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The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8-33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.
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Errores Innatos del Metabolismo de los Aminoácidos , Fenotipo , Succionato-Semialdehído Deshidrogenasa , Humanos , Succionato-Semialdehído Deshidrogenasa/deficiencia , Succionato-Semialdehído Deshidrogenasa/genética , Niño , Masculino , Femenino , Preescolar , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/genética , Lactante , Adolescente , Adulto Joven , Discapacidades del Desarrollo/genética , Trastornos del Movimiento/genética , Mutación , Hipotonía Muscular/genéticaRESUMEN
In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11-61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney U-test, P < 0.0001) and were correlated inversely with age (Spearman's rank correlation coefficient r = -0.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.
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Paraplejía Espástica Hereditaria , Humanos , Preescolar , Paraplejía Espástica Hereditaria/genética , Estudios Transversales , Diagnóstico Tardío , Proteínas/genética , MutaciónRESUMEN
BACKGROUND: Patients carrying pathogenic variants in GNAO1 often present with early-onset central hypotonia and global developmental delay, with or without epilepsy. As the disorder progresses, a complex hypertonic and hyperkinetic movement disorder is a common phenotype. A genotype-phenotype correlation has not yet been described and there are no evidence-based therapeutic recommendations. METHODS: To improve understanding of the clinical course and pathophysiology of this ultra-rare disorder, we built up a registry for GNAO1 patients in Germany. In this retrospective, multicentre cohort study, we collected detailed clinical data, treatment effects and genetic data for 25 affected patients. RESULTS: The main clinical features were symptom onset within the first months of life, with central hypotonia or seizures. Within the first year of life, nearly all patients developed a movement disorder comprising dystonia (84%) and choreoathetosis (52%). Twelve (48%) patients suffered life-threatening hyperkinetic crises. Fifteen (60%) patients had epilepsy with poor treatment response. Two patients showed an atypical phenotype and seven novel pathogenic variants in GNAO1 were identified. Nine (38%) patients were treated with bilateral deep brain stimulation of the globus pallidus internus. Deep brain stimulation reduced hyperkinetic symptoms and prevented further hyperkinetic crises. The in silico prediction programmes did not predict the phenotype by the genotype. CONCLUSION: The broad clinical spectrum and genetic findings expand the phenotypical spectrum of GNAO1-associated disorder and therefore disprove the assumption that there are only two main phenotypes. No specific overall genotype-phenotype correlation was identified. We highlight deep brain stimulation as a useful treatment option in this disorder.
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Epilepsia , Trastornos del Movimiento , Humanos , Estudios Retrospectivos , Estudios de Cohortes , Hipotonía Muscular , Estudios de Asociación Genética , Epilepsia/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genéticaRESUMEN
ß-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyses the conversion of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid to ß-alanine and ß-aminoisobutyric acid, ammonia and CO2. To date, only a limited number of genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 10 newly identified ß-ureidopropionase deficient individuals. Patients presented mainly with neurological abnormalities and markedly elevated levels of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in urine. Analysis of UPB1, encoding ß-ureidopropionase, showed 5 novel missense variants and two novel splice-site variants. Functional expression of the UPB1 variants in mammalian cells showed that recombinant ß-ureidopropionase carrying the p.Ala120Ser, p.Thr129Met, p.Ser300Leu and p.Asn345Ile variant yielded no or significantly decreased ß-ureidopropionase activity. Analysis of the crystal structure of human ß-ureidopropionase indicated that the point mutations affect substrate binding or prevent the proper subunit association to larger oligomers and thus a fully functional ß-ureidopropionase. A minigene approach showed that the intronic variants c.[364 + 6 T > G] and c.[916 + 1_916 + 2dup] led to skipping of exon 3 and 8, respectively, in the process of UPB1 pre-mRNA splicing. The c.[899C > T] (p.Ser300Leu) variant was identified in two unrelated Swedish ß-ureidopropionase patients, indicating that ß-ureidopropionase deficiency may be more common than anticipated.
