RESUMEN
l-2-hydroxyglutarate dehydrogenase (L2HGDH) is a mitochondrial membrane-associated metabolic enzyme, which catalyzes the oxidation of l-2-hydroxyglutarate (l-2-HG) to 2-oxoglutarate (2-OG). Mutations in human L2HGDH lead to abnormal accumulation of l-2-HG, which causes a neurometabolic disorder named l-2-hydroxyglutaric aciduria (l-2-HGA). Here, we report the crystal structures of Drosophila melanogaster L2HGDH (dmL2HGDH) in FAD-bound form and in complex with FAD and 2-OG and show that dmL2HGDH exhibits high activity and substrate specificity for l-2-HG. dmL2HGDH consists of an FAD-binding domain and a substrate-binding domain, and the active site is located at the interface of the two domains with 2-OG binding to the re-face of the isoalloxazine moiety of FAD. Mutagenesis and activity assay confirmed the functional roles of key residues involved in the substrate binding and catalytic reaction and showed that most of the mutations of dmL2HGDH equivalent to l-2-HGA-associated mutations of human L2HGDH led to complete loss of the activity. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of L2HGDH and provide insights into the functional roles of human L2HGDH mutations in the pathogeneses of l-2-HGA.
Asunto(s)
Oxidorreductasas de Alcohol , Encefalopatías Metabólicas Innatas , Drosophila melanogaster , Modelos Moleculares , Animales , Humanos , Oxidorreductasas de Alcohol/química , Oxidorreductasas de Alcohol/metabolismo , Encefalopatías Metabólicas Innatas/enzimología , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/fisiopatología , Drosophila melanogaster/enzimología , Glutaratos/metabolismo , Mutación , Dominio Catalítico/genética , Especificidad por Sustrato/genética , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
Episodic encephalopathy due to mutations in the thiamine pyrophosphokinase 1 (TPK1) gene is a rare autosomal recessive metabolic disorder. Patients reported so far have onset in early childhood of acute encephalopathic episodes, which result in a progressive neurologic dysfunction including ataxia, dystonia, and spasticity. Here, we report the case of an infant with TPK1 deficiency (compound heterozygosity for two previously described pathogenic variants) presenting with two encephalopathic episodes and clinical stabilization under oral thiamine and biotin supplementation. In contrast to other reported cases, our patient showed an almost normal psychomotor development, which might be due to an early diagnosis and subsequent therapy.
Asunto(s)
Encefalopatías Metabólicas Innatas/dietoterapia , Tiamina Pirofosfoquinasa/deficiencia , Tiamina/farmacología , Complejo Vitamínico B/farmacología , Biotina/administración & dosificación , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/fisiopatología , Suplementos Dietéticos , Humanos , Lactante , Tiamina/administración & dosificación , Complejo Vitamínico B/administración & dosificaciónRESUMEN
Glucose transporter type I deficiency syndrome (GLUT1DS) is an encephalopathic disorder due to a chronic insufficient transport of glucose into the brain. PET studies in GLUT1DS documented a widespread cortico-thalamic hypometabolism and a signal increase in the basal ganglia, regardless of age and clinical phenotype. Herein, we captured the pattern of functional connectivity of distinct striatal, cortical, and cerebellar regions in GLUT1DS (10 children, eight adults) and in healthy controls (HC, 19 children, 17 adults) during rest. Additionally, we explored for regional connectivity differences in GLUT1 children versus adults and according to the clinical presentation. Compared to HC, GLUT1DS exhibited increase connectivity within the basal ganglia circuitries and between the striatal regions with the frontal cortex and cerebellum. The excessive connectivity was predominant in patients with movement disorders and in children compared to adults, suggesting a correlation with the clinical phenotype and age at fMRI study. Our findings highlight the primary role of the striatum in the GLUT1DS pathophysiology and confirm the dependency of symptoms to the patients' chronological age. Despite the reduced chronic glucose uptake, GLUT1DS exhibit increased connectivity changes in regions highly sensible to glycopenia. Our results may portrait the effect of neuroprotective brain strategy to overcome the chronic poor energy supply during vulnerable ages.
Asunto(s)
Ganglios Basales , Encefalopatías Metabólicas Innatas , Cerebelo , Transportador de Glucosa de Tipo 1/deficiencia , Desarrollo Humano , Red Nerviosa , Neuroprotección , Corteza Prefrontal , Adolescente , Adulto , Ganglios Basales/diagnóstico por imagen , Ganglios Basales/metabolismo , Ganglios Basales/fisiopatología , Encefalopatías Metabólicas Innatas/diagnóstico por imagen , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/metabolismo , Encefalopatías Metabólicas Innatas/fisiopatología , Cerebelo/diagnóstico por imagen , Cerebelo/metabolismo , Cerebelo/fisiopatología , Niño , Enfermedad Crónica , Epilepsia/diagnóstico por imagen , Epilepsia/etiología , Epilepsia/metabolismo , Epilepsia/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos del Movimiento/diagnóstico por imagen , Trastornos del Movimiento/etiología , Trastornos del Movimiento/metabolismo , Trastornos del Movimiento/fisiopatología , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/metabolismo , Red Nerviosa/fisiopatología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Adulto JovenRESUMEN
BACKGROUND: Variants in the SLC25A1 gene are associated with a severe neurometabolic disease, D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). A report in 2014 presented the first account of congenital myasthenic syndrome (CMS) with mild intellectual disability (ID) caused by SLC25A1. To date, only two missense variants in SLC25A1 have been linked to CMS. CASE PRESENTATIONS: A Chinese boy presented fatigable muscular weakness, myasthenic crisis, epilepsy and developmental delay along with mild elevation of urinary 2-ketoglutarate (2-KG) and lactic acid levels. He showed a partial response to pyridostigmine. Genetic analysis using trio whole-exome sequencing (WES), Sanger sequencing, and cosegregation analyses revealed two novel pathogenic variants of SLC25A1 (c.628C > T, p.R210X; c.145G > A, p.V49M). CONCLUSIONS: We report a boy who carries novel compound heterozygous variants of SLC25A1 and presents a phenotype intermediate between CMS and D/L-2-HGA. This case expands the range of known phenotypes and genotypes associated with SLC25A1.
Asunto(s)
Encefalopatías Metabólicas Innatas , Proteínas Mitocondriales/genética , Mutación Missense/genética , Síndromes Miasténicos Congénitos , Transportadores de Anión Orgánico/genética , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/fisiopatología , Niño , Humanos , Masculino , Síndromes Miasténicos Congénitos/genética , Síndromes Miasténicos Congénitos/fisiopatología , FenotipoRESUMEN
The term "cerebral palsy mimic" is used to describe a number of neurogenetic disorders that may present with motor symptoms in early childhood, resulting in a misdiagnosis of cerebral palsy. Cerebral palsy describes a heterogeneous group of neurodevelopmental disorders characterized by onset in infancy or early childhood of motor symptoms (including hypotonia, spasticity, dystonia, and chorea), often accompanied by developmental delay. The primary etiology of a cerebral palsy syndrome should always be identified if possible. This is particularly important in the case of genetic or metabolic disorders that have specific disease-modifying treatment. In this article, we discuss clinical features that should alert the clinician to the possibility of a cerebral palsy mimic, provide a practical framework for selecting and interpreting neuroimaging, biochemical, and genetic investigations, and highlight selected conditions that may present with predominant spasticity, dystonia/chorea, and ataxia. Making a precise diagnosis of a genetic disorder has important implications for treatment, and for advising the family regarding prognosis and genetic counseling. © 2019 International Parkinson and Movement Disorder Society.
Asunto(s)
Parálisis Cerebral/diagnóstico , Diagnóstico Diferencial , Trastornos del Movimiento/diagnóstico , Adenilil Ciclasas/genética , Ataxia/fisiopatología , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/fisiopatología , Ataxia Telangiectasia/terapia , Encéfalo/diagnóstico por imagen , Encefalopatías Metabólicas Innatas/diagnóstico , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/fisiopatología , Encefalopatías Metabólicas Innatas/terapia , Errores Innatos del Metabolismo de los Carbohidratos/diagnóstico , Errores Innatos del Metabolismo de los Carbohidratos/genética , Errores Innatos del Metabolismo de los Carbohidratos/fisiopatología , Errores Innatos del Metabolismo de los Carbohidratos/terapia , Parálisis Cerebral/fisiopatología , Corea/fisiopatología , Creatina/deficiencia , Creatina/genética , Discinesias/diagnóstico , Discinesias/genética , Discinesias/fisiopatología , Discinesias/terapia , Distonía/fisiopatología , Deficiencia de Ácido Fólico/diagnóstico , Deficiencia de Ácido Fólico/genética , Deficiencia de Ácido Fólico/fisiopatología , Deficiencia de Ácido Fólico/terapia , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Humanos , Hiperargininemia/diagnóstico , Hiperargininemia/genética , Hiperargininemia/fisiopatología , Hiperargininemia/terapia , Síndrome de Lesch-Nyhan/diagnóstico , Síndrome de Lesch-Nyhan/genética , Síndrome de Lesch-Nyhan/fisiopatología , Síndrome de Lesch-Nyhan/terapia , Imagen por Resonancia Magnética , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/genética , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Discapacidad Intelectual Ligada al Cromosoma X/terapia , Proteínas de Transporte de Monosacáridos/deficiencia , Proteínas de Transporte de Monosacáridos/genética , Trastornos del Movimiento/genética , Trastornos del Movimiento/fisiopatología , Trastornos del Movimiento/terapia , Deficiencia Múltiple de Carboxilasa/diagnóstico , Deficiencia Múltiple de Carboxilasa/genéticaRESUMEN
Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations.
Asunto(s)
Encefalopatías Metabólicas Innatas/genética , Disfunción Cognitiva/genética , Creatina/deficiencia , Discapacidad Intelectual/genética , Proteínas de Transporte de Membrana/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/deficiencia , Envejecimiento/genética , Envejecimiento/patología , Animales , Encéfalo/fisiopatología , Encefalopatías Metabólicas Innatas/fisiopatología , Disfunción Cognitiva/fisiopatología , Creatina/genética , Modelos Animales de Enfermedad , Humanos , Discapacidad Intelectual/fisiopatología , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Ratones , Ratones Transgénicos , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genéticaRESUMEN
BACKGROUND: X-linked creatine transporter deficiency (OMIM#300036,CRTR-D) is characterized by cerebral creatine deficiency, intellectual disabilities, severe speech impairment, seizures and behavioral problems. Mutations in the creatine transporter gene SLC6A8, a member of the solute-carrier family 6 mapped to Xq28, have been reported to cause the creatine transporter deficiency. CASE PRESENTATION: The proband presented at 5 yrs. 1 month of age with delays in intellectual and development, seizures and behavioral problems. A novel missense mutation, c.1181C > A (p.Thr394Lys), in the SLC6A8 gene (NM_005629.3) was detected via targeted exome sequencing, and then validated by Sanger sequencing. Multiple in silico variant effect analysis methods, including SIFT, PolyPhen2, PROVEAN, and Mutation Taster predicted that this variant was likely damaging or diseasing-causing. This hemizygous variation was also identified in the affected brother with the same clinical condition and inherited from the heterozygous carrier mother. The diagnosis was suggested by increased urinary creatine/creatinine (Cr:Crn) ratio and markedly reduced creatine content peak by brain proton magnetic resonance spectroscopy (MRS). The proband's mother became pregnant with a 3rd sibling, in whom the Sanger sequencing result of c.1181C > A was negative. CONCLUSION: The novel mutation c.1181C > A in the SLC6A8 gene reported in a Chinese family has expanded the mutation spectrum of CRTR-D. The combination of powerful new technologies such as targeted exome sequencing with thorough systematic clinical evaluation of patients will improve the diagnostic yield, and assist in genetic counselling and prenatal diagnosis for suspected genetic disorders.
Asunto(s)
Encefalopatías Metabólicas Innatas/genética , Creatina/deficiencia , Discapacidad Intelectual/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Mutación Missense , Proteínas del Tejido Nervioso/genética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/deficiencia , Convulsiones/genética , Pueblo Asiatico , Secuencia de Bases , Encefalopatías Metabólicas Innatas/etnología , Encefalopatías Metabólicas Innatas/fisiopatología , Encefalopatías Metabólicas Innatas/orina , Preescolar , Cromosomas Humanos Par 10/química , Creatina/genética , Creatina/orina , Creatinina/orina , Análisis Mutacional de ADN , Exoma , Expresión Génica , Humanos , Discapacidad Intelectual/etnología , Discapacidad Intelectual/fisiopatología , Discapacidad Intelectual/orina , Herencia Materna , Discapacidad Intelectual Ligada al Cromosoma X/etnología , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Discapacidad Intelectual Ligada al Cromosoma X/orina , Linaje , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/orina , Convulsiones/etnología , Convulsiones/fisiopatología , Convulsiones/orina , HermanosRESUMEN
OBJECTIVES: A family with homocarnosinosis was reported in the literature in 1976. Three affected siblings had spastic paraplegia, retinitis pigmentosa, mental retardation, and cerebrospinal fluid (CSF) homocarnosine concentrations 20 times higher than in controls. Based on the clinical findings and new genetic techniques, we have been able to establish a precise genetic diagnosis. METHOD: The medical records were re-evaluated, and genetic analyses were performed post-mortem in this original family. SNP array-based whole genome homozygosity mapping and Sanger sequencing of the SPG11 gene were performed. Seven additional Norwegian SPG11 patients and their disease-causing variants and clinical findings were evaluated. Homocarnosine levels in CSF were measured in four of these seven patients. RESULTS: A homozygous pathogenic splice-site variant in the SPG11 gene, c.2316 + 1G>A, was found. The clinical findings in the original family correlate with the heterogeneous SPG11 phenotype. The same variant was found in seven other Norwegian SPG11 patients, unrelated to the original family, either as homozygous or compound heterozygous constellation. Normal homocarnosine levels were found in the CSF of all unrelated SPG11 patients. CONCLUSIONS: A re-evaluation of the clinical symptoms and findings in the original family correlates with the SPG11 phenotype. The increased levels of homocarnosine do not seem to be a biomarker for SPG11 in our patients. Homocarnosinosis is still a biochemical aberration with unknown clinical significance.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Encefalopatías Metabólicas Innatas/genética , Dipeptidasas/deficiencia , Proteínas/genética , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/patología , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Encefalopatías Metabólicas Innatas/patología , Encefalopatías Metabólicas Innatas/fisiopatología , Dipeptidasas/genética , Femenino , Estudios de Seguimiento , Humanos , Masculino , Mutación , Linaje , FenotipoRESUMEN
Anophthalmia and microphthalmia are the most severe malformations of the eye, referring to a congenital absence, and a reduced size of the eyeball respectively. More than 20 genes have been shown to be mutated in patients with syndromic and non-syndromic forms of anophthalmia-microphthalmia. In a recent study combining autozygome and exome analysis, a homozygous loss of function mutation in TENM3 (previously named ODZ3) was reported in two siblings with isolated bilateral colobomatous microphthalmia from a consanguineous Saudi family. Herein, we report a third patient (not related to the previously reported family) with bilateral colobomatous microphthalmia and developmental delay in whom genetic studies identified a homozygous TENM3 splicing mutation c.2968-2A>T (p.Val990Cysfs*13). This report supports the association of TENM3 mutations with colobomatous microphthalmia and expands the phenotypic spectrum associated with mutations in this gene. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Encefalopatías Metabólicas Innatas/genética , Coloboma/genética , Opacidad de la Córnea/genética , Discapacidades del Desarrollo/genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Microcefalia/genética , Microftalmía/genética , Proteínas del Tejido Nervioso/genética , Empalme Alternativo/genética , Encefalopatías Metabólicas Innatas/fisiopatología , Niño , Coloboma/fisiopatología , Opacidad de la Córnea/fisiopatología , Discapacidades del Desarrollo/fisiopatología , Homocigoto , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Microcefalia/fisiopatología , Microftalmía/fisiopatología , MutaciónRESUMEN
Bosma arhinia microphthalmia syndrome (Bosma syndrome)(OMIM 603457) is a congenital condition characterized by microphthalmia with coloboma, arhinia and endocrine findings in the setting of normal intelligence and brain structure. This condition is quite rare with fewer than 50 case reports and series. Although pathogenesis is presumed to be genetic, the cause remains unknown. We report an individual with Bosma syndrome who had bilateral colobomatous microphthalmia, arhinia, high arched palate, mild ear malformations, and hypogonadotropic hypogonadism requiring growth hormone treatment in childhood, and normal intelligence. Clinical evaluation was significant for a geometrically abnormal aorta with effacement of the sinotubular ridge, a finding not previously reported in this condition. An MRI revealed absent olfactory bulbs. Suggested criteria for diagnosis of Bosma should include arhinia, hypoplastic maxilla, normal cognition, and hypogonadotropic hypogonadism in males.
Asunto(s)
Anomalías Múltiples/fisiopatología , Atresia de las Coanas/fisiopatología , Coloboma/fisiopatología , Microftalmía/fisiopatología , Nariz/anomalías , Anomalías Múltiples/genética , Adulto , Encefalopatías Metabólicas Innatas/diagnóstico por imagen , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/fisiopatología , Atresia de las Coanas/diagnóstico por imagen , Atresia de las Coanas/genética , Coloboma/diagnóstico por imagen , Coloboma/genética , Opacidad de la Córnea/diagnóstico por imagen , Opacidad de la Córnea/genética , Opacidad de la Córnea/fisiopatología , Huesos Faciales/anomalías , Huesos Faciales/diagnóstico por imagen , Huesos Faciales/patología , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Imagen por Resonancia Magnética , Masculino , Microcefalia/diagnóstico por imagen , Microcefalia/genética , Microcefalia/fisiopatología , Microftalmía/diagnóstico por imagen , Microftalmía/genética , Nariz/diagnóstico por imagen , Nariz/fisiopatología , Bulbo Olfatorio/diagnóstico por imagen , Bulbo Olfatorio/patologíaRESUMEN
BACKGROUND: L-2-hydroxyglutaric aciduria is a rare autosomal recessive encephalopathy caused by mutations in the L-2-hydroxyglutarate dehydrogenase gene. We describe some novel clinical and molecular characteristics found in a boy with L-2-hydroxyglutaric aciduria. CASE PRESENTATION: We report an 8-year-old Chinese boy, who had characteristic developmental delay, ataxia and acrocephaly as the main symptoms. He also complained of paroxysmal headache and palpitation. Brain image revealed a symmetrical, extensive subcortical white matter lesion. Urine test for organic acids showed a significantly increased level of 2-hydroxyglutaric acid (106.74 mmol/mol cre, normal range 0.6 ~ 5.9 mmol/mol cre), leading to the diagnosis of L-2-hydroxyglutaric aciduria. Genetic testing uncovered two heterozygous missense mutations in L-2-hydroxyglutarate dehydrogenase gene: c.169G > A in exon 2 and c.542G > T in exon 5, not hitherto been described. CONCLUSION: Novel gene mutation and associated clinical symptoms can contribute for the understanding and identification of this rare disease. Possible genotype-phenotype correlation waits for further study.
Asunto(s)
Oxidorreductasas de Alcohol/genética , Pueblo Asiatico/genética , Encefalopatías Metabólicas Innatas/genética , Encéfalo/patología , Mutación Missense , Encefalopatías Metabólicas Innatas/sangre , Encefalopatías Metabólicas Innatas/patología , Encefalopatías Metabólicas Innatas/fisiopatología , Niño , Pruebas Genéticas , Genotipo , Glutaratos/sangre , Heterocigoto , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Neuroimagen , FenotipoRESUMEN
Creatine transporter deficiency was discovered in 2001 as an X-linked cause of intellectual disability characterized by cerebral creatine deficiency. This review describes the current knowledge regarding creatine metabolism, the creatine transporter and the clinical aspects of creatine transporter deficiency. The condition mainly affects the brain while other creatine requiring organs, such as the muscles, are relatively spared. Recent studies have provided strong evidence that creatine synthesis also occurs in the brain, leading to the intriguing question of why cerebral creatine is deficient in creatine transporter deficiency. The possible mechanisms explaining the cerebral creatine deficiency are discussed. The creatine transporter knockout mouse provides a good model to study the disease. Over the past years several treatment options have been explored but no treatment has been proven effective. Understanding the pathogenesis of creatine transporter deficiency is of paramount importance in the development of an effective treatment.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Encefalopatías Metabólicas Innatas/fisiopatología , Creatina/deficiencia , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Discapacidad Intelectual/etiología , Proteínas de Transporte de Membrana/deficiencia , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Errores Innatos del Metabolismo de los Aminoácidos/patología , Animales , Encefalopatías Metabólicas Innatas/complicaciones , Encefalopatías Metabólicas Innatas/genética , Creatina/genética , Humanos , Discapacidad Intelectual/genética , Proteínas de Transporte de Membrana/genética , Discapacidad Intelectual Ligada al Cromosoma X/complicaciones , Discapacidad Intelectual Ligada al Cromosoma X/genética , Ratones , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genéticaRESUMEN
Neuroferritinopathy is an autosomal dominant progressive movement disorder which occurs due to mutations in the ferritin light chain gene (FTL1). It presents in mid-adult life and is the only autosomal dominant disease in a group of conditions termed neurodegeneration with brain iron accumulation (NBIA). We performed brain MRI scans on 12 asymptomatic descendants of known mutation carriers. All three harbouring the pathogenic c.460InsA mutation showed iron deposition; these findings show pathological iron accumulation begins in early childhood which is of major importance in understanding and developing treatment for NBIA.
Asunto(s)
Encefalopatías Metabólicas Innatas/patología , Encefalopatías Metabólicas Innatas/fisiopatología , Encéfalo/metabolismo , Encéfalo/patología , Hierro/metabolismo , Distrofias Neuroaxonales/patología , Distrofias Neuroaxonales/fisiopatología , Adolescente , Adulto , Apoferritinas/genética , Apoferritinas/metabolismo , Niño , Humanos , Trastornos del Metabolismo del Hierro , Imagen por Resonancia Magnética , Mutación , Adulto JovenRESUMEN
INTRODUCTION: Cerebral creatine deficiency syndromes (CCDS) are a group of potentially treatable neurometabolic disorders. The clinical, genetic profile and follow up outcome of Indian CCDS patients is presented. MATERIALS AND METHODS: This was a retrospective cohort of CCDS patients seen over six-years. Diagnosis was based either on low creatine peak on proton magnetic resonance spectroscopy (MRS) and/or genetic evaluation. RESULTS: Thirteen patients were eligible [8 creatine transporter deficiency (CTD), 4 guanidinoacetate methyltransferase (GAMT) deficiency and 1 could not be classified]. The mean (±SD) age at diagnosis was 7.2(±5.0) years. Clinical manifestations included intellectual disability (ID) with significant expressive speech delay in all. Most had significant behavior issues (8/13) and/or autism (8/13). All had history of convulsive seizures (11/13 had epilepsy; 2 patients only had febrile seizures) and 2/13 had movement disorder. Constipation was the commonest non-neurological manifestation (5/13 patients). Cranial MRI was normal in all CTD patients but showed globus pallidus hyperintensity in all four with GAMT deficiency. MRS performed in 11/13 patients, revealed abnormally low creatine peak. A causative genetic variant (novel mutation in nine) was identified in 12 patients. Three GAMT deficiency and one CTD patient reported neurodevelopmental improvement and good seizure control after creatine supplementation. CONCLUSION: Intellectual disability, disproportionate speech delay, autism, and epilepsy, were common in our CCDS patients. A normal structural neuroimaging with easily controlled febrile and/or afebrile seizures differentiated CTD from GAMT deficiency patients who had abnormal neuroimaging and often difficult to control epilepsy and movement disorder.
Asunto(s)
Encefalopatías Metabólicas Innatas/diagnóstico , Creatina/deficiencia , Guanidinoacetato N-Metiltransferasa/deficiencia , Trastornos del Desarrollo del Lenguaje/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Trastornos del Movimiento/congénito , Trastornos del Neurodesarrollo/diagnóstico , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/deficiencia , Encefalopatías Metabólicas Innatas/complicaciones , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/fisiopatología , Niño , Preescolar , Creatina/genética , Femenino , Estudios de Seguimiento , Guanidinoacetato N-Metiltransferasa/genética , Humanos , India , Trastornos del Desarrollo del Lenguaje/complicaciones , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/fisiopatología , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/complicaciones , Discapacidad Intelectual Ligada al Cromosoma X/genética , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Trastornos del Movimiento/complicaciones , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/genética , Trastornos del Movimiento/fisiopatología , Trastornos del Neurodesarrollo/etiología , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/fisiopatología , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genética , Estudios RetrospectivosRESUMEN
Organic acidurias or organic acidemias constitute a group of inherited disorders caused by deficient activity of specific enzymes of amino acids, carbohydrates or lipids catabolism, leading to large accumulation and excretion of one or more carboxylic (organic) acids. Affected patients usually present neurologic symptoms and abnormalities, sometimes accompanied by cardiac and skeletal muscle alterations, whose pathogenesis is poorly known. However, in recent years growing evidence has emerged indicating that mitochondrial dysfunction is directly or indirectly involved in the pathology of various organic acidemias. Mitochondrial impairment in some of these diseases are generally due to mutations in nuclear genes of the tricarboxylic acid cycle or oxidative phosphorylation, while in others it seems to result from toxic influences of the endogenous organic acids to the mitochondrion. In this minireview, we will briefly summarize the present knowledge obtained from human and animal studies showing that disruption of mitochondrial homeostasis may represent a relevant pathomechanism of tissue damage in selective organic acidemias. The discussion will focus on mitochondrial alterations found in patients affected by organic acidemias and by the deleterious effects of the accumulating organic acids on mitochondrial pathways that are crucial for ATP formation and transfer. The elucidation of the mechanisms of toxicity of these acidic compounds offers new perspectives for potential novel adjuvant therapeutic strategies in selected disorders of this group.
Asunto(s)
Adenosina Trifosfato/metabolismo , Ácidos Carboxílicos/metabolismo , Homeostasis/fisiología , Errores Innatos del Metabolismo/fisiopatología , Mitocondrias/fisiología , Enfermedades Mitocondriales/fisiopatología , Acetil-CoA C-Aciltransferasa/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Animales , Síndrome de Barth/fisiopatología , Encefalopatías Metabólicas/fisiopatología , Encefalopatías Metabólicas Innatas/fisiopatología , Glutaril-CoA Deshidrogenasa/deficiencia , Humanos , Mitocondrias/metabolismo , Acidemia Propiónica/fisiopatología , Púrpura/fisiopatologíaRESUMEN
In glutaric aciduria type 1, glutaryl-coenzyme A and its derivatives are produced from intracerebral lysine and entrapped at high concentrations within the brain, where they interfere with energy metabolism. Biochemical toxicity is thought to trigger stroke-like striatal degeneration in susceptible children under 2 years of age. Here, we explore vascular derangements that might also contribute to brain damage. We studied injured and non-injured Amish glutaric aciduria type 1 patients using magnetic resonance imaging (n = 26), transcranial Doppler ultrasound (n = 35) and perfusion computed tomography (n = 6). All glutaric aciduria type 1 patients had wide middle cerebral, internal carotid and basilar arteries. In non-injured patients, middle cerebral artery velocities were 18-26% below control values throughout late infancy and early childhood, whereas brain-injured children had an early velocity peak (18 months) and low values thereafter. Perfusion scans from six patients showed that tissue blood flow did not undergo a normal developmental surge. We observed four different perfusion patterns. (i) Three children (two non-injured) had low cerebral blood flow, prolonged mean transit time, elevated cerebral blood volume and high mean transit time/cerebral blood flow and cerebral blood volume/cerebral blood flow ratios. This pattern optimizes substrate extraction at any given flow rate but indicates low perfusion pressure and limited autoregulatory reserve. (ii) Ten hours after the onset of striatal necrosis in an 8-month-old infant, mean transit time and cerebral blood volume were low relative to cerebral blood flow, which varied markedly from region to region. This pattern indicates disturbed autoregulation, regional perfusion pressure gradients, or redistribution of flow from functional capillaries to non-exchanging vessels. (iii) In an infant with atrophic putaminal lesions, striatal flow was normal but mean transit time and cerebral blood volume were low, consistent with perfusion in excess of metabolic demand. (iv) Finally, a brain-injured adult with glutaric aciduria type 1 had regional perfusion values within the normal range, but the putamina, which normally have the highest regional perfusion, had cerebral blood flow values 24% below cortical grey matter. Although metabolic toxicity appears central to the pathophysiology of striatal necrosis, cerebrovascular changes probably also contribute to the process. These changes may be the primary cause of expanded cerebrospinal fluid volume in newborns, intracranial and retinal haemorrhages in infants and interstitial white matter oedema in children and adults. This pilot study suggests important new areas for clinical investigation.
Asunto(s)
Encéfalo/irrigación sanguínea , Encéfalo/enzimología , Circulación Cerebrovascular/fisiología , Glutaril-CoA Deshidrogenasa/deficiencia , Adolescente , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Arteriolas/fisiopatología , Volumen Sanguíneo/fisiología , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/fisiopatología , Niño , Preescolar , Femenino , Glutaril-CoA Deshidrogenasa/genética , Humanos , Lactante , Recién Nacido , Masculino , Proyectos Piloto , Vasoconstricción/fisiologíaRESUMEN
INTRODUCTION: We examine those prenatal encephalopathies with clinical or neuroimaging data of encephalopathy before the birth. They affect a significant number of children seen by paediatric neurologists. They can be of disruptive origin (due to vascular problems, drugs, toxins or congenital infections), and genetically determined. We include cases of autism spectrum disorder and mental retardation with no history of perinatal of postnatal damages. MATERIAL AND METHODS: We analysed our 19 year neuro-paediatric data base in search of prenatal encephalopathies and their diagnostic origin. We also analyse the studies made in the cases with a diagnosis of unknown origin. RESULTS: The 19 year period of study in the data base included 11,910 children, and 1596 (13.5%) were considered as prenatal encephalopathies; 1307 children (81.4%) had a diagnosis of unknown origin, despite many investigations being done in a large number of them. DISCUSSION: Most of the children included in this study suffer a rare disease, and whether they are identified or not, they increasingly require an early diagnosis. Peroxisomal, mitochondrial, lysosomal diseases, carbohydrate glycosylation deficiency syndrome and other inborn error of metabolism, congenital infections and genetic encephalopathies, can be clinically indistinguishable in early life and require specific studies to identify them. Early diagnosis requires strategies using step-wise systematic studies, giving priority to those diseases that could be treated, and in many cases using an individualised approach. We believe that the potential benefits of early diagnosis, including savings on further studies, genetic counselling and prenatal diagnosis, overcome the financial costs.
Asunto(s)
Encefalopatías Metabólicas Innatas , Enfermedades Fetales , Pruebas Genéticas , Complicaciones Infecciosas del Embarazo , Diagnóstico Prenatal , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/patología , Encefalopatías Metabólicas Innatas/fisiopatología , Femenino , Enfermedades Fetales/diagnóstico , Enfermedades Fetales/fisiopatología , Asesoramiento Genético , Humanos , Embarazo , Complicaciones Infecciosas del Embarazo/genética , Complicaciones Infecciosas del Embarazo/patología , Complicaciones Infecciosas del Embarazo/fisiopatologíaRESUMEN
We explored the benefits of triheptanoin as a treatment for Short Chain Enoyl Co-A Hydratase (SCEH) deficiency. One child with early onset, severe SCEH Deficiency was treated with triheptanoin, an odd chain oil with anapleurotic properties, for 37 months. Blood and urine chemistry safety measures, motor skills assessment, physical exam, and neurological assessment were monitored over a 27 month period. Modest sustained gains in motor skills, attention, muscle bulk, and strength were observed without any significant adverse effects. Triheptanoin appears to be a promising effective treatment for SCEH Deficiency.
Asunto(s)
Encefalopatías Metabólicas Innatas/tratamiento farmacológico , Enoil-CoA Hidratasa/deficiencia , Triglicéridos/farmacología , Encefalopatías Metabólicas Innatas/metabolismo , Encefalopatías Metabólicas Innatas/fisiopatología , Niño , Femenino , Humanos , Triglicéridos/administración & dosificaciónRESUMEN
Ethylmalonic encephalopathy (EE) is a rare autosomal recessive inborn error of metabolism. To study the molecular effects of ETHE1 p. D165H mutation, we employed mass spectrometry-based mitochondrial proteome and phosphoproteome profiling in the human skeletal muscle. Eighty-six differentially altered proteins were identified, of which thirty-seven mitochondrial proteins were differentially expressed, and most of the proteins (37%) were down-regulated in the OXPHOS complex-IV. Also, nine phosphopeptides that correspond to eight mitochondrial proteins were significantly affected in EE patient. These altered proteins recognized are involved in several pathways and molecular functions, predominantly in oxidoreductase activity. This is the first study that has integrated proteome and phosphoproteome of skeletal muscle and identified multiple proteins associated in the pathogenesis of EE.
Asunto(s)
Encefalopatías Metabólicas Innatas/genética , Mitocondrias Musculares/fisiología , Proteínas Mitocondriales/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Mutación , Proteínas de Transporte Nucleocitoplasmático/genética , Proteoma , Púrpura/genética , Adulto , Encefalopatías Metabólicas Innatas/fisiopatología , Regulación hacia Abajo , Humanos , Masculino , Fosforilación Oxidativa , Proteómica/métodos , Púrpura/fisiopatología , Transducción de SeñalRESUMEN
Ethylmalonic encephalopathy is a rare autosomal recessive mitochondrial disorder caused by pathogenic biallelic variants in the ETHE1 gene. The phenotype of this disease has been attributed to deficiency in the mitochondrial sulfur dioxygenase leading to many downstream effects. Ethylmalonic encephalopathy classically presents with developmental regression, petechiae, acrocyanosis, and chronic diarrhea. The neurologic phenotype includes hypotonia, spastic diplegia, ataxia, and developmental delay. As more patients with this condition are described, the neurologic phenotype continues to expand. Although strokelike episodes or metabolic strokes have been studied in other mitochondrial disorders, they have not been thoroughly reported in this disorder. Herein, we describe 3 patients with ethylmalonic encephalopathy who presented clinically with strokelike episodes and strokelike abnormalities on brain magnetic resonance imaging in the setting of acute illness, and the long-term sequelae with evolution into cystic changes in one of these subjects.