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1.
Mol Genet Metab ; 131(3): 316-324, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33127324

RESUMEN

Propionic acidemia (PA) is caused by inherited deficiency of mitochondrial propionyl-CoA carboxylase (PCC) and results in significant neurodevelopmental and cardiac morbidity. However, relationships among therapeutic intervention, biochemical markers, and disease progression are poorly understood. Sixteen individuals homozygous for PCCB c.1606A > G (p.Asn536Asp) variant PA participated in a two-week suspension of therapy. Standard metabolic markers (plasma amino acids, blood spot methylcitrate, plasma/urine acylcarnitines, urine organic acids) were obtained before and after stopping treatment. These same markers were obtained in sixteen unaffected siblings. Echocardiography and electrocardiography were obtained from all subjects. We characterized the baseline biochemical phenotype of untreated PCCB c.1606A > G homozygotes and impact of treatment on PCC deficiency biomarkers. Therapeutic regimens varied widely. Suspension of therapy did not significantly alter branched chain amino acid levels, their alpha-ketoacid derivatives, or urine ketones. Carnitine supplementation significantly increased urine propionylcarnitine and its ratio to total carnitine. Methylcitrate blood spot and urine levels did not correlate with other biochemical measures or cardiac outcomes. Treatment of PCCB c.1606A > G homozygotes with protein restriction, prescription formula, and/or various dietary supplements has a limited effect on core biomarkers of PCC deficiency. These patients require further longitudinal study with standardized approaches to better understand the relationship between biomarkers and disease burden.


Asunto(s)
Ligasas de Carbono-Carbono/genética , Corazón/fisiopatología , Trastornos del Neurodesarrollo/genética , Acidemia Propiónica/genética , Ácidos/sangre , Ácidos/orina , Adolescente , Adulto , Aminoácidos/sangre , Aminoácidos/orina , Biomarcadores/sangre , Biomarcadores/orina , Ligasas de Carbono-Carbono/sangre , Ligasas de Carbono-Carbono/orina , Carnitina/sangre , Carnitina/orina , Niño , Preescolar , Ecocardiografía , Femenino , Corazón/diagnóstico por imagen , Humanos , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación/genética , Trastornos del Neurodesarrollo/sangre , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/orina , Compuestos Orgánicos/sangre , Compuestos Orgánicos/orina , Fenotipo , Acidemia Propiónica/sangre , Acidemia Propiónica/diagnóstico por imagen , Acidemia Propiónica/orina , Adulto Joven
2.
Cereb Cortex ; 30(4): 2358-2371, 2020 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-31812984

RESUMEN

2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1α heterozygous mice (Nrxn1α+/- mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1α heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic "rich club" and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic "rich club" regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1α+/- mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1α deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1α deletion may be NMDA receptor-dependent.


Asunto(s)
Proteínas de Unión al Calcio/genética , Ketamina/administración & dosificación , Moléculas de Adhesión de Célula Nerviosa/genética , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/genética , Corteza Prefrontal/diagnóstico por imagen , Tálamo/diagnóstico por imagen , Animales , Modelos Animales de Enfermedad , Eliminación de Gen , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/efectos de los fármacos , Trastornos del Neurodesarrollo/tratamiento farmacológico , Corteza Prefrontal/efectos de los fármacos , Tálamo/efectos de los fármacos
3.
J Child Neurol ; 34(12): 778-781, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31282308

RESUMEN

BACKGROUND: WARS2 encodes a tryptophanyl tRNA synthetase, which is involved in mitochondrial protein synthesis. Biallelic mutations in WARS2 are rare and have been associated with a spectrum of clinical presentations, including neurodevelopmental disorder with abnormal movements, lactic acidosis with or without seizures (NEMMLAS). CASE PRESENTATION: Here we present the case of an 8-year-old girl with ataxia and parkinsonism with periventricular white matter abnormalities on magnetic resonance imaging (MRI) and global developmental delay. The initial investigations revealed an elevated lactate level. Extensive metabolic testing, including a muscle biopsy, was inconclusive. Cerebrospinal fluid (CSF) neurotransmitter levels were low; however, a trial of levodopa was unremarkable. The chromosomal microarray and initial ataxia gene panel was normal. Zinc supplementation for a heterozygous variant of unknown significance in the CP gene on the ataxia exome panel was not effective in treating her symptoms. Reanalysis of the ataxia exome panel highlighted biallelic mutations in WARS2, which lead to the diagnosis of neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS). This lead to parental genetic testing, redirected therapy, and helped to expand the symptomology of this rare condition. CONCLUSION: Here we emphasize the importance of imminent and repeat expanded genetic testing to ensure early diagnosis and treatment for rare pediatric disorders. The patient is being trialed on a mitochondrial cocktail in an attempt to compensate for defects in mitochondrial protein synthesis associated with this variant. Longitudinal monitoring of disease manifestation will help establish the currently unknown natural history of this condition.


Asunto(s)
Acidosis Láctica/diagnóstico , Discinesias/diagnóstico , Trastornos del Neurodesarrollo/diagnóstico , Convulsiones/diagnóstico , Triptófano-ARNt Ligasa/genética , Acidosis Láctica/diagnóstico por imagen , Acidosis Láctica/genética , Encéfalo/diagnóstico por imagen , Niño , Discinesias/diagnóstico por imagen , Discinesias/genética , Femenino , Humanos , Imagen por Resonancia Magnética , Mitocondrias/genética , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/genética , Fenotipo , Convulsiones/diagnóstico por imagen , Convulsiones/genética , Síndrome , Sustancia Blanca/diagnóstico por imagen
4.
Hum Reprod ; 32(6): 1230-1237, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28453631

RESUMEN

STUDY QUESTION: CAN WE assess human prenatal cerebellar growth from the first until the third trimester of pregnancy and create growth trajectories to investigate associations with periconceptional maternal and fetal characteristics? SUMMARY ANSWER: Prenatal growth trajectories of the human cerebellum between 9 and 32 weeks gestational age (GA) were created using three-dimensional ultrasound (3D-US) and show negative associations with pre-pregnancy and early first trimester BMI calculated from self-reported and standardized measured weight and height, respectively. WHAT IS KNOWN ALREADY: The cerebellum is essential for normal neurodevelopment and abnormal cerebellar development has been associated with neurodevelopmental impairments and psychiatric diseases. Cerebellar development is particularly susceptible to exposures during the prenatal period, including maternal folate status, smoking habit and alcohol consumption. STUDY DESIGN, SIZE, DURATION: From 2013 until 2015, we included 182 singleton pregnancies during the first trimester as a subgroup in a prospective periconception cohort with follow-up until birth. For the statistical analyses, we selected 166 pregnancies ending in live born infants without congenital malformations. PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured transcerebellar diameter (TCD) at 9, 11, 22, 26 and 32 weeks GA on ultrasound scans. Growth rates were calculated and growth trajectories of the cerebellum were created. Linear mixed models were used to estimate associations between cerebellar growth and maternal age, parity, mode of conception, geographic origin, pre-pregnancy and first trimester BMI, periconceptional smoking, alcohol consumption, timing of folic acid supplement initiation and fetal gender. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 166 pregnancies provided 652 (87%) ultrasound images eligible for TCD measurements. Cerebellar growth rates increased with advancing GA being 0.1691 mm/day in the first trimester, 0.2336 mm/day in the second trimester and 0.2702 mm/day in the third trimester. Pre-pregnancy BMI, calculated from self-reported body weight and height, was significantly associated with decreased cerebellar growth trajectories (ß = -0.0331 mm, 95% CI = -0.0638; -0.0024, P = 0.035). A similar association was found between cerebellar growth trajectories and first trimester BMI, calculated from standardized measurements of body weight and height (ß = -0.0325, 95% CI = -0.0642; -0.0008, P = 0.045, respectively). LIMITATIONS, REASONS FOR CAUTION: As the study population largely consisted of tertiary hospital patients, external validity should be studied in the general population. Whether small differences in prenatal cerebellar growth due to a higher pre-pregnancy and first trimester BMI have consequences for neurodevelopmental outcome needs further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Our findings further substantiate previous evidence for the detrimental impact of a higher maternal BMI on neurodevelopmental health of offspring in later life. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Department of Obstetrics and Gynecology, Erasmus MC University Medical Centre and Sophia Children's Hospital Fund, Rotterdam, The Netherlands (SSWO grant number 644). No competing interests are declared.


Asunto(s)
Cerebelo/diagnóstico por imagen , Trastornos del Neurodesarrollo/diagnóstico por imagen , Neurogénesis , Obesidad/fisiopatología , Sobrepeso/fisiopatología , Complicaciones del Embarazo/fisiopatología , Adulto , Índice de Masa Corporal , Cerebelo/embriología , Estudios de Cohortes , Femenino , Edad Gestacional , Humanos , Imagenología Tridimensional , Estudios Longitudinales , Persona de Mediana Edad , Países Bajos/epidemiología , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/etiología , Neuroimagen , Embarazo , Estudios Prospectivos , Riesgo , Ultrasonografía Prenatal , Adulto Joven
5.
PLoS One ; 11(5): e0156064, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27223474

RESUMEN

Very low birth weight is associated with long term neurodevelopmental complications. Macroscopic brain abnormalities in prematurity survivors have been investigated in several studies. However, there is limited data regarding local cerebral metabolic status and neurodevelopmental outcomes. The purpose of this study was to characterize the relationship between proton magnetic resonance spectra in basal ganglia, frontal white matter and frontoinsular gray matter, neurodevelopmental outcomes assessed with the Leiter scale and the Developmental Test of Visual Perception and selected socioeconomic variables in a cohort of very low birth weight children at the age of four. Children were divided in three groups based on the severity of neurodevelopmental impairment. There were no differences in spectroscopy in basal ganglia and frontal white matter between the groups. Lower concentrations of N-acetylaspartate (NAA), choline (Cho) and myoinositol (mI) were observed in the frontoinsular cortex of the left hemisphere in children with neurodevelopmental impairment compared to children with normal neurodevelopmental outcomes. Higher parental education, daycare attendance and breastfeeding after birth were associated with more favorable neurodevelopmental prognosis, whereas rural residence was more prevalent in children with moderate and severe impairment. Our study demonstrates the role of long term neurometabolic disruption in the left frontoinsular cortex and selected socioeconomic variables in determination of neurodevelopmental prognosis in prematurity survivors.


Asunto(s)
Ácido Aspártico/análogos & derivados , Colina/metabolismo , Lóbulo Frontal , Sustancia Gris , Recién Nacido de muy Bajo Peso , Inositol/metabolismo , Trastornos del Neurodesarrollo , Espectroscopía de Protones por Resonancia Magnética , Ácido Aspártico/metabolismo , Preescolar , Femenino , Estudios de Seguimiento , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/metabolismo , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/metabolismo , Humanos , Recién Nacido , Masculino , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/metabolismo , Factores de Riesgo , Factores Socioeconómicos
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