Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 85
Filtrar
1.
Am J Hum Genet ; 108(11): 2130-2144, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34653363

RESUMO

Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Genes Dominantes , Hexosiltransferases/genética , Proteínas de Membrana/genética , Doenças Musculoesqueléticas/genética , Doenças do Sistema Nervoso/genética , Adolescente , Adulto , Sequência de Aminoácidos , Domínio Catalítico , Pré-Escolar , Feminino , Heterozigoto , Hexosiltransferases/química , Humanos , Masculino , Proteínas de Membrana/química , Pessoa de Meia-Idade , Linhagem , Homologia de Sequência de Aminoácidos
3.
J Inherit Metab Dis ; 44(6): 1393-1408, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34494673

RESUMO

Cystinosis is an inherited metabolic disorder caused by autosomal recessive mutations in the CTNS gene leading to lysosomal cystine accumulation. The disease primarily affects the kidneys followed by extra-renal organ involvement later in life. Azoospermia is one of the unclarified complications which are not improved by cysteamine, which is the only available disease-modifying treatment. We aimed at unraveling the origin of azoospermia in cysteamine-treated cystinosis by confirming or excluding an obstructive factor, and investigating the effect of cysteamine on fertility in the Ctns-/- mouse model compared with wild type. Azoospermia was present in the vast majority of infantile type cystinosis patients. While spermatogenesis was intact, an enlarged caput epididymis and reduced levels of seminal markers for obstruction neutral α-glucosidase (NAG) and extracellular matrix protein 1 (ECM1) pointed towards an epididymal obstruction. Histopathological examination in human and mouse testis revealed a disturbed blood-testis barrier characterized by an altered zonula occludens-1 (ZO-1) protein expression. Animal studies ruled out a negative effect of cysteamine on fertility, but showed that cystine accumulation in the testis is irresponsive to regular cysteamine treatment. We conclude that the azoospermia in infantile cystinosis is due to an obstruction related to epididymal dysfunction, irrespective of the severity of an evolving primary hypogonadism. Regular cysteamine treatment does not affect fertility but has subtherapeutic effects on cystine accumulation in testis.

4.
BMC Neurol ; 21(1): 313, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384384

RESUMO

BACKGROUND: SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset spine rigidity and respiratory insufficiency. A muscular dystrophy caused by mutations in the LAMA2 gene (LAMA2-related muscular dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe, early-onset due to complete Laminin subunit α2 deficiency (merosin-deficient congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or adult-onset due to partial Laminin subunit α2 deficiency. For both muscle diseases, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data and appropriate clinical and functional outcome measures are needed to reach trial readiness. METHODS: LAST STRONG is a natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM or LAMA2-MD, starting August 2020. Patients have four visits at our hospital over a period of 1.5 year. At all visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, questionnaires (patient report and/or parent proxy; age ≥ 2 years), muscle ultrasound including diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), and accelerometry for 8 days (age ≥ 2 years); at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography; age ≥ 2 years), spine X-ray (age ≥ 2 years), dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years) and full body magnetic resonance imaging (MRI) (age ≥ 10 years). All examinations are adapted to the patient's age and functional abilities. Correlation between key parameters within and between subsequent visits will be assessed. DISCUSSION: Our study will describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD, enabling us to select relevant clinical and functional outcome measures for reaching clinical trial-readiness. Moreover, our detailed description (deep phenotyping) of the clinical features will optimize clinical management and will establish a well-characterized baseline cohort for prospective follow-up. CONCLUSION: Our natural history study is an essential step for reaching trial readiness in SELENON-RM and LAMA2-MD. TRIAL REGISTRATION: This study has been approved by medical ethical reviewing committee Region Arnhem-Nijmegen (NL64269.091.17, 2017-3911) and is registered at ClinicalTrial.gov ( NCT04478981 ).


Assuntos
Distrofias Musculares , Adulto , Criança , Humanos , Laminina/genética , Imageamento por Ressonância Magnética , Distrofias Musculares/genética , Distrofias Musculares/terapia , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos
5.
Orphanet J Rare Dis ; 16(1): 295, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34217336

RESUMO

BACKGROUND: No curative therapy for mitochondrial disease (MD) exists, prioritizing supportive treatment for symptom relief. In animal and cell models ketones decrease oxidative stress, increase antioxidants and scavenge free radicals, putting ketogenic diets (KDs) on the list of management options for MD. Furthermore, KDs are well-known, safe and effective treatments for epilepsy, a frequent symptom of MD. This systematic review evaluates efficacy and safety of KD for MD. METHODS: We searched Pubmed, Cochrane, Embase and Cinahl (November 2020) with search terms linked to MD and KD. From the identified records, we excluded studies on Pyruvate Dehydrogenase Complex deficiency. From these eligible reports, cases without a genetically confirmed diagnosis and cases without sufficient data on KD and clinical course were excluded. The remaining studies were included in the qualitative analysis. RESULTS: Only 20 cases (14 pediatric) from the 694 papers identified met the inclusion criteria (one controlled trial (n = 5), 15 case reports). KD led to seizure control in 7 out of 8 cases and improved muscular symptoms in 3 of 10 individuals. In 4 of 20 cases KD reversed the clinical phenotype (e.g. cardiomyopathy, movement disorder). In 5 adults with mitochondrial DNA deletion(s) related myopathy rhabdomyolysis led to cessation of KD. Three individuals with POLG mutations died while being on KD, however, their survival was not different compared to individuals with POLG mutations without KD. CONCLUSION: Data on efficacy and safety of KD for MD is too scarce for general recommendations. KD should be considered in individuals with MD and therapy refractory epilepsy, while KD is contraindicated in mitochondrial DNA deletion(s) related myopathy. When considering KD for MD the high rate of adverse effects should be taken into account, but also spectacular improvements in individual cases. KD is a highly individual management option in this fragile patient group and requires an experienced team. To increase knowledge on this-individually-promising management option more (prospective) studies using adequate outcome measures are crucial.


Assuntos
Dieta Cetogênica , Epilepsia Resistente a Medicamentos , Epilepsia , Doenças Mitocondriais , Adulto , Animais , Criança , Humanos , Doenças Mitocondriais/genética , Estudos Prospectivos
6.
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.

7.
JIMD Rep ; 58(1): 70-79, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33728249

RESUMO

Background: Reliable measurement of phenylalanine (Phe) is a prerequisite for adequate follow-up of phenylketonuria (PKU) patients. However, previous studies have raised concerns on the intercomparability of plasma and dried blood spot (DBS) Phe results. In this study, we made an inventory of differences in (pre-)analytical methodology used for Phe determination across Dutch laboratories, and compared DBS and plasma results. Methods: Through an online questionnaire, we assessed (pre-)analytical Phe measurement procedures of seven Dutch metabolic laboratories. To investigate the difference between plasma and DBS Phe, participating laboratories received simultaneously collected plasma-DBS sets from 23 PKU patients. In parallel, 40 sample sets of DBS spotted from either venous blood or capillary fingerprick were analyzed. Results: Our data show that there is no consistency on standard operating procedures for Phe measurement. The association of DBS to plasma Phe concentration exhibits substantial inter-laboratory variation, ranging from a mean difference of -15.5% to +30.6% between plasma and DBS Phe concentrations. In addition, we found a mean difference of +5.8% in Phe concentration between capillary DBS and DBS prepared from venous blood. Conclusions: The results of our study point to substantial (pre-)analytical variation in Phe measurements, implicating that bloodspot Phe results should be interpreted with caution, especially when no correction factor is applied. To minimize variation, we advocate pre-analytical standardization and analytical harmonization of Phe measurements, including consensus on application of a correction factor to adjust DBS Phe to plasma concentrations.

8.
Neurosci Biobehav Rev ; 125: 57-77, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33582231

RESUMO

Mitochondrial diseases (MDs) are rare, heterogeneous, hereditary and progressive in nature. In addition to the serious somatic symptoms, patients with MD also experience problems regarding their cognitive functioning and mental health. We provide an overview of all published studies reporting on any aspect of cognitive functioning and/or mental health in patients with MD and their relatives. A total of 58 research articles and 45 case studies were included and critically reviewed. Cognitive impairments in multiple domains were reported. Mental disorders were frequently reported, especially depression and anxiety. Furthermore, most studies showed impairments in self-reported psychological functioning and high prevalence of mental health problems in (matrilineal) relatives. The included studies showed heterogeneity regarding patient samples, measurement instruments and reference groups, making comparisons cautious. Results highlight a high prevalence of cognitive impairments and mental disorders in patients with MD. Recommendations for further research as well as tailored patientcare with standardized follow-up are provided. Key gaps in the literature are identified, of which studies on natural history are of highest importance.


Assuntos
Saúde Mental , Doenças Mitocondriais , Cognição , Depressão , Humanos , Doenças Mitocondriais/complicações , Doenças Mitocondriais/genética , Qualidade de Vida
9.
Metabolomics ; 17(1): 10, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33438095

RESUMO

INTRODUCTION: The m.3243A > G mitochondrial DNA mutation is one of the most common mitochondrial disease-causing mutations, with a carrier rate as high as 1:400. This point mutation affects the MT-TL1 gene, ultimately affecting the oxidative phosphorylation system and the cell's energy production. Strikingly, the m.3243A > G mutation is associated with different phenotypes, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD) and myopathy. OBJECTIVES: We investigated urine metabolomes of MELAS, MIDD and myopathy patients in order to identify affected metabolic pathways and possible treatment options. METHODS: A multiplatform metabolomics approach was used to comprehensively analyze the metabolome and compare metabolic profiles of different phenotypes caused by the m.3243A > G mutation. Our analytical array consisted of NMR spectroscopy, LC-MS/MS and GC-TOF-MS. RESULTS: The investigation revealed phenotypic specific metabolic perturbations, as well as metabolic similarities between the different phenotypes. We show that glucose metabolism is highly disturbed in the MIDD phenotype, but not in MELAS or myopathy, remodeled fatty acid oxidation is characteristic of the MELAS patients, while one-carbon metabolism is strongly modified in both MELAS and MIDD, but not in the myopathy group. Lastly we identified increased creatine in the urine of the myopathy patients, but not in MELAS or MIDD. CONCLUSION: We conclude by giving novel insight on the phenotypes of the m.3243A > G mutation from a metabolomics point of view. Directives are also given for future investigations that could lead to better treatment options for patients suffering from this debilitating disease.


Assuntos
Surdez/genética , Surdez/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Síndrome MELAS/genética , Síndrome MELAS/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Musculares/genética , Doenças Musculares/metabolismo , Mutação , Fenótipo , Cromatografia Líquida , Surdez/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Predisposição Genética para Doença , Humanos , Síndrome MELAS/diagnóstico , Espectroscopia de Ressonância Magnética , Metaboloma , Metabolômica/métodos , Doenças Mitocondriais/diagnóstico , Doenças Musculares/diagnóstico , Espectrometria de Massas em Tandem
11.
J Inherit Metab Dis ; 44(3): 777-786, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33089527

RESUMO

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 µmol/L, range 69-266, to 90 µmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.

12.
JPEN J Parenter Enteral Nutr ; 45(1): 165-174, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32189351

RESUMO

BACKGROUND: Whether decreased physical functioning of patients with mitochondrial disease (MD) is related to altered body composition or low protein intake needs clarification at the background of the nutrition state. METHODS: In this 2-site cross-sectional study, MD patients were age-, body mass index (BMI)-, and gender-matched to controls. Body composition was assessed by dual-energy x-ray absorptiometry. Physical functioning was measured by handgrip strength, 6-minute walking test, 30-second sit-to-stand test (30SCT), and 6-minute mastication test. Total daily protein intake was calculated by 3-day food records. Malnutrition was assessed by Patient-Generated Subjective Global Assessment and the Global Leadership Initiative on Malnutrition (GLIM) criteria and sarcopenia by the 2018 consensus. Data were analyzed using independent samples t-tests, Fisher exact test, and Spearman and Pearson correlation coefficients. RESULTS: Thirty-seven MD patients (42 ± 12 years, BMI: 23 ± 4 kg/m2 , 59% females) and 37 matched controls were included. Handgrip strength was moderate, inversely related to fat mass index in both MD patients and controls, whereas it correlated with fat-free mass index in controls solely. Protein intake was associated with muscle strength (handgrip strength and 30SCT) in MD patients but not in controls. Twenty-seven MD patients (73%) were malnourished, and 5 (14%) were classified as sarcopenic. CONCLUSIONS: Muscle strength is related to body composition and protein intake in MD patients. This, in combination with the high incidence of both malnutrition and sarcopenia, warrants individual nutrition assessment in MD patients.


Assuntos
Doenças Mitocondriais , Sarcopenia , Absorciometria de Fóton , Adulto , Composição Corporal , Índice de Massa Corporal , Estudos Transversais , Feminino , Força da Mão , Humanos , Masculino
13.
JPEN J Parenter Enteral Nutr ; 45(1): 158-164, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32696575

RESUMO

AIM: We aimed to identify the optimal method to estimate total energy expenditure (TEE) in mitochondrial disease (MD) patients. METHODS: Resting energy expenditure (REE) was measured in MD patients carrying the m3243A>G mutation using indirect calorimetry (IC) and compared with results of 21 predictive equations (PEs) for REE and with REE-IC measurements in healthy controls. Physical activity level (PAL) was measured using accelerometery (SenseWear) and compared with a fixed average PAL (1.4) as well as patients' self-estimated activity levels. TEE was calculated as REE-IC × PAL SenseWear and compared with usual care and energy recommendations for healthy adults. RESULTS: Thirty-eight MD patients (age: 48 ± 13 years; body mass index 24 ± 4 kg/m2 ; male 20%) and 25 matched controls were included. The accuracy of most PEs was between 63% and 76%. The difference in REE-IC in healthy controls (1532 ± 182 kcal) and MD patients (1430 ± 221) was borderline not significant (P = .052). Patients' estimations PAL were 18%-34% accurate at the individual level. The fixed activity factor was 53% accurate. Patients overestimated their PAL. Usual care predicted TEE accurately in only 32% of patients. CONCLUSION: TEE is lower in these MD patients than the recommendations for healthy adults because of their lower physical activity. In MD patients, 6 PEs for REE provide a reliable alternative for IC, with an accuracy of 71%-76%. As PAL is highly variable and not reliably estimated by patients, measurement of PAL using accelerometery is recommended in this population.


Assuntos
DNA Mitocondrial , Metabolismo Energético , Adulto , Metabolismo Basal , Índice de Massa Corporal , Calorimetria Indireta , DNA Mitocondrial/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Necessidades Nutricionais
14.
J Clin Apher ; 36(3): 340-347, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33368569

RESUMO

BACKGROUND AND AIMS: Standard treatment for naïve hereditary hemochromatosis patients consists of phlebotomy or a personalized erythrocytapheresis. Erythrocytapheresis is more efficient, but infrequently used because of perceived costs and specialized equipment being needed. The main aim of our study was to develop a model that predicts the number of initial treatment procedures for both treatment methods. This information may help the clinician to select the optimal treatment modality for the individual patient. METHODS: We analyzed retrospective data of 125 newly diagnosed patients (C282Y homozygous), treated either with phlebotomy (n = 54) or erythrocytapheresis (n = 71) until serum ferritin (SF) reached levels ≤100 µg/L. To estimate the required number of treatment procedures multiple linear regression analysis was used for each treatment method separately. RESULTS: The linear regression model with the best predictive quality (R2  = 0.74 and 0.73 for erythrocytapheresis and phlebotomy respectively) included initial SF, initial hemoglobin (Hb) level, age, and BMI, where initial SF was independently related to the total number of treatment procedures for both treatment methods. The prediction error expressed in RMSPE and RMSDR was lower for erythrocytapheresis than for phlebotomy (3.8 and 4.1 vs 7.0 and 8.0 respectively), CONCLUSIONS: Although the prediction error of the developed model was relatively large, the model may help the clinician to choose the most optimal treatment method for an individual patient. Generally erythrocytapheresis halves the number of treatment procedures for all patients, where the largest reduction (between 55% and 64%) is reached in patients with an initial Hb level ≥ 9 mmol/L (14.5 g/dL). ClinicalTrials.gov number NCT00202436.

15.
Mol Genet Metab ; 131(4): 370-379, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33199205

RESUMO

BACKGROUND: Classical Galactosemia (CG) is an inherited disorder of galactose metabolism caused by a deficiency of the galactose-1-phosphate uridylyltransferase (GALT) enzyme resulting in neurocognitive complications. As in many Inborn Errors of Metabolism, the metabolic pathway of CG is well-defined, but the pathophysiology and high variability in clinical outcome are poorly understood. The aim of this study was to investigate structural changes of the brain of CG patients on MRI and their association with clinical outcome. METHODS: In this prospective cohort study an MRI protocol was developed to evaluate gray matter (GM) and white matter (WM) volume of the cerebrum and cerebellum, WM hyperintensity volume, WM microstructure and myelin content with the use of conventional MRI techniques, diffusion tensor imaging (DTI) and quantitative T1 mapping. The association between several neuroimaging parameters and both neurological and intellectual outcome was investigated. RESULTS: Twenty-one patients with CG (median age 22 years, range 8-47) and 24 controls (median age 30, range 16-52) were included. Compared to controls, the WM of CG patients was lower in volume and the microstructure of WM was impaired both in the whole brain and corticospinal tract (CST) and the lower R1 values of WM, GM and the CST were indicative of less myelin. The volume of WM lesions were comparable between patients and controls. The 9/16 patients with a poor neurological outcome (defined as the presence of a tremor and/or dystonia), demonstrated a lower WM volume, an impaired WM microstructure and lower R1 values of the WM indicative of less myelin content compared to 7/16 patients without movement disorders. In 15/21 patients with a poor intellectual outcome (defined as an IQ < 85) both GM and WM were affected with a lower cerebral and cerebellar WM and GM volume compared to 6/21 patients with an IQ ≥ 85. Both the severity of the tremor (as indicated by the Tremor Rating Scale) and IQ (as continuous measure) were associated with several neuroimaging parameters such as GM volume, WM volume, CSF volume, WM microstructure parameters and R1 values of GM and WM. CONCLUSION: In this explorative study performed in patients with Classical Galactosemia, not only WM but also GM pathology was found, with more severe brain abnormalities on MRI in patients with a poor neurological and intellectual outcome. The finding that structural changes of the brain were associated with the severity of long-term complications indicates that quantitative MRI techniques could be of use to explain neurological and cognitive dysfunction as part of the disease spectrum. Based on the clinical outcome of patients, the absence of widespread WM lesions and the finding that both GM and WM are affected, CG could be primarily a GM disease with secondary damage to the WM as a result of neuronal degeneration. To investigate this further the course of GM and WM should be evaluated in longitudinal research, which could also clarify if CG is a neurodegenerative disease.


Assuntos
Galactosemias/metabolismo , Substância Cinzenta/metabolismo , UTP-Hexose-1-Fosfato Uridililtransferase/genética , Substância Branca/metabolismo , Adolescente , Adulto , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Cerebelo/patologia , Cérebro/diagnóstico por imagem , Cérebro/metabolismo , Cérebro/patologia , Feminino , Galactosemias/diagnóstico por imagem , Galactosemias/genética , Galactosemias/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Neuroimagem/métodos , UTP-Hexose-1-Fosfato Uridililtransferase/metabolismo , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto Jovem
17.
Brain Commun ; 2(1): fcaa006, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32954279

RESUMO

Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was <85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in N-glycan peaks were found between controls and patients. However, no significant differences in either N-glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome < 85) and normal intellectual outcome (intellectual outcome ≥ 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients (P < 0.0005). Qualitative analysis of the MRI's demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and N-glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abnormalities and clinical outcome should be further investigated by quantitative analysis of the MR images. The variability in clinical outcome necessitates individual and standardized evaluation of all classical galactosemia patients.

18.
Mitochondrion ; 53: 128-132, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32464279

RESUMO

Mitochondrial respiratory chain dysfunction may be predisposing for the development of migraine, reflected in high migraine prevalence in patients with mitochondrial disease. Prevalence and impact of migraine in patients with proven mitochondrial disease and the current treatment efficacy were studied using online questionnaires. Patients were selected at the Internal Medicine Department. Headache was reported by 34 (55%) out of 62 patients. Migraine-criteria were met by 85% of them. Efficacy of migraine treatment was achieved in 4 patients. Given the high prevalence of migraine and current treatment insufficiency, migraine is a major threat of quality of life patients with mitochondrial disease.


Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/epidemiologia , Doenças Mitocondriais/complicações , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/etiologia , Doenças Mitocondriais/genética , Países Baixos/epidemiologia , Prevalência , Qualidade de Vida , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
19.
Orphanet J Rare Dis ; 15(1): 76, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209104

RESUMO

BACKGROUND: Mitochondrial diseases (MD) are generally serious and progressive, inherited metabolic diseases. There is a high comorbidity of anxiety and depression and limitations in daily functioning. The complexity and duration of the diagnostic process and lack of knowledge about prognosis leads to uncertainty. In this study, we investigated the psychological well-being of children who are suspected for MD and their parents. METHODS: In total 122 children suspected for MD and their parents, received questionnaires as part of standard clinical investigation. RESULTS: Parent proxy report revealed a lower quality of life (QoL) compared to norms and even more physical problems compared to chronically ill patients. They also reported more behavioral problems in general and more internalizing problems compared to the norms. Most frequent reported somatic complaints were tiredness and pain. Parents did not report enhanced levels of stress regarding parenting and experienced sufficient social support. At the end of the diagnostic process, 5.7% of the children received the genetically confirmed diagnosis of MD, 26% showed non-conclusive abnormalities in the muscle biopsy, 54% did not receive any diagnosis, and the remaining received other diagnoses. Strikingly, children without a diagnosis showed equally QoL and behavioral problems as children with a diagnosis, and even more internalizing problems. CONCLUSIONS: This study highlights the psychological concerns of children with a suspicion of MD. It is important to realize that as well as children with a confirmed diagnosis, children without a diagnosis are vulnerable since explanation for their complaints is still lacking.


Assuntos
Doenças Mitocondriais , Qualidade de Vida , Criança , Humanos , Doenças Mitocondriais/diagnóstico , Poder Familiar , Pais , Apoio Social , Inquéritos e Questionários
20.
Orphanet J Rare Dis ; 15(1): 42, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32033562

RESUMO

BACKGROUND: Despite early diagnosis and treatment, Classical Galactosemia (CG) patients frequently develop long-term complications, such as cognitive impairment. Available literature primarily reports on general intellectual abilities and shows a substantially lower Full Scale Intelligence Quotient (FSIQ) in CG patients than in the general population. Both problems in social functioning as well as internalizing problems are often reported in CG patients. The combination of intelligence, cognitive functioning, behavior and social functioning has not been studied systematically in CG patients. METHODS: To determine if CG patients demonstrate a specific neuropsychological and psychosocial profile, we investigated intelligence, functioning on multiple cognitive domains, behavior and social functioning with a comprehensive neuropsychological test battery and questionnaires (self- and proxy-reported). RESULTS: The data of 48 patients, aged 4-47 years are reported. FSIQ ranged from 45 to 103 (mean 77 ± 14). A negative correlation between age and FSIQ was demonstrated (p = 0.037) which resulted directly from the inclusion of four young 'milder' patients detected by newborn screening (NBS) with an expected better clinical outcome. Compared to normative data, patients had significantly lower but highly variable scores on all cognitive domains, especially on tests requiring mental speed. In the context of the FSIQ, 43% of the cognitive test results exceeded IQ based expectations. Overall, the patients' scores on social functioning were in the normal range but internalizing problems were frequently reported. In our cohort, an early initiation of dietary treatment due to NBS or family screening did not result in a more favorable neuropsychological outcome. CONCLUSIONS: In this study, we demonstrated that as a cohort, CG patients have a below average intelligence and impaired cognitive functioning without a distinctive neuropsychological profile. The effect of age on neurocognitive functioning should be assessed in longitudinal studies. Social functioning was not impaired, but patients may be at risk for internalizing problems. Considering the large variability in cognitive, behavioral and social functioning and the finding that cognitive outcomes may exceed IQ based expectations, an individual evaluation and follow-up is warranted in all CG patients to ensure timely support if needed.


Assuntos
Galactosemias , Cognição , Humanos , Recém-Nascido , Inteligência , Testes Neuropsicológicos , Funcionamento Psicossocial
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...