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Errores Innatos del Metabolismo de la Purina-Pirimidina , Precursores del ARN , Anomalías Múltiples , Amidohidrolasas/deficiencia , Amidohidrolasas/genética , Animales , Encefalopatías , Humanos , Mamíferos/genética , Trastornos del Movimiento , Mutación , Errores Innatos del Metabolismo de la Purina-Pirimidina/genética , beta-Alanina/genética , beta-Alanina/orinaRESUMEN
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter γ-amino butyric acid (GABA). Pathogenic variants in the ALDH5A1 gene that cause an enzymatic dysfunction of succinic semialdehyde dehydrogenase (SSADH) lead to an accumulation of potentially toxic metabolites, including γ-hydroxybutyrate (GHB). Here, we present a patient with a severe phenotype of SSADHD caused by a novel genetic variant c.728T > C that leads to an exchange of leucine to proline at residue 243, located within the highly conserved nicotinamide adenine dinucleotide (NAD)+ binding domain of SSADH. Proline harbors a pyrrolidine within its side chain known for its conformational rigidity and disruption of protein secondary structures. We investigate the effect of this novel variant in vivo, in vitro, and in silico. We furthermore examine the mutational spectrum of all previously described disease-causing variants and computationally assess all biologically possible missense variants of ALDH5A1 to identify mutational hotspots.
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Errores Innatos del Metabolismo de los Aminoácidos , Simulación por Computador , Discapacidades del Desarrollo , Mutación Missense , Succionato-Semialdehído Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Errores Innatos del Metabolismo de los Aminoácidos/genética , Sustitución de Aminoácidos , Discapacidades del Desarrollo/enzimología , Discapacidades del Desarrollo/genética , Células HEK293 , Humanos , Dominios Proteicos , Succionato-Semialdehído Deshidrogenasa/genética , Succionato-Semialdehído Deshidrogenasa/metabolismoRESUMEN
Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.
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Alelos , Encefalopatías/genética , Mutación/genética , Proteínas/metabolismo , Enzimas Activadoras de Ubiquitina/genética , Edad de Inicio , Animales , Mapeo Encefálico , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Niño , Preescolar , Neuronas Colinérgicas/metabolismo , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Epilepsia/genética , Exoma/genética , Femenino , Fibroblastos , Genes Recesivos/genética , Humanos , Discapacidad Intelectual/genética , Imagen por Resonancia Magnética , Masculino , Microcefalia/genética , Trastornos del Movimiento , Proteínas/genética , Transmisión Sináptica/genética , Ubiquitina/genética , Ubiquitina/metabolismo , Enzimas Activadoras de Ubiquitina/deficiencia , Enzimas Activadoras de Ubiquitina/metabolismo , Ubiquitinas/genética , Ubiquitinas/metabolismo , Pez Cebra/genética , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (KMT2B) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations. The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients. We discovered three novel KMT2B mutations. Our analyses revealed that the mutation in patient 1 (c.7463A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to KMT2B instability. The mutations in patients 2 and 3 (c.3596_3697insC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense-mediated decay. Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of KMT2B mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.
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Distonía/diagnóstico , Distonía/etiología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , N-Metiltransferasa de Histona-Lisina/genética , Mutación , Fenotipo , Edad de Inicio , Alelos , Niño , Preescolar , Progresión de la Enfermedad , Distonía/terapia , Femenino , Estudios de Asociación Genética/métodos , Genómica/métodos , Genotipo , N-Metiltransferasa de Histona-Lisina/química , Humanos , Masculino , Modelos Moleculares , Neuroimagen/métodos , Linaje , Conformación Proteica , Relación Estructura-Actividad , Evaluación de Síntomas , Secuenciación Completa del GenomaRESUMEN
Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (KMT2B) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations.The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients.We discovered three novel KMT2B mutations. Our analyses revealed that the mutation in patient 1 (c.7463 A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to KMT2B instability. The mutations in patients 2 and 3 (c.3602dupC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense mediated decay.Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of KMT2B mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Neurotransmitter deficiencies are rare neurological disorders with clinical onset during childhood. The disorders are caused by genetic defects in the enzymes involved in synthesis, degradation, or transport of neurotransmitters or by defects in the cofactor biosynthesis such as tetrahydrobiopterin (BH4). With the newly described DNAJC12 deficiency, a chaperon-associated neurotransmitter disorder, the pathophysiological spectrum has been broadened. All deficiencies result in a lack of monoamine neurotransmitters, especially dopamine and its products, with a subset leading to decreased levels of serotonin. Symptoms can occur already in the neonatal period. Classical signs are hypotonia, movement disorders, autonomous dysregulations, and impaired development. Diagnosis depends on quantitative detection of neurotransmitters in cerebrospinal fluid, since peripheral markers in blood or urine are less reliable. Treatment is based on supplementation of the missing neurotransmitter precursors or restoring deficient cofactors for endogenous enzymatic synthesis. In recent years, knowledge about this orphan group of diseases increased substantially among clinicians. However, the difficult task of integrating clinical symptoms and laboratory values still leads to a critical delay in diagnosis and therapy for patients. This review aims at enhancing the understanding of neurotransmitter disorders and should help practicing clinicians to choose useful diagnostic steps on the way to a valid diagnosis.
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Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/metabolismo , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/metabolismo , Neurotransmisores/deficiencia , Animales , Dopamina/deficiencia , Dopamina/uso terapéutico , Humanos , Trastornos del Movimiento/tratamiento farmacológico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Neurotransmisores/uso terapéutico , Serotonina/deficiencia , Serotonina/uso terapéuticoRESUMEN
Neurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative disorders characterized by iron accumulation in the basal ganglia. Recently, mutations in CoA synthase (COASY) have been identified as a cause of a novel NBIA subtype (COASY Protein-Associated Neurodegeneration, CoPAN) in two patients with dystonic paraparesis, parkinsonian features, cognitive impairment, behavior abnormalities, and axonal neuropathy. COASY encodes an enzyme required for Coenzyme A (CoA) biosynthesis. Using whole exome sequencing (WES) we identified compound heterozygous COASY mutations in two siblings with intellectual disability, ataxic gait, progressive spasticity, and obsessive-compulsive behavior. The "eye-of-the tiger-sign," a characteristic hypointense spot within the hyperintense globi pallidi on MRI found in the most common subtype of NBIA (Pantothenate Kinase-Associated Neurodegeneration, PKAN), was not present. Instead, bilateral hyperintensity and swelling of caudate nucleus, putamen, and thalamus were found. In addition, our patients showed a small corpus callosum and frontotemporal and parietal white matter changes, expanding the brain phenotype of patients with CoPAN. Metabolic investigations showed increased free carnitine and decreased acylcarnitines in the patients dried blood samples. Carnitine palmitoyl transferase 1 (CPT1) deficiency was excluded by further enzymatic and metabolic investigations. As CoA and its derivate Acetyl-CoA play an essential role in fatty acid metabolism, we assume that abnormal acylcarnitine profiles are a result of the COASY mutations. This report not only illustrates that WES is a powerful tool to elucidate the etiology of rare genetic diseases, but also identifies unique neuroimaging and metabolic findings that may be key features for an early diagnosis of CoPAN.
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Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6 years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kölker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals.
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Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Encefalopatías Metabólicas/diagnóstico , Encefalopatías Metabólicas/tratamiento farmacológico , Glutaril-CoA Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Encefalopatías Metabólicas/metabolismo , Suplementos Dietéticos , Glutaratos/metabolismo , Glutaril-CoA Deshidrogenasa/metabolismo , Humanos , Lisina/metabolismoRESUMEN
The system of assigning locus symbols to specify chromosomal regions that are associated with a familial disorder has a number of problems when used as a reference list of genetically determined disorders,including (I) erroneously assigned loci, (II) duplicated loci, (III) missing symbols or loci, (IV) unconfirmed loci and genes, (V) a combination of causative genes and risk factor genes in the same list, and (VI) discordance between phenotype and list assignment. In this article, we report on the recommendations of the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders and present a system for naming genetically determined movement disorders that addresses these problems. We demonstrate how the system would be applied to currently known genetically determined parkinsonism, dystonia, dominantly inherited ataxia, spastic paraparesis, chorea, paroxysmal movement disorders, neurodegeneration with brain iron accumulation, and primary familial brain calcifications. This system provides a resource for clinicians and researchers that, unlike the previous system, can be considered an accurate and criterion-based list of confirmed genetically determined movement disorders at the time it was last updated.
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Trastornos del Movimiento/clasificación , Trastornos del Movimiento/genética , Sociedades Médicas/normas , HumanosRESUMEN
ß-ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid to ß-alanine and ß-aminoisobutyric acid, ammonia and CO(2). To date, only five genetically confirmed patients with a complete ß-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified ß-ureidopropionase deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological abnormalities (intellectual disabilities, seizures, abnormal tonus regulation, microcephaly, and malformations on neuro-imaging) and markedly elevated levels of N-carbamyl-ß-alanine and N-carbamyl-ß-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding ß-ureidopropionase, showed 6 novel missense mutations and one novel splice-site mutation. Heterologous expression of the 6 mutant enzymes in Escherichia coli showed that all mutations yielded mutant ß-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human ß-ureidopropionase generated using the crystal structure of the enzyme from Drosophila melanogaster indicated that the point mutations p.G235R, p.R236W and p.S264R lead to amino acid exchanges in the active site and therefore affect substrate binding and catalysis. The mutations L13S, R326Q and T359M resulted most likely in folding defects and oligomer assembly impairment. Two mutations were identified in several unrelated ß-ureidopropionase patients, indicating that ß-ureidopropionase deficiency may be more common than anticipated.
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Amidohidrolasas/deficiencia , Amidohidrolasas/genética , Enfermedades del Sistema Nervioso Central/genética , Errores Innatos del Metabolismo de la Purina-Pirimidina/genética , Pirimidinas/metabolismo , Adulto , Secuencia de Aminoácidos , Sustitución de Aminoácidos/fisiología , Ácidos Aminoisobutíricos/sangre , Ácidos Aminoisobutíricos/orina , Animales , Biocatálisis , Dominio Catalítico/fisiología , Enfermedades del Sistema Nervioso Central/enzimología , Niño , Preescolar , Drosophila melanogaster , Escherichia coli , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Mutación Missense , Mutación Puntual , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas/fisiología , Errores Innatos del Metabolismo de la Purina-Pirimidina/enzimología , Grupos Raciales/genética , beta-Alanina/sangre , beta-Alanina/orinaRESUMEN
BACKGROUND: Metabolic treatment in glutaric aciduria type I (GA-I) including a low lysine diet with lysine-free, tryptophan-reduced amino acid supplements (AAS), carnitine supplementation and early start of emergency treatment during putatively threatening episodes of intermittent febrile illness dramatically improves the outcome and thus has been recommended by an international guideline group (Kölker et al, J Inherit Metab Dis 30:5-22, 2007). However, possible affection of linear growth, weight gain and biochemical follow-up monitoring has not been studied systematically. METHODS: Thirty-three patients (n = 29 asymptomatic, n = 4 dystonic) with GA-I who have been identified by newborn screening in Germany from 1999 to 2009 were followed prospectively during the first six years of life. Dietary treatment protocols, anthropometrical and biochemical parameters were longitudinally evaluated. RESULTS: Mean daily intake as percentage of guideline recommendations was excellent for lysine (asymptomatic patients: 101 %; dystonic patients: 103 %), lysine-free, tryptophan-reduced AAS (108 %; 104 %), energy (106 %; 110 %), and carnitine (92 %; 102 %). Low lysine diet did not affect weight gain (mean SDS 0.05) but mildly impaired linear growth in asymptomatic patients (mean SDS -0.38), while dystonic patients showed significantly reduced weight gain (mean SDS -1.32) and a tendency towards linear growth retardation (mean SDS -1.03). Patients treated in accordance with recent recommendations did not show relevant abnormalities of routine biochemical follow-up parameters. INTERPRETATION: Low lysine diet promotes sufficient intake of essential nutrients and anthropometric development in asymptomatic children up to age 6 year, whereas individualized nutritional concepts are required for dystonic patients. Revised recommendations for biochemical monitoring might be required for asymptomatic patients.
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Errores Innatos del Metabolismo de los Aminoácidos/dietoterapia , Pesos y Medidas Corporales , Encefalopatías Metabólicas/dietoterapia , Alimentos Formulados , Glutaril-CoA Deshidrogenasa/deficiencia , Lisina/administración & dosificación , Errores Innatos del Metabolismo de los Aminoácidos/sangre , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Antropometría , Biomarcadores/análisis , Biomarcadores/sangre , Encefalopatías Metabólicas/sangre , Encefalopatías Metabólicas/metabolismo , Encefalopatías Metabólicas/fisiopatología , Carnitina/administración & dosificación , Niño , Preescolar , Suplementos Dietéticos , Ingestión de Alimentos/fisiología , Femenino , Estudios de Seguimiento , Glutaril-CoA Deshidrogenasa/sangre , Glutaril-CoA Deshidrogenasa/metabolismo , Humanos , Lactante , Masculino , Monