Asunto(s)
Encefalopatías , Síndrome de la Persona Rígida , Humanos , Lactante , Rigidez Muscular , Mutación , Receptores AMPARESUMEN
d-2-hydroxyglutaric (D-2-HGA) and l-2-hydroxyglutaric (L-2-HGA) acidurias are rare neurometabolic disorders biochemically characterized by increased levels of d-2-hydroxyglutaric acid (D-2-HG) and l-2-hydroxyglutaric acid (L-2-HG) respectively, in biological fluids and tissues. These diseases are caused by mutations in the specific enzymes involved in the metabolic pathways of these organic acids. In the present work, we first investigated whether D-2-HG and L-2-HGA could provoke DNA oxidative damage in blood leukocytes and whether l-carnitine (LC) could prevent the in vitro DNA damage induced by these organic acids. It was verified that 50µM of D-2-HG and 30µM of L-2-HG significantly induced DNA damage that was prevented by 30 and 150µM of LC. We also evaluated oxidative stress parameters in urine of L-2-HGA patients and observed a significant increase of oxidized guanine species and di-tyrosine, biomarkers of oxidative DNA and protein damage, respectively. In contrast, no significant changes of urinary isoprostanes and reactive nitrogen species levels were observed in these patients. Taken together, our data indicate the involvement of oxidative damage, especially on DNA, in patients affected by these diseases and the protective effect of LC.
Asunto(s)
Encefalopatías Metabólicas Innatas/genética , Carnitina/farmacología , Daño del ADN/efectos de los fármacos , Glutaratos/toxicidad , Sustancias Protectoras/farmacología , Adolescente , Adulto , Encefalopatías Metabólicas Innatas/orina , Niño , Preescolar , Ensayo Cometa , Dinoprost/análogos & derivados , Dinoprost/orina , Guanina/análogos & derivados , Guanina/orina , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies de Nitrógeno Reactivo/orina , Tirosina/análogos & derivados , Tirosina/orina , Adulto JovenRESUMEN
OBJECTIVE: The natural history of succinic semialdehyde dehydrogenase (SSADH) deficiency in adulthood is unknown; we elucidate the clinical manifestations of the disease later in life. METHODS: A 63-year-old man with long-standing intellectual disability was diagnosed with SSADH deficiency following hospitalization for progressive decline, escalating seizures, and prolonged periods of altered consciousness. We present a detailed review of his clinical course and reviewed our SSADH deficiency database adult cohort to derive natural history information. RESULTS: Of 95 patients in the database for whom age at diagnosis is recorded, there are 40 individuals currently aged 18 years or older. Only 3 patients were diagnosed after age 18 years. Of 25 adults for whom data are available after age 18, 60% have a history of epilepsy. Predominant seizure types are generalized tonic-clonic, absence, and myoclonic. EEGs showed background slowing or generalized epileptiform discharges in two-thirds of adults for whom EEG data were collected. History of psychiatric symptoms was prominent, with frequent anxiety, sleep disturbances, and obsessive-compulsive disorder. CONCLUSIONS: We identified patients older than 18 years with SSADH deficiency in our database following identification and review of a patient diagnosed in the seventh decade of life. The illness had a progressive course with escalating seizures in the index case, with fatality at age 63. Diagnosis in adulthood is rare. Epilepsy is more common in the adult than the pediatric SSADH deficiency cohort; neuropsychiatric morbidity remains prominent.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/psicología , Bases de Datos Factuales/tendencias , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/psicología , Succionato-Semialdehído Deshidrogenasa/deficiencia , Adolescente , Adulto , Estudios Transversales , Resultado Fatal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Aberrations in about 10-15% of X-chromosome genes account for intellectual disability (ID); with a prevalence of 1-3% (Gécz et al., 2009 [1]). The SLC6A8 gene, mapped to Xq28, encodes the creatine transporter (CTR1). Mutations in SLC6A8, and the ensuing decrease in brain creatine, lead to co-occurrence of speech/language delay, autism-like behaviors and epilepsy with ID. A splice variant of SLC6A8-SLC6A8C, containing intron 4 and exons 5-13, was identified. Herein, we report the identification of a novel variant - SLC6A8D, and functional relevance of these isoforms. METHODS: Via (quantitative) RT-PCR, uptake assays, and confocal microscopy, we investigated their expression and function vis-à-vis creatine transport. RESULTS: SLC6A8D is homologous to SLC6A8C except for a deletion of exon 9 (without occurrence of a frame shift). Both contain an open reading frame encoding a truncated protein but otherwise identical to CTR1. Like SLC6A8, both variants are predominantly expressed in tissues with high energy requirement. Our experiments reveal that these truncated isoforms do not transport creatine. However, in SLC6A8 (CTR1)-overexpressing cells, a subsequent infection (transduction) with viral constructs encoding either the SLC6A8C (CTR4) or SLC6A8D (CTR5) isoform resulted in a significant increase in creatine accumulation compared to CTR1 cells re-infected with viral constructs containing the empty vector. Moreover, transient transfection of CTR4 or CTR5 into HEK293 cells resulted in significantly higher creatine uptake. CONCLUSIONS: CTR4 and CTR5 are possible regulators of the creatine transporter since their overexpression results in upregulated CTR1 protein and creatine uptake. GENERAL SIGNIFICANCE: Provides added insight into the mechanism(s) of creatine transport regulation.
Asunto(s)
Empalme Alternativo , Regulación de la Expresión Génica , Proteínas de Transporte de Membrana/genética , Células 3T3 , Animales , Secuencia de Bases , Creatina/metabolismo , Retículo Endoplásmico/metabolismo , Células HEK293 , Humanos , Proteínas de Transporte de Membrana/fisiología , Ratones , Datos de Secuencia Molecular , Especificidad de Órganos , Transcripción GenéticaRESUMEN
We evaluated a family with a 16-month-old boy with cirrhosis and hepatocellular carcinoma and his 30-month-old brother with cirrhosis. After failing to identify a diagnosis after routine metabolic evaluation, we utilized a combination of RNA-Seq and whole exome sequencing to identify a novel homozygous p.Ser171Phe Transaldolase (TALDO1) variant in the proband, his brother with cirrhosis, as well as a clinically asymptomatic older 8-year-old brother. Metabolite analysis and enzymatic testing of TALDO1 demonstrated elevated ribitol, sedoheptitol, and sedoheptulose-7P, and lack of activity of TALDO1 in the three children homozygous for the p.Ser171Phe mutation. Our findings expand the phenotype of transaldolase deficiency to include early onset hepatocellular carcinoma in humans and demonstrate that, even within the same family, individuals with the same homozygous mutation demonstrate a wide range of phenotypes.
RESUMEN
Interconversion between phosphocreatine and creatine, catalyzed by creatine kinase is crucial in the supply of ATP to tissues with high energy demand. Creatine's importance has been established by its use as an ergogenic aid in sport, as well as the development of intellectual disability in patients with congenital creatine deficiency. Creatine biosynthesis is complemented by dietary creatine uptake. Intracellular transport of creatine is carried out by a creatine transporter protein (CT1/CRT/CRTR) encoded by the SLC6A8 gene. Most tissues express this gene, with highest levels detected in skeletal muscle and kidney. There are lower levels of the gene detected in colon, brain, heart, testis and prostate. The mechanism(s) by which this regulation occurs is still poorly understood. A duplicated unprocessed pseudogene of SLC6A8-SLC6A10P has been mapped to chromosome 16p11.2 (contains the entire SLC6A8 gene, plus 2293 bp of 5'flanking sequence and its entire 3'UTR). Expression of SLC6A10P has so far only been shown in human testis and brain. It is still unclear as to what is the function of SLC6A10P. In a patient with autism, a chromosomal breakpoint that intersects the 5'flanking region of SLC6A10P was identified; suggesting that SLC6A10P is a non-coding RNA involved in autism. Our aim was to investigate the presence of cis-acting factor(s) that regulate expression of the creatine transporter, as well as to determine if these factors are functionally conserved upstream of the creatine transporter pseudogene. Via gene-specific PCR, cloning and functional luciferase assays we identified a 1104 bp sequence proximal to the mRNA start site of the SLC6A8 gene with promoter activity in five cell types. The corresponding 5'flanking sequence (1050 bp) on the pseudogene also had promoter activity in all 5 cell lines. Surprisingly the pseudogene promoter was stronger than that of its parent gene in 4 of the cell lines tested. To the best of our knowledge, this is the first experimental evidence of a pseudogene with stronger promoter activity than its parental gene.
Asunto(s)
Proteínas de Transporte de Membrana/genética , Proteínas del Tejido Nervioso/genética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genética , Regiones Promotoras Genéticas/genética , Seudogenes/genética , Animales , Células Cultivadas , Clonación Molecular , Creatina/metabolismo , Regulación de la Expresión Génica , Células HEK293 , Células HeLa , Humanos , Masculino , Ratones , Isoformas de Proteínas/genética , Análisis de Secuencia de ADN , Homología de Secuencia , Células 3T3 SwissRESUMEN
A two-month-old male infant presented with jaundice, pallor, and hepatomegaly. The first child of non-consanguineous parents had also suffered from hemolytic anemia and neuromotor retardation and died at the age of 21 months. The patient required phototherapy and transfusion in the newborn period but hemolysis was mild thereafter. The patient had neuromotor retardation, and at the age of 14 months, ventilatory support was necessary, and the patient lived until 17 months. Triose-phosphate isomerase (TPI) deficiency, which is a rare autosomal recessive multisystem disorder of glycolysis, was detected. There was homozygous missense mutation in the TPI1 gene (p.Glu105Asp). This is the most common mutation with a severe phenotype that requires ventilator support in the second year of life. In patients with hemolysis and neuromotor retardation, TPI deficiency must be considered. There is no specific treatment, but detection of the index case may provide the opportunity for genetic counseling and prenatal diagnosis.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica/diagnóstico , Anemia Hemolítica Congénita no Esferocítica/genética , Glucólisis , Triosa-Fosfato Isomerasa/deficiencia , Anemia Hemolítica Congénita no Esferocítica/terapia , Resultado Fatal , Asesoramiento Genético , Humanos , Lactante , Masculino , Errores Innatos del Metabolismo , Destreza Motora , Mutación Missense , Diagnóstico Prenatal , Respiración ArtificialRESUMEN
We report 4 pyridoxine-dependent epilepsy patients in which good outcome was determined in three. The 4 patients were male and aged from 7 to 24 years old (from three unrelated Caucasian families). A clinical diagnosis of neonatal pyridoxine-dependent epilepsy was confirmed by biochemical and genetic studies. Clinical evaluation was performed and medical records were reviewed for therapy implementation and management, neurodevelopment outcome, magnetic resonance imaging, and electroencephalography. All were taking pyridoxine treatment and were seizure-free. Elevated urinary alpha-aminoadipic semialdehyde excretion was found in all patients. Antiquitin gene analysis identified a large homozygous deletion in one patient and two heterozygous mutations in the others. Treatment with pyridoxine should be attempted for all cases of infantile and childhood refractory epilepsy, as has been the case over the last 20 years. Currently, urinary alpha-aminoadipic semialdehyde is a reliable biomarker of pyridoxine-dependent epilepsy, even under pyridoxine treatment. Detection of mutations in the antiquitin gene, encoding alpha-aminoadipic semialdehyde dehydrogenase, establishes the diagnosis and allows for adequate genetic counselling.
Asunto(s)
Aldehído Deshidrogenasa/deficiencia , Electroencefalografía , Epilepsia/genética , Adulto , Niño , Electroencefalografía/métodos , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Humanos , Masculino , Mutación/genética , Piridoxina/efectos adversos , Piridoxina/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Mosaic IDH1 mutations are described as the cause of metaphyseal chondromatosis with increased urinary excretion of D-2-hydroxyglutarate (MC-HGA), and mutations in IDH2 as the cause of D-2-hydroxyglutaric aciduria (D-2HGA) type II. Mosaicism for IDH2 mutations has not previously been reported as a cause of D-2HGA. Here we describe three cases: one MC-HGA case with IDH1 mosaic mutations, and two D-2HGA type II cases. In one D-2HGA case we identified mosaicism for an IDH2 mutation as the genetic cause of this disorder; the other D-2HGA case was caused by a heterozygous IDH2 mutation, while the unaffected mother was a mosaic carrier. METHODS: We performed amplicon deep sequencing using the 454 GS Junior platform, next to Sanger sequencing, to identify and confirm mosaicism of IDH1 or IDH2 mutations in MC-HGA or D-2HGA, respectively. RESULTS AND CONCLUSIONS: We identified different mutant allele percentages in DNA samples derived from different tissues (blood vs fibroblasts). Furthermore, we found that mutant allele percentages of IDH1 decreased after more passages had occurred in fibroblast cell cultures. We describe a method for the detection and validation of mosaic mutations in IDH1 and IDH2, making quantification with laborious cloning techniques obsolete.
Asunto(s)
Encefalopatías Metabólicas Innatas/genética , Isocitrato Deshidrogenasa/genética , Mosaicismo , Encefalopatías Metabólicas Innatas/diagnóstico , Células Cultivadas , Niño , Femenino , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mutación , PadresRESUMEN
The Krebs cycle is of fundamental importance for the generation of the energetic and molecular needs of both prokaryotic and eukaryotic cells. Both enantiomers of metabolite 2-hydroxyglutarate are directly linked to this pivotal biochemical pathway and are found elevated not only in several cancers, but also in different variants of the neurometabolic disease 2-hydroxyglutaric aciduria. Recently we showed that cancer-associated IDH2 germline mutations cause one variant of 2-hydroxyglutaric aciduria. Complementary to these findings, we now report recessive mutations in SLC25A1, the mitochondrial citrate carrier, in 12 out of 12 individuals with combined D-2- and L-2-hydroxyglutaric aciduria. Impaired mitochondrial citrate efflux, demonstrated by stable isotope labeling experiments and the absence of SLC25A1 in fibroblasts harboring certain mutations, suggest that SLC25A1 deficiency is pathogenic. Our results identify defects in SLC25A1 as a cause of combined D-2- and L-2-hydroxyglutaric aciduria.
Asunto(s)
Proteínas de Transporte de Anión/genética , Encefalopatías Metabólicas Innatas/etiología , Ácido Cítrico/metabolismo , Genes Recesivos , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , Mutación/genética , Secuencia de Aminoácidos , Biomarcadores/análisis , Encefalopatías Metabólicas Innatas/metabolismo , Encefalopatías Metabólicas Innatas/patología , Estudios de Casos y Controles , Células Cultivadas , Cromatografía Liquida , Exoma/genética , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Glutaratos/orina , Humanos , Masculino , Datos de Secuencia Molecular , Transportadores de Anión Orgánico , Fenotipo , Estructura Terciaria de Proteína , Estudios Retrospectivos , Homología de Secuencia de Aminoácido , Estereoisomerismo , Espectrometría de Masas en TándemRESUMEN
PURPOSE: Transaldolase deficiency is a recently described inborn error of pentose phosphate pathway. We conducted this study to further delineate the associated phenotype. METHODS AND RESULTS: We report on 12 new cases representing six families with this metabolic defect that were observed over an 8 year span. None of these cases received the correct diagnosis initially because of significant overlap in the presenting symptoms (growth retardation, dysmorphic features, cutis laxa, congenital heart disease, hepatosplenomegaly, pancytopenia, and bleeding tendency) with a wide range of genetic disorders. However, the consanguineous nature of these families allowed us to pursue autozygome analysis, which highlighted TALDO as the likely candidate gene and sequencing confirmed segregation of a novel homozygous mutation with the disease in all the studied families. Biochemical analysis was also consistent with transaldolase deficiency. CONCLUSION: This study expands the clinical definition of transaldolase deficiency, and adds to its allelic heterogeneity. In addition, we emphasize the diagnostic challenge posed by this rare and pleiotropic metabolic disorder.
Asunto(s)
Errores Innatos del Metabolismo de los Carbohidratos/diagnóstico , Errores Innatos del Metabolismo de los Carbohidratos/genética , Transaldolasa/deficiencia , Niño , Preescolar , Consanguinidad , Familia , Resultado Fatal , Femenino , Heterogeneidad Genética , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Fenotipo , Transaldolasa/genéticaRESUMEN
We screened for the presence of inborn errors of metabolism (IEM) in 187 children (105 males; 82 females, ages 4-14 years old) who presented with confirmed features of autism spectrum disorder (ASD). Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2), succinic semialdehyde dehydrogenase (SSADH) deficiency (2), and phenylketonuria (1) (2.7%). Additional metabolic disturbances suggestive of IEMs included two patients whose increased urine 3-OH-IVA was accompanied by elevated methylcitrate and lactate in sera, and 30 patients that showed abnormal glucose-loading tests. In the latter group, 16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD). Five patients showed decreased serum ketone body production with glucose loading. Twelve of 187 patients demonstrated non-specific MRI pathology, while 25/187 had abnormal electroencephalogram (EEG) findings. Finally, family history was positive for 22/187 patients (1st or 2nd degree relative with comparable symptomatology) and consanguinity was documented for 12/187 patients. Our data provide evidence for a new biomarker (3-OH-IVA) and novel treatment approaches in ASD patients. Concise 1 sentence take-home message: Detailed metabolic screening in a Greek cohort of ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum b-OH-b) in 7% (13/187) of patients for whom biotin supplementation or institution of a KD resulted in mild to significant clinical improvement in autistic features.
RESUMEN
This review summarizes a presentation made at the retirement Symposium of Prof. Dr. Cornelis Jakobs in November of 2011, highlighting the progress toward clinical trials in succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder first recognized in 1981. Active and potential clinical interventions, including vigabatrin, L-cycloserine, the GHB receptor antagonist NCS-382, and the ketogenic diet, are discussed. Several biomarkers to gauge clinical efficacy have been identified, including cerebrospinal fluid metabolites, neuropsychiatric testing, MRI, EEG, and measures of GABAergic function including (11 C)flumazenil positron emission tomography (PET) and transcranial magnetic stimulation (TMS). Thirty years after its discovery, encompassing extensive studies in both patients and the corresponding murine model, we are now running an open-label trial of taurine intervention, and are poised to undertake a phase II trial of the GABAB receptor antagonist SGS742.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Succionato-Semialdehído Deshidrogenasa/deficiencia , Ácido gamma-Aminobutírico/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/historia , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Animales , Ensayos Clínicos como Asunto , Discapacidades del Desarrollo , Antagonistas de Receptores de GABA-B/uso terapéutico , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Ratones , Modelos Biológicos , Succionato-Semialdehído Deshidrogenasa/historia , Succionato-Semialdehído Deshidrogenasa/metabolismo , Factores de Tiempo , Ácido gamma-Aminobutírico/deficienciaRESUMEN
Apoptosis of endothelial cells related to homocysteine (Hcy) has been reported in several studies. In this study, we evaluated whether reactive oxygen species (ROS)-producing signaling pathways contribute to Hcy-induced apoptosis induction, with specific emphasis on NADPH oxidases. Human umbilical vein endothelial cells were incubated with 0.01-2.5 mM Hcy. We determined the effect of Hcy on caspase-3 activity, annexin V positivity, intracellular NOX1, NOX2, NOX4, and p47(phox) expression and localization, nuclear nitrotyrosine accumulation, and mitochondrial membrane potential (ΔΨ m). Hcy induced caspase-3 activity and apoptosis; this effect was concentration dependent and maximal after 6-h exposure to 2.5 mM Hcy. It was accompanied by a significant increase in ΔΨ m. Cysteine was inactive on these parameters excluding a reactive thiol group effect. Hcy induced an increase in cellular NOX2, p47(phox), and NOX4, but not that of NOX1. 3D digital imaging microscopy followed by image deconvolution analysis showed nuclear accumulation of NOX2 and p47(phox) in endothelial cells exposed to Hcy, but not in control cells, which coincided with accumulation of nuclear nitrotyrosine residues. Furthermore, Hcy enhanced peri-nuclear localization of NOX4 coinciding with accumulation of peri-nuclear nitrotyrosine residues, a reflection of local ROS production. p47(phox) was also increased in the peri-nuclear region. The Hcy-induced increase in caspase-3 activity was prevented by DPI and apocynin, suggesting involvement of NOX activity. The data presented in this article reveal accumulation of nuclear NOX2 and peri-nuclear NOX4 accumulation as potential source of ROS production in Hcy-induced apoptosis in endothelial cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Homocisteína/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , NADPH Oxidasas/metabolismo , Relación Dosis-Respuesta a Droga , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , NADPH Oxidasa 2 , NADPH Oxidasa 4 , Óxido Nítrico/metabolismo , Transporte de Proteínas/efectos de los fármacosRESUMEN
BACKGROUND: Choline is essential for mammalian cell function. It plays a critical role in cell membrane integrity, neurotransmission, cell signaling and lipid metabolism. Moreover, choline is involved in methylation in two ways: a) its synthesis requires methyl groups donated by S-adenosyl-methionine (AdoMet); and b) choline oxidation product betaine methylates homocysteine (Hcy) to methionine (Met) and produces dimethylglycine. This later donates one carbon units to tetrahydrofolate (THF). METHODS: To evaluate the correlations of choline and betaine with folate, AdoMet, S-anenosyl-homocysteine (AdoHcy), total homocysteine (tHcy), and DNA methylation, choline, betaine and dimethylglycine were measured by LC-MS/MS in plasma of 109 healthy volunteers, in whom folate, AdoMet, AdoHcy, tHcy, and DNA methylation have previously been reported. RESULTS: Using a bivariate model, choline and betaine showed strong positive correlations with folate (r = 0.346 and r = 0.226), AdoHcy (r = 0.468 and r = 0.296), and correlated negatively with AdoMet/AdoHcy ratio (r = 0.246 and r = 0.379). Only choline was positively correlated with AdoMet (r = 0.453). Using a multivariate linear regression model, choline correlated strongly with folate ( ß = 17.416), AdoMet ( ß = 61.272), and AdoHcy ( ß = 9.215). Betaine correlated positively with folate ( ß = 0.133) and negatively with tHcy ( ß = 0.194) ratio. Choline is an integral part of folate and methylation pathways. CONCLUSIONS: Our data highlight the importance of integrating choline in studies concerning addressing pathological conditions related to folate, homocysteine and methylation metabolism.
Asunto(s)
Betaína/sangre , Colina/sangre , Ácido Fólico/sangre , S-Adenosilhomocisteína/sangre , S-Adenosilmetionina/sangre , Adolescente , Adulto , Cromatografía Líquida de Alta Presión , Metilación de ADN , Femenino , Hormonas Esteroides Gonadales/metabolismo , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Sarcosina/análogos & derivados , Sarcosina/sangre , Factores Sexuales , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of dietary lysine restriction as an adjunct to pyridoxine therapy on biochemical parameters, seizure control, and developmental/cognitive outcomes in children with pyridoxine-dependent epilepsy (PDE) caused by antiquitin (ATQ) deficiency. METHODS: In this observational study, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring. Biochemical outcomes were evaluated using pipecolic acid and α-aminoadipic semialdehyde (AASA) levels in body fluids; developmental/cognitive outcomes were evaluated using age-appropriate tests and parental observations. RESULTS: Lysine restriction was well tolerated with good compliance; no adverse events were reported. Reduction in biomarker levels (measurement of the last value before and first value after initiation of dietary lysine restriction) ranged from 20 to 67% for plasma pipecolic acid, 13 to 72% for urinary AASA, 45% for plasma AASA and 42% for plasma P6C. For the 1 patient in whom data were available and who showed clinical deterioration upon interruption of diet, cerebrospinal fluid levels decreased by 87.2% for pipecolic acid and 81.7% for AASA. Improvement in age-appropriate skills was observed in 4 out of 5 patients showing pre-diet delays, and seizure control was maintained or improved in 6 out 7 children. CONCLUSIONS: This observational study provides Level 4 evidence that lysine restriction is well tolerated with significant decrease of potentially neurotoxic biomarkers in different body compartments, and with the potential to improve developmental outcomes in children with PDE caused by ATQ deficiency. To generate a strong level of evidence before this potentially burdensome dietary therapy becomes the mainstay treatment, we have established: an international PDE consortium to conduct future studies with an all-inclusive integrated study design; a website containing up-to-date information on PDE; a methodological toolbox; and an online registry to facilitate the participation of interested physicians, scientists, and families in PDE research.
Asunto(s)
Aldehído Deshidrogenasa/genética , Epilepsia/dietoterapia , Lisina/administración & dosificación , Ácido 2-Aminoadípico/análogos & derivados , Ácido 2-Aminoadípico/sangre , Ácido 2-Aminoadípico/líquido cefalorraquídeo , Ácido 2-Aminoadípico/orina , Aldehído Deshidrogenasa/deficiencia , Niño , Preescolar , Cognición , Dieta , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Epilepsia/patología , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Ácidos Pipecólicos/sangre , Ácidos Pipecólicos/líquido cefalorraquídeo , Ácidos Pipecólicos/orina , Piridoxina/uso terapéuticoRESUMEN
AIM: The long-term outcome of the Dutch pyridoxine-dependent epilepsy cohort and correlations between patient characteristics and follow-up data were retrospectively studied. METHOD: Fourteen patients recruited from a national reference laboratory were included (four males, 10 females, from 11 families; median age at assessment 6y; range 2y 6mo-16y). The following data were retrieved: sex; age at seizure onset; age at the start of pyridoxine therapy; level of urinary alpha-aminoadipic semialdehyde; antiquitin mutations; developmental milestones; evaluation of neurocognitive functioning and school career; magnetic resonance imaging (MRI) and electroencephalography (EEG) assessments. RESULTS: Pyridoxine was started antenatally in two children, in the first week of life in five, in the first month of life in three, or after the first month of life (range 2.5-8mo) in four. No child was physically disabled; however, only five walked at 2 years of age. Mental development was delayed in most: median IQ or developmental index was 72 (SD 19). Pyridoxine monotherapy controlled seizures in 10 of 14 children, whereas four needed additional antiepileptic drugs. Seizure persistence, antiepileptic drugs (other than pyridoxine), EEG background, and epileptiform activity were not associated with outcome. On neonatal MRI, structural and white matter abnormalities occurred in five of eight children; on follow-up, the number of abnormal MRIs was increased. Delayed initiation of pyridoxine medication and corpus callosum abnormalities were significantly associated with unfavourable neurodevelopmental outcome, but normal follow-up imaging did not predict a good outcome. INTERPRETATION: Outcome of patients with pyridoxine-dependent epilepsy remains poor. Individual outcome cannot be predicted by the evaluated characteristics. We suggest that collaborated research in structured settings could help to improve treatment strategies and outcome for pyridoxine-dependent epilepsy.
Asunto(s)
Epilepsia/diagnóstico , Adolescente , Factores de Edad , Aldehído Deshidrogenasa/genética , Encéfalo/patología , Niño , Preescolar , Estudios de Cohortes , Cuerpo Calloso/patología , Análisis Mutacional de ADN , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/tratamiento farmacológico , Discapacidades del Desarrollo/genética , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Femenino , Humanos , Lactante , Recién Nacido , Leucoencefalopatías/diagnóstico , Leucoencefalopatías/tratamiento farmacológico , Leucoencefalopatías/genética , Imagen por Resonancia Magnética , Masculino , Embarazo , Piridoxina/uso terapéutico , Estudios RetrospectivosRESUMEN
We report here a 6-year-old boy exhibiting severe dystonia, profound intellectual and developmental disability with liver disease, and sensorineural deafness. A deficient creatine peak in brain (1)H-MR spectroscopy and high ratio of creatine/creatinine concentration in his urine lead us to suspect a creatine transporter (solute carrier family 6, member 8; SLC6A8) deficiency, which was confirmed by the inability to take up creatine into fibroblasts. We found a large ~19 kb deletion encompassing exons 5-13 of SLC6A8 and exons 5-8 of the B-cell receptor-associated protein (BAP31) gene. This case is the first report in which the SLC6A8 and BAP31 genes are both deleted. The phenotype of BAP31 mutations has been reported only as a part of Xq28 deletion syndrome or contiguous ATP-binding cassette, sub-family D, member 1 (ABCD1)/DXS1375E (BAP31) deletion syndrome [MIM ID #300475], where liver dysfunction and sensorineural deafness have been suggested to be attributed to the loss of function of BAP31. Our case supports the idea that the loss of BAP31 is related to liver dysfunction and hearing loss.