTERPRETATION: Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy. FUNDING: Swedish Orphan Biovitrum (Sobi).


Assuntos
Cicloexanonas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Nitrobenzoatos/uso terapêutico , Tirosinemias/diagnóstico , Tirosinemias/tratamento farmacológico , Adolescente , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Criança , Pré-Escolar , Cicloexanonas/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Nefropatias/induzido quimicamente , Nefropatias/diagnóstico , Estudos Longitudinais , Masculino , Triagem Neonatal/métodos , Nitrobenzoatos/efeitos adversos , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
10.
Genet Med ; 23(9): 1604-1615, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34040193

RESUMO

PURPOSE: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature. METHODS: Nineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival. RESULTS: Our cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old. CONCLUSION: Prolidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH.


Assuntos
Doença de Crohn , Úlcera da Perna , Deficiência de Prolidase , Criança , Pré-Escolar , Diagnóstico Tardio , Humanos , Fenótipo , Deficiência de Prolidase/diagnóstico , Deficiência de Prolidase/genética
11.
JIMD Rep ; 59(1): 110-119, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33977036

RESUMO

Maple syrup urine disease (MSUD) is a rare inborn metabolic disorder, managed with a strict protein-restricted diet. At any time or age patients may still experience metabolic decompensations, requiring administration of branched chain amino acid (BCAA)-free formula to reduce leucine levels. This retrospective observational study of 126 decompensation episodes from 54 MSUD patients treated at five centers in France and Germany from 2010 to 2016, describes episodes and outcomes for patients stratified into groups who received enteral/oral or intravenous (IV) BCAA-free formula, and by pediatric or adult age categories. IV administration of BCAA-free formula was required in cases of gastric intolerance (33%), refusal to undergo nasogastric tubing (31%), "emergency" (14%) or coma patients (8%), and as prophylaxis before surgery (6%). Overall, mean duration of hospitalization was 6.6 days with oral/enteral BCAA-free formula and 5.4 days with IV formula. Leucine levels at discharge decreased by a mean of 548.5 µmol/L (69.3%) in the oral/enteral group and 657.2 µmol/L (71.3%) in the IV group. In the pediatric subgroup, there were no marked differences between administration groups on any outcome. In the adult subgroup, mean time to episode resolution was 15.8 days in the oral/enteral group and 7.7 days in the IV group (P = .008); mean duration of hospitalization was 6 days in the oral/enteral group and 4.6 days in the IV group (P = NS). Overall, seven serious adverse events in two patients were reported, of which only nausea and vomiting were treatment related.

12.
Front Pediatr ; 9: 621200, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33748042

RESUMO

Objective: To characterize the electro-clinical presentation of patients with pyridoxine-dependent epilepsy (PDE) and pyridoxal phosphate (PLP)-dependent epilepsy in order to determine whether some of them could be diagnosed as de novo West syndrome, i. e., West syndrome that starts after the age of 2 months without other types of seizures (focal seizures for instance) before the onset of epileptic spasms. Methods: We analyzed data from an unpublished cohort of 28 genetically confirmed cases of PDE with antiquitine (ATQ) deficiency and performed a review of the literature looking for description of West syndrome in patients with either PDE with ATQ deficiency or PLP-dependent epilepsy with Pyridox(am)ine phosphate oxidase (PNPO) deficiency. Results: Of the 28 cases from the ATQ deficiency French cohort, 5 had spasms. In four cases, spasms were associated with other types of seizures (myoclonus, focal seizures). In the last case, seizures started on the day of birth. None of these cases corresponded to de novo West syndrome. The review of the literature found only one case of PNPO deficiency presenting as de novo West syndrome and no case of ATQ deficiency. Significance: The presentation of PDE- and PLP-dependent epilepsy as de novo West syndrome is so exceptional that it probably does not justify a systematic trial of pyridoxine or PLP. We propose considering a therapeutic trial with these vitamins in West syndrome if spasms are associated with other seizure types or start before the age of 2 months.

13.
Mol Genet Metab ; 132(4): 227-233, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33610471

RESUMO

INTRODUCTION: Triheptanoin provides long-chain fatty acid oxidation disorder (LC-FAOD) patients with an alternative to medium-even-chain triglycerides therapy. MATERIAL-METHODS: Retrospective analysis of 18 French LC-FAOD patients benefiting from early access to triheptanoin treatment. RESULTS: Eight female and 10 male patients with LC-FAOD (VLCAD, LCHAD, CACT, CPTII and MTP) were treated with triheptanoin for a median duration of 22 months (range: 9-228 months). At last consultation, triheptanoin accounted for 15-35% of their daily caloric intake. In the year following the introduction of triheptanoin, patients reported a reduction of intermittent snacking and nocturnal meals. Three patients, including 1 adult, became free of severe hypoglycaemic events. Ten of 12 paediatric patients and 4 of 6 adult patients reported reduced fatigue with reductions in the number and severity of episodes of myalgia. Of 6 patients, including 1 adult, that had required the use of a wheelchair in the year prior to triheptanoin, all but one no longer required its use. The number of emergency hospitalizations decreased, and none were recorded for paediatric patients during these 12 months. Cumulative annual days of emergency care in the home were reduced from 286 to 51 days in the year before and after initiation, respectively, and 13 patients required no such interventions. Adverse events were limited to digestive issues that dissipated over time. CONCLUSIONS: Our case-series suggests that long-term treatment of LC-FAOD paediatric and adult patients with triheptanoin is safe and leads to marked improvement of symptoms and an improved quality of life.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/genética , Doenças Metabólicas/tratamento farmacológico , Triglicerídeos/administração & dosagem , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Adolescente , Adulto , Carnitina/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Oxirredução/efeitos dos fármacos , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
14.
J Inherit Metab Dis ; 44(4): 903-915, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33634872

RESUMO

Carnitine acyl-carnitine translocase deficiency (CACTD) is a rare autosomal recessive disorder of mitochondrial long-chain fatty-acid transport. Most patients present in the first 2 days of life, with hypoketotic hypoglycaemia, hyperammonaemia, cardiomyopathy or arrhythmia, hepatomegaly and elevated liver enzymes. Multi-centre international retrospective chart review of clinical presentation, biochemistry, treatment modalities including diet, subsequent complications, and mode of death of all patients. Twenty-three patients from nine tertiary metabolic units were identified. Seven attenuated patients of Pakistani heritage, six of these homozygous c.82G>T, had later onset manifestations and long-term survival without chronic hyperammonemia. Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15). Where recorded, ammonia levels were elevated in all but one severe case (13/14 measured) and 14/16 had hypoglycaemia. Nine classical patients survived longer-term-most with feeding difficulties and cognitive delay. Hyperammonaemia appears refractory to ammonia scavenger treatment and carglumic acid, but responds well to high glucose delivery during acute metabolic crises. High-energy intake seems necessary to prevent decompensation. Anaplerosis utilising therapeutic d,l-3-hydroxybutyrate, Triheptanoin and increased protein intake, appeared to improve chronic hyperammonemia and metabolic stability where trialled in individual cases. CACTD is a rare disorder of fatty acid oxidation with a preponderance to severe cardiac dysfunction. Long-term survival is possible in classical early-onset cases with long-chain fat restriction, judicious use of glucose infusions, and medium chain triglyceride supplementation. Adjunctive therapies supporting anaplerosis may improve longer-term outcomes.

15.
Doc Ophthalmol ; 142(3): 371-380, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33392894

RESUMO

BACKGROUND: LCHAD (long-chain 3-hydroxyacyl-CoA dehydrogenase) deficiency is a rare genetic disorder of mitochondrial long-chain fatty acid oxidation inherited as a recessive trait. Affected patients can present with hypoglycaemia, rhabdomyolysis and cardiomyopathy. About half of the patients may suffer from retinopathy. CASE REPORT: A 19-year-old girl was diagnosed as suffering from LCHAD deficiency with recurrent rhabdomyolysis episodes at the age of 7 months by an inaugural coma with hypoglycaemia and hepatomegaly. Appropriate dietary management with carnitine supplementation was initiated. Retinopathy was diagnosed at age two. Ophthalmological assessments including visual acuity, visual field, OCT, flash ERGs, P-ERG, flash VEPs and EOG recordings were conducted over a 17-year period. RESULTS: Visual acuity was decreased. Fundi showed a progressive retinopathy and chorioretinopathy. Photophobia was noticed 2 years before the decrease in photopic-ERG amplitude with normal scotopic-ERGs. Scotopic-ERG amplitude decreased 10 years after the decrease in photopic-ERG amplitude. No EOG light rise was observed. Flash VEPs remained normal. These results suggest that the cone system dysfunction occurs largely prior to the rod system dysfunction with a relative preservation of the macula function. COMMENTS: This dysfunction of cones prior to the dysfunction of rods was not reported previously. This could be related to mitochondrial energy failure in cones as cones are greater consumers of ATP than rods. This hypothesis needs to be further confirmed as other long-chain fatty oxidation defective patients (VLCAD and CPT2 deficiencies) do not exhibit retinopathy.


Assuntos
Cardiomiopatias , Doenças Retinianas , Rabdomiólise , 3-Hidroxiacil-CoA Desidrogenases/genética , 3-Hidroxiacil-CoA Desidrogenase , Adulto , Eletroculografia , Eletrorretinografia , Feminino , Humanos , Lactente , Erros Inatos do Metabolismo Lipídico , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa , Miopatias Mitocondriais , Proteína Mitocondrial Trifuncional/deficiência , Doenças do Sistema Nervoso , Doenças Retinianas/diagnóstico , Regulador Transcricional ERG , Adulto Jovem
16.
Genet Med ; 23(3): 543-554, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33149277

RESUMO

PURPOSE: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority. METHODS: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC. RESULTS: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts. CONCLUSION: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.


Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Actinas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Humanos , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões
17.
J Med Genet ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199448

RESUMO

BACKGROUND: Biallelic variants in PNPT1 cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs. OBJECTIVE AND METHODS: To document neuroimaging data in six patients with PNPT1 highlighting novel findings. RESULTS: Two patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection. CONCLUSION: We suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations.

18.
J Inherit Metab Dis ; 43(6): 1360-1369, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33098580

RESUMO

Mannose phosphate isomerase MPI-CDG (formerly CDG-1b) is a potentially fatal inherited metabolic disease which is readily treatable with oral D-mannose. We retrospectively reviewed long-term outcomes of patients with MPI-CDG, all but one of whom were treated with D-mannose. Clinical, biological, and histological data were reviewed at diagnosis and on D-mannose treatment. Nine patients were diagnosed with MPI-CDG at a median age of 3 months. The presenting symptoms were diarrhea (n = 9), hepatomegaly (n = 9), hypoglycemia (n = 8), and protein loosing enteropathy (n = 7). All patients survived except the untreated one who died at 2 years of age. Oral D-mannose was started in eight patients at a median age of 7 months (mean 38 months), with a median follow-up on treatment of 14 years 9 months (1.5-20 years). On treatment, two patients developed severe portal hypertension, two developed venous thrombosis, and 1 displayed altered kidney function. Poor compliance with D-mannose was correlated with recurrence of diarrhea, thrombosis, and abnormal biological parameters including coagulation factors and transferrin profiles. Liver fibrosis persisted despite treatment, but two patients showed improved liver architecture during follow-up. This study highlights (i) the efficacy and safety of D-mannose treatment with a median follow-up on treatment of almost 15 years (ii) the need for life-long treatment (iii) the risk of relapse with poor compliance, (iii) the importance of portal hypertension screening (iv) the need to be aware of venous and renal complications in adulthood.


Assuntos
Defeitos Congênitos da Glicosilação/tratamento farmacológico , Manose-6-Fosfato Isomerase/deficiência , Manose/administração & dosagem , Manose/efeitos adversos , Administração Oral , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão/etiologia , Lactente , Cirrose Hepática/patologia , Masculino , Adesão à Medicação , Estudos Retrospectivos , Transferrina/análise , Resultado do Tratamento , Trombose Venosa/etiologia
19.
J Nutr ; 150(Suppl 1): 2556S-2560S, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33000154

RESUMO

Lysine is an essential amino acid, and inherited diseases of its metabolism therefore represent defects of lysine catabolism. Although some of these enzyme defects are not well described yet, glutaric aciduria type I (GA1) and antiquitin (2-aminoadipic-6-semialdehyde dehydrogenase) deficiency represent the most well-characterized diseases. GA1 is an autosomal recessive disorder due to a deficiency of glutaryl-CoA dehydrogenase. Untreated patients exhibit early onset macrocephaly and may present a neurological deterioration with regression and movement disorder at the time of a presumably "benign" infection most often during the first year of life. This is associated with a characteristic neuroimaging pattern with frontotemporal atrophy and striatal injuries. Diagnosis relies on the identification of glutaric and 3-hydroxyglutaric acid in urine along with plasma glutarylcarnitine. Treatment consists of a low-lysine diet aiming at reducing the putatively neurotoxic glutaric and 3-hydroxyglutaric acids. Additional therapeutic measures include administration of l-carnitine associated with emergency measures at the time of intercurrent illnesses aiming at preventing brain injury. Early treated (ideally through newborn screening) patients exhibit a favorable long-term neurocognitive outcome, whereas late-treated or untreated patients may present severe neurocognitive irreversible disabilities. Antiquitin deficiency is the most common form of pyridoxine-dependent epilepsy. α-Aminoadipic acid semialdehyde (AASA) and Δ-1-piperideine-6-carboxylate (P6C) accumulate proximal to the enzymatic block. P6C forms a complex with pyridoxal phosphate (PLP), a key vitamer of pyridoxine, thereby reducing PLP bioavailability and subsequently causing epilepsy. Urinary AASA is a biomarker of antiquitin deficiency. Despite seizure control, only 25% of the pyridoxine-treated patients show normal neurodevelopment. Low-lysine diet and arginine supplementation are proposed in some patients with decrease of AASA, but the impact on neurodevelopment is unclear. In summary, GA1 and antiquitin deficiency are the 2 main human defects of lysine catabolism. Both include neurological impairment. Lysine dietary restriction is a key therapy for GA1, whereas its benefits in antiquitin deficiency appear less clear.


Assuntos
Aldeído Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Encefalopatias Metabólicas Congênitas/metabolismo , Encefalopatias Metabólicas/metabolismo , Encéfalo/metabolismo , Epilepsia/metabolismo , Glutaril-CoA Desidrogenase/deficiência , Lisina/metabolismo , Ácido 2-Aminoadípico/análogos & derivados , Ácido 2-Aminoadípico/metabolismo , Aldeído Desidrogenase/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Arginina/uso terapêutico , Encéfalo/patologia , Encefalopatias Metabólicas/terapia , Encefalopatias Metabólicas Congênitas/terapia , Carnitina/análogos & derivados , Carnitina/metabolismo , Carnitina/uso terapêutico , Epilepsia/terapia , Glutaratos/metabolismo , Glutaril-CoA Desidrogenase/metabolismo , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Doenças Metabólicas/terapia , Fosfato de Piridoxal/metabolismo , Piridoxina/metabolismo , Piridoxina/uso terapêutico
20.
Neuromuscul Disord ; 30(7): 593-598, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32654952

RESUMO

Diaphragmatic dysfunction has been reported in congenital myopathies, muscular dystrophies, and occasionally, mitochondrial respiratory chain deficiency. Using a minimally invasive procedure in 3 young girls, 1 with a heteroplasmic MT-CYB mutation and 2 with biallelic pathogenic TK2 variants, we provided functional evidence of diaphragmatic dysfunction with global respiratory muscle weakness in mitochondrial respiratory chain deficiency. Analysis of respiratory muscle performance using esogastric pressures revealed paradoxical breathing and severe global inspiratory and expiratory muscle weakness with a sniff esophageal inspiratory pressure and a gastric pressure during cough averaging 50% and 40% of predicted values, respectively. This diaphragmatic dysfunction was responsible for severe undiagnosed nocturnal hypoventilation, requiring noninvasive ventilation. Our results underline the interest of this minimally invasive procedure for the evaluation of respiratory muscle performance and its potential value for the monitoring of future clinical trials in respiratory chain deficiency.


Assuntos
Diafragma/fisiopatologia , Hipoventilação/etiologia , Doenças Mitocondriais/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Mutação/genética , Ventilação não Invasiva , Músculos Respiratórios/fisiopatologia
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