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1.
J Inherit Metab Dis ; 46(5): 839-847, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37428623

RESUMEN

Over the past two decades, the field of vitamin B6 -dependent epilepsies has evolved by the recognition of a growing number of gene defects (ALDH7A1, PNPO, ALPL, ALDH4A1, PLPBP as well as defects of the glycosylphosphatidylinositol anchor proteins) that all lead to reduced availability of pyridoxal 5'-phosphate, an important cofactor in neurotransmitter and amino acid metabolism. In addition, positive pyridoxine response has been observed in other monogenic defects such as MOCS2 deficiency or KCNQ2 and there may be more defects to be discovered. Most entities lead to neonatal onset pharmaco-resistant myoclonic seizures or even status epilepticus and pose an emergency to the treating physician. Research has unraveled specific biomarkers for several of these entities (PNPO deficiency, ALDH7A1 deficiency, ALDH4A1 deficiency, ALPL deficiency causing congenital hypophosphatasia and glycosylphosphatidylinositol anchoring defects with hyperphosphatasia), that can be detected in plasma or urine, while there is no biomarker to test for PLPHP deficiency. Secondary elevation of glycine or lactate was recognized as diagnostic pitfall. An algorithm for a standardized trial with vitamin B6 should be in place in every newborn unit in order not to miss these well-treatable inborn errors of metabolism. The Komrower lecture of 2022 provided me with the opportunity to tell the story about the conundrums of research into vitamin B6 -dependent epilepsies that kept some surprises and many novel insights into pathomechanisms of vitamin metabolism. Every single step had benefits for the patients and families that we care for and advocates for a close collaboration of clinician scientists with basic research.


Asunto(s)
Epilepsia , Vitamina B 6 , Recién Nacido , Humanos , Vitamina B 6/metabolismo , Piridoxina , Fosfato de Piridoxal , Epilepsia/diagnóstico , Biomarcadores , Vitaminas
2.
J Inherit Metab Dis ; 46(1): 129-142, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36225138

RESUMEN

Deficiency of antiquitin (α-aminoadipic semialdehyde dehydrogenase), an enzyme involved in lysine degradation and encoded by ALDH7A1, is the major cause of vitamin B6 -dependent epilepsy (PDE-ALDH7A1). Despite seizure control with high dose pyridoxine (PN), developmental delay still occurs in approximately 70% of patients. We aimed to investigate metabolic perturbations due to possible previously unidentified roles of antiquitin, which may contribute to developmental delay, as well as metabolic effects of high dose pyridoxine supplementation reflecting the high doses used for seizure control in patients with PDE-ALDH7A1. Untargeted metabolomics by high resolution mass spectrometry (HRMS) was used to analyze plasma of patients with PDE-ALDH7A1 and two independently generated lines of cultured ReNcell CX human neuronal progenitor cells (NPCs) with CRISPR/Cas mediated antiquitin deficiency. Accumulation of lysine pathway metabolites in antiquitin-deficient NPCs and western-blot analysis confirmed knockdown of ALDH7A1. Metabolomics analysis of antiquitin-deficient NPCs in conditions of lysine restriction and PN supplementation identified changes in metabolites related to the transmethylation and transsulfuration pathways and osmolytes, indicating a possible unrecognized role of antiquitin outside the lysine degradation pathway. Analysis of plasma samples of PN treated patients with PDE-ALDH7A1 and antiquitin-deficient NPCs cultured in conditions comparable to the patient plasma samples demonstrated perturbation of metabolites of the gamma-glutamyl cycle, suggesting potential oxidative stress-related effects in PN-treated patients with PDE-ALDH7A1. We postulate that a model of human NPCs with CRISPR/Cas mediated antiquitin deficiency is well suited to characterize previously unreported roles of antiquitin, relevant to this most prevalent form of pyridoxine-dependent epilepsy.


Asunto(s)
Epilepsia , Piridoxina , Humanos , Piridoxina/uso terapéutico , Lisina/metabolismo , Aldehído Deshidrogenasa , Epilepsia/metabolismo , Convulsiones , Metabolómica
3.
J Inherit Metab Dis ; 46(3): 482-519, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36221165

RESUMEN

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Encefalopatías Metabólicas , Humanos , Glutaril-CoA Deshidrogenasa , Lisina/metabolismo , Encefalopatías Metabólicas/diagnóstico , Encefalopatías Metabólicas/genética , Encefalopatías Metabólicas/terapia , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Glutaratos/metabolismo
4.
Neuropediatrics ; 54(6): 422-425, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36577449

RESUMEN

To describe a new phenotype and the diagnostic workup of a vitamin-B6-dependent epilepsy due to pyridoxal 5'-phosphate-binding protein (PLPBP) deficiency in an infant with early-onset epilepsy at the age of 5 years 6 months. Following immediate and impressive clinical response to treatment with pyridoxine, metabolic screening for vitamin-B6-dependent epilepsies and targeted next-generation sequencing (NGS)-based gene panel analysis were performed. Potentially pathogenic variants were confirmed by Sanger sequencing in the patient, and variants were analyzed in both parents to confirm biallelic inheritance. The clinical phenotype and course of disease were compared to the 44 cases reported in the literature, harboring variants in pyridoxal phosphate homeostasis protein (PLPHP) and with cases of vitamin-B6-dependent epilepsy due to other known causative genes. Levels of alpha-aminoadipic semialdehyde in urine and amino acids were normal. Two inherited pathogenic variations in PLPHP were found in compound heterozygosity, including one novel deletion. We here describe a previously unreported individual harboring biallelic pathogenic PLPHP variants presenting with paroxysmal eye-head movements followed by epileptic spasms and an almost normal interictal electroencephalogram, thus expanding the clinical spectrum of PLPBP deficiency. This warrants consideration of vitamin-B6-dependent epilepsies in patients with early-onset epilepsy, including epileptic spasms, and eye movement disorders also beyond the neonatal period even when metabolic screening for vitamin-B6-dependent epilepsies is negative. PLPHP should be included systematically in NGS epilepsy gene panels.


Asunto(s)
Epilepsia , Espasmos Infantiles , Recién Nacido , Humanos , Lactante , Preescolar , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/genética , Movimientos de la Cabeza , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Epilepsia/etiología , Vitamina B 6/uso terapéutico , Piridoxina/uso terapéutico , Espasmo/complicaciones , Espasmo/tratamiento farmacológico , Vitaminas/uso terapéutico
5.
J Med Genet ; 59(7): 662-668, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-34379057

RESUMEN

BACKGROUND: Genes implicated in the Golgi and endosomal trafficking machinery are crucial for brain development, and mutations in them are particularly associated with postnatal microcephaly (POM). METHODS: Exome sequencing was performed in three affected individuals from two unrelated consanguineous families presenting with delayed neurodevelopment, intellectual disability of variable degree, POM and failure to thrive. Patient-derived fibroblasts were tested for functional effects of the variants. RESULTS: We detected homozygous truncating variants in ATP9A. While the variant in family A is predicted to result in an early premature termination codon, the variant in family B affects a canonical splice site. Both variants lead to a substantial reduction of ATP9A mRNA expression. It has been shown previously that ATP9A localises to early and recycling endosomes, whereas its depletion leads to altered gene expression of components from this compartment. Consistent with previous findings, we also observed overexpression of ARPC3 and SNX3, genes strongly interacting with ATP9A. CONCLUSION: In aggregate, our findings show that pathogenic variants in ATP9A cause a novel autosomal recessive neurodevelopmental disorder with POM. While the physiological function of endogenous ATP9A is still largely elusive, our results underline a crucial role of this gene in endosomal transport in brain tissue.


Asunto(s)
Adenosina Trifosfatasas/genética , Discapacidad Intelectual , Proteínas de Transporte de Membrana/genética , Microcefalia , Malformaciones del Sistema Nervioso , Trastornos del Neurodesarrollo , Insuficiencia de Crecimiento , Homocigoto , Humanos , Discapacidad Intelectual/genética , Microcefalia/patología , Trastornos del Neurodesarrollo/genética , Linaje
6.
J Med Genet ; 59(10): 957-964, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34916232

RESUMEN

BACKGROUND: Mucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I-IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate. Knockout of Arsk in mice was consistent with mild storage pathology, but no human phenotype has yet been described. METHODS: In this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Functional consequences of the two ARSK variants were assessed by mutation-specific ARSK constructs derived by site-directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LC-MS)/MS analysis. RESULTS: The phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS. CONCLUSION: Our work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X.


Asunto(s)
Arilsulfatasas , Mucopolisacaridosis , Animales , Cromatografía Liquida/métodos , Dermatán Sulfato , Disacáridos/análisis , Glicosaminoglicanos/genética , Glicosaminoglicanos/metabolismo , Humanos , Ratones , Ratones Noqueados , Sulfatos , Espectrometría de Masas en Tándem/métodos
7.
Int J Mol Sci ; 24(2)2023 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-36675224

RESUMEN

Even though the application of Next-Generation Sequencing (NGS) has significantly facilitated the identification of disease-associated mutations, the diagnostic rate of rare diseases is still below 50%. This causes a diagnostic odyssey and prevents specific treatment, as well as genetic counseling for further family planning. Increasing the diagnostic rate and reducing the time to diagnosis in children with unclear disease are crucial for a better patient outcome and improvement of quality of life. In many cases, NGS reveals variants of unknown significance (VUS) that need further investigations. The delineation of novel (lipid) biomarkers is not only crucial to prove the pathogenicity of VUS, but provides surrogate parameters for the monitoring of disease progression and therapeutic interventions. Lipids are essential organic compounds in living organisms, serving as building blocks for cellular membranes, energy storage and signaling molecules. Among other disorders, an imbalance in lipid homeostasis can lead to chronic inflammation, vascular dysfunction and neurodegenerative diseases. Therefore, analyzing lipids in biological samples provides great insight into the underlying functional role of lipids in healthy and disease statuses. The method of choice for lipid analysis and/or huge assemblies of lipids (=lipidome) is mass spectrometry due to its high sensitivity and specificity. Due to the inherent chemical complexity of the lipidome and the consequent challenges associated with analyzing it, progress in the field of lipidomics has lagged behind other omics disciplines. However, compared to the previous decade, the output of publications on lipidomics has increased more than 17-fold within the last decade and has, therefore, become one of the fastest-growing research fields. Combining multiple omics approaches will provide a unique and efficient tool for determining pathogenicity of VUS at the functional level, and thereby identifying rare, as well as novel, genetic disorders by molecular techniques and biochemical analyses.


Asunto(s)
Lipidómica , Enfermedades Metabólicas , Niño , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Lípidos/química , Medicina de Precisión , Calidad de Vida , Metabolismo de los Lípidos , Enfermedades Metabólicas/diagnóstico , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/terapia
8.
Int J Mol Sci ; 24(6)2023 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-36983033

RESUMEN

X-linked adrenoleukodystrophy (X-ALD) is a rare inborn error of the peroxisomal metabolism caused by pathologic variants in the ATP-binding cassette transporter type D, member 1 (ABCD1) gene located on the X-chromosome. ABCD1 protein, also known as adrenoleukodystrophy protein, is responsible for transport of the very long chain fatty acids (VLCFA) from cytoplasm into the peroxisomes. Therefore, altered function or lack of the ABCD1 protein leads to accumulation of VLCFA in various tissues and blood plasma leading to either rapidly progressive leukodystrophy (cerebral ALD), progressive adrenomyeloneuropathy (AMN), or isolated primary adrenal insufficiency (Addison's disease). We report two distinct single nucleotide deletions in the ABCD1 gene, c.253delC [p.Arg85Glyfs*18] in exon 1, leading to both cerebral ALD and to AMN phenotype in one family, and c.1275delA [p.Phe426Leufs*15] in exon 4, leading to AMN and primary adrenal insufficiency in a second family. For the latter variant, we demonstrate reduced mRNA expression and a complete absence of the ABCD1 protein in PBMC. Distinct mRNA and protein expression in the index patient and heterozygous carriers does not associate with VLCFA concentration in plasma, which is in line with the absence of genotype-phenotype correlation in X-ALD.


Asunto(s)
Enfermedad de Addison , Adrenoleucodistrofia , Humanos , Adrenoleucodistrofia/patología , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética , Nucleótidos/metabolismo , Leucocitos Mononucleares/metabolismo , Fenotipo , ARN Mensajero , Ácidos Grasos/metabolismo
9.
J Inherit Metab Dis ; 45(2): 235-247, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34671989

RESUMEN

BACKGROUND: The metabolic defect in glycogen storage disease type I (GSDI) results in fasting hypoglycemia and typical secondary metabolic abnormalities (eg, hypertriglyceridemia, hyperlactatemia, hyperuricemia). The aim of this study was to assess further perturbations of the metabolic network in GSDI patients under ongoing treatment. METHODS: In this prospective observational study, plasma samples of 14 adult patients (11 GSDIa, 3 GSDIb. Mean age 26.4 years, range 16-46 years) on standard treatment were compared to a cohort of 31 healthy controls utilizing ultra-high performance liquid chromatography (UHPLC) in combination with high resolution tandem mass spectrometry (HR-MS/MS) and subsequent statistical multivariate analysis. In addition, plasma fatty acid profiling was performed by GC/EI-MS. RESULTS: The metabolomic profile showed alterations of metabolites in different areas of the metabolic network in both GSD subtypes, including pathways of fuel metabolism and energy generation, lipids and fatty acids, amino acid and methyl-group metabolism, the urea cycle, and purine/pyrimidine metabolism. These alterations were present despite adequate dietary treatment, did not correlate with plasma triglycerides or lactate, both parameters typically used to assess the quality of metabolic control in clinical practice, and were not related to the presence or absence of complications (ie, nephropathy or liver adenomas). CONCLUSION: The metabolic defect of GSDI has profound effects on a variety of metabolic pathways in addition to the known typical abnormalities. These alterations are present despite optimized dietary treatment, which may contribute to the risk of developing long-term complications, an inherent problem of GSDI which appears to be only partly modified by current therapy.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo I , Hipoglucemia , Adolescente , Adulto , Cromatografía Líquida de Alta Presión , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Humanos , Hipoglucemia/complicaciones , Metabolómica , Persona de Mediana Edad , Espectrometría de Masas en Tándem , Adulto Joven
10.
J Inherit Metab Dis ; 45(2): 144-156, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34595757

RESUMEN

Inherited metabolic disorders (IMDs) are a heterogeneous group of rare disorders characterized by disruption of metabolic pathways. To date, data on incidence and prevalence of IMDs are limited. Taking advantage of a functioning network within the Austrian metabolic group, our registry research aimed to update the data of the "Registry for Inherited Metabolic Disorders" started between 1985 and 1995 with retrospectively retrieved data on patients with IMDs according to the Society for the Study of Inborn Errors of Metabolism International Classification of Diseases 11 (SSIEM ICD11) catalogue. Included in this retrospective register were 2631 patients with an IMD according to the SSIEM ICD11 Classification, who were treated in Austria. Thus, a prevalence of 1.8/10 000 for 2020 and a median minimal birth prevalence of 16.9/100 000 (range 0.7/100 000-113/100 000) were calculated for the period 1921 to February 2021. We detected a male predominance (m:f = 1.2:1) and a mean age of currently alive patients of 17.6 years (range 5.16 months-100 years). Most common diagnoses were phenylketonuria (17.7%), classical galactosaemia (6.6%), and biotinidase deficiency (4.2%). The most common diagnosis categories were disorders of amino acid and peptide metabolism (819/2631; 31.1%), disorders of energy metabolism (396/2631; 15.1%), and lysosomal disorders (395/2631; 15.0%). In addition to its epidemiological relevance, the "Registry for Inherited Metabolic Disorders" is an important tool for enhancing an exchange between care providers. Moreover, by pooling expertise it prospectively improves patient treatment, similar to pediatric oncology protocols. A substantial requirement for ful filling this goal is to regularly update the registry and provide nationwide coverage with inclusion of all medical specialties.


Asunto(s)
Enfermedades Metabólicas , Errores Innatos del Metabolismo , Austria/epidemiología , Niño , Femenino , Humanos , Lactante , Masculino , Enfermedades Metabólicas/diagnóstico , Enfermedades Metabólicas/epidemiología , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/epidemiología , Prevalencia , Sistema de Registros , Estudios Retrospectivos
11.
Brain ; 144(10): 3036-3049, 2021 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-34037727

RESUMEN

Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes are membrane-tethering heterotetramers located at the trans-Golgi network and recycling endosomes, respectively. GARP and EARP share the three subunits VPS51, VPS52 and VPS53, while VPS50 is unique to EARP and VPS54 to GARP. Retrograde transport of endosomal cargos to the trans-Golgi network is mediated by GARP and endocytic recycling by EARP. Here we report two unrelated individuals with homozygous variants in VPS50, a splice variant (c.1978-1G>T) and an in-frame deletion (p.Thr608del). Both patients had severe developmental delay, postnatal microcephaly, corpus callosum hypoplasia, seizures and irritability, transient neonatal cholestasis and failure to thrive. Light and transmission electron microscopy of liver from one revealed the absence of gamma-glutamyltransferase at bile canaliculi, with mislocalization to basolateral membranes and abnormal tight junctions. Using patient-derived fibroblasts, we identified reduced VPS50 protein accompanied by reduced levels of VPS52 and VPS53. While the transferrin receptor internalization rate was normal in cells of both patients, recycling of the receptor to the plasma membrane was significantly delayed. These data underscore the importance of VPS50 and/or the EARP complex in endocytic recycling and suggest an additional function in establishing cell polarity and trafficking between basolateral and apical membranes in hepatocytes. Individuals with biallelic hypomorphic variants in VPS50, VPS51 or VPS53 show an overarching neurodegenerative disorder with severe developmental delay, intellectual disability, microcephaly, early-onset epilepsy and variable atrophy of the cerebellum, cerebrum and/or brainstem. The term 'GARP/EARP deficiency' designates disorders in such individuals.


Asunto(s)
Colestasis/diagnóstico , Colestasis/genética , Variación Genética/genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Proteínas de Transporte Vesicular/genética , Alelos , Células Cultivadas , Preescolar , Colestasis/complicaciones , Humanos , Lactante , Recién Nacido , Masculino , Trastornos del Neurodesarrollo/complicaciones , Linaje , Proteínas de Transporte Vesicular/metabolismo , Red trans-Golgi/fisiología
12.
Neuroimage ; 239: 118281, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34147627

RESUMEN

Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.


Asunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato/fisiopatología , Ondas Encefálicas/fisiología , Electroencefalografía/métodos , Plasticidad Neuronal , Receptores de N-Metil-D-Aspartato/deficiencia , Fases del Sueño/fisiología , Adolescente , Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Masculino , Receptores de N-Metil-D-Aspartato/inmunología , Estudios Retrospectivos , Adulto Joven
13.
Genet Med ; 23(2): 352-362, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33106617

RESUMEN

PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.


Asunto(s)
Discapacidad Intelectual , Microcefalia , Trastornos del Neurodesarrollo , Humanos , Discapacidad Intelectual/genética , Hipotonía Muscular , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/genética , Proteína Fosfatasa 2/genética , Factores de Transcripción
14.
Mol Genet Metab ; 133(3): 257-260, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34083143

RESUMEN

BACKGROUND: High rates of lost to follow-up (LTFU) adult patients are a major concern in the long-term management of phenylketonuria (PKU). To address this issue, we designed the project "Backtoclinic" with the purpose of identifying LTFU adult PKU patients in Austria as a first step to reestablish appropriate treatment. SUBJECTS AND METHODS: Individuals born between 1966 and 1999 and diagnosed with PKU through the National Austrian Newborn Screening Program (NANSP) were identified using the NANSP's database. Follow-up data were collected in the Austrian metabolic centers (Medical University of Vienna, Graz, Innsbruck and Salzburg). Patients with no contact to any of these centers within the previous two years were classified as LTFU. Epidemiological characteristics of the whole study population as well as of LTFU- and currently in follow-up patients were analyzed. RESULTS: Between 1966 and 1999, 281 individuals were diagnosed with PKU through the NANSP. Two patients died in their first year of life and were excluded from the analysis. Of the remaining 279 patients (mean age ± SD: 36.7 ± 9.1 y, 42.7% females), 177 (63.4%) are currently LTFU. The rate of LTFU patients is higher in men than in women (68.1% vs 57.5%), and markedly increases with age in both sexes. The gender gap is greatest in young adults (52.6% vs. 25.0% in the age range 20.0-24.9 y) and declines with age (94.4% vs. 80.0% in the age range > 45.0 y). CONCLUSIONS: We found an alarming rate of 63.4% of LTFU adult PKU patients in Austria, and observed a gender gap in the PKU state of care. Our findings illustrate the urgent need for the metabolic community to identify LTFU adult PKU patients and to develop strategies to reestablish appropriate treatment for men and women with PKU.


Asunto(s)
Perdida de Seguimiento , Fenilcetonurias/diagnóstico , Fenilcetonurias/tratamiento farmacológico , Adulto , Factores de Edad , Instituciones de Atención Ambulatoria , Austria , Manejo de la Enfermedad , Femenino , Humanos , Recién Nacido , Masculino , Persona de Mediana Edad , Tamizaje Neonatal , Fenilcetonurias/epidemiología , Factores Sexuales
15.
Ann Neurol ; 88(5): 867-877, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32808683

RESUMEN

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.


Asunto(s)
Distonía/genética , Enfermedades por Almacenamiento Lisosomal/genética , Proteínas de Transporte Vesicular/genética , Adulto , Costo de Enfermedad , Distonía/patología , Exoma/genética , Femenino , Fibroblastos/patología , Predisposición Genética a la Enfermedad/genética , Variación Genética , Humanos , Enfermedades por Almacenamiento Lisosomal/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Linaje
16.
J Inherit Metab Dis ; 44(1): 178-192, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33200442

RESUMEN

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.


Asunto(s)
Arginina/administración & dosificación , Suplementos Dietéticos , Epilepsia/dietoterapia , Epilepsia/diagnóstico , Aldehído Deshidrogenasa/deficiencia , Consenso , Epilepsia/tratamiento farmacológico , Humanos , Cooperación Internacional , Lisina/deficiencia , Piridoxina/uso terapéutico
17.
J Inherit Metab Dis ; 43(5): 1102-1111, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32319100

RESUMEN

Rapid diagnosis and early specific treatment of metabolic epilepsies due to inborn errors of metabolism (IEMs) is crucial to avoid irreversible sequalae. Nowadays, besides the profile analysis of amino- and organic acids, a range of additional targeted assays is used for the selective screening of those diseases. This strategy can lead to long turn-around times, repeated sampling and diagnostic delays. To replace those individual targeted assays, we developed a new liquid chromatography mass spectrometry method (LC-MS/MS) for the differential diagnosis of inherited metabolic epilepsies that are potentially treatable. The method was developed to simultaneously quantify 12 metabolites (sulfocysteine, guanidinoacetate, creatine, pipecolic acid, Δ1 -piperideine-6-carboxylate (P6C), proline, Δ1 -pyrroline-5-carboxylate (P5C), and the B6 -vitamers) enabling the diagnosis of nine different treatable IEMs presenting primarily with early-onset epilepsy. Plasma and urine samples were mixed with internal standards, precipitated and the supernatants were analyzed by LC-MS/MS. In comparison with previous assays, no derivatization of the metabolites is necessary for analysis. This LC-MS method was validated for quantitative results for all metabolites except P6C and P5C for which semiquantitative results were obtained due to the absence of commercially available standards. Coefficients of variation for all analytes were below 15% and recovery rates range between 80% and 120%. Analysis of patient samples with known IEMs demonstrated the diagnostic value of the method. The presented assay covers a selected panel of biochemical markers, improves the efficiency in the laboratory, and potentially leads to faster diagnoses and earlier treatment avoiding irreversible damage in patients affected with IEMs.


Asunto(s)
Cromatografía Liquida/métodos , Epilepsia/sangre , Errores Innatos del Metabolismo/sangre , Convulsiones/sangre , Espectrometría de Masas en Tándem/métodos , Aldehído Deshidrogenasa/sangre , Aldehído Deshidrogenasa/deficiencia , Biomarcadores/sangre , Diagnóstico Diferencial , Epilepsia/diagnóstico , Humanos , Errores Innatos del Metabolismo/diagnóstico , Ácidos Picolínicos/sangre , Ácidos Pipecólicos/sangre , Convulsiones/diagnóstico
18.
J Inherit Metab Dis ; 43(4): 891-900, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31930735

RESUMEN

Antiquitin (ATQ) deficiency leads to tissue, plasma, and urinary accumulation of alpha-aminoadipic semialdehyde (AASA) and its Schiff base delta-1-piperideine-6-carboxylate (P6C). Although genetic testing of ALDH7A1 is the most definitive diagnostic method, quantifications of pathognomonic metabolites are important for the diagnosis and evaluation of therapeutic and dietary interventions. Current metabolite quantification methods use laborious, technically highly complex, and expensive liquid chromatography-tandem mass spectro-metry, which is available only in selected laboratories worldwide. Incubation of ortho-aminobenzaldehyde (oABA) with P6C leads to the formation of a triple aromatic ring structure with characteristic absorption and fluorescence properties. The mean concentration of P6C in nine urine samples from seven ATQ-deficient patients under standard treatment protocols was statistically highly significantly different (P < .001) compared to the mean of 74 healthy controls aged between 2 months and 57 years. Using this limited data set the specificity and sensitivity is 100% for all tested age groups using a P6C cut-off of 2.11 µmol/mmol creatinine, which represents the 99% prediction interval of the P6C concentrations in 17 control urine samples from children below 6 years of age. Plasma P6C concentrations were only elevated in one ATQ subject, possibly because P6C is trapped by pyridoxal-5-phosphate (PLP) blocking fusing with oABA. Nevertheless, both urine and plasma samples were amenable to the quantification of exogenous P6C with high response rates. The P6C quantification method using fusion of oABA with P6C is fast, simple, and inexpensive and might be readily implemented into routine clinical diagnostic laboratories for the early diagnosis of neonatal pyridoxine-dependent epilepsy.


Asunto(s)
Aldehído Deshidrogenasa/deficiencia , Benzaldehídos/orina , Epilepsia/orina , Ácidos Picolínicos/orina , Adolescente , Adulto , Aldehído Deshidrogenasa/genética , Estudios de Casos y Controles , Niño , Preescolar , Dieta , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/metabolismo , Femenino , Humanos , Lactante , Lisina/metabolismo , Masculino , Persona de Mediana Edad , Adulto Joven
19.
Brain ; 142(6): 1561-1572, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-31135052

RESUMEN

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.


Asunto(s)
Trastornos Heredodegenerativos del Sistema Nervioso/genética , Fenotipo , Paraplejía Espástica Hereditaria/genética , Niño , Estudios de Cohortes , Enfermedades Desmielinizantes/genética , Femenino , Humanos , Masculino , Oxigenasas de Función Mixta/genética , Mutación/genética , Linaje , Estudios Retrospectivos , Paraplejía Espástica Hereditaria/clasificación
20.
Eur J Pediatr ; 179(11): 1729-1737, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32415337

RESUMEN

Children born with esophageal atresia (EA) might suffer from significant oral feeding problems which could evolve into tube dependency. The primary aim of the study was to define the outcome of tube weaning in children after successful EA repair and to compare outcomes in children with short gap/TEF (tracheoesophageal fistula) and long-gap EA. Data of 64 children (28 with short-gap EA/TEF with primary anastomosis and 36 with long-gap EA with delayed surgical repair) who participated in a standardized tube weaning program based on the "Graz model of tube weaning" (in/outpatients in an intensive 3-week program, online coaching (Netcoaching) only, or a combined 2-week intensive onsite followed by online treatment "Eating School") from 2009 to 2019 was evaluated. Sixty-one patients completed the program by transitioning to exclusive oral intake (95.3%). Three children (4.7%) were left partially weaned at the time of discharge. No significant differences could be found between short gap/TEF and long-gap EA group regarding outcomes.Conclusions: The study's findings support the efficacy of tube weaning based on the published "Graz model of tube weaning" for children born with EA/TEF and indicate the necessity of specialized tube weaning programs for these patients. What is Known: • Children with esophageal atresia/tracheoesophageal fistula often suffer from feeding problems and tube dependency. • Different tube weaning programs and outcomes have been published, but not specifically for children with EA. What is New: • Evaluation of a large sample of children referred for tube weaning after EA repair. • Most children with EA can be weaned off their feeding tubes successfully after attending a specialized tube weaning program.


Asunto(s)
Atresia Esofágica , Fístula Traqueoesofágica , Niño , Atresia Esofágica/cirugía , Humanos , Estudios Retrospectivos , Fístula Traqueoesofágica/etiología , Fístula Traqueoesofágica/cirugía , Resultado del Tratamiento , Destete
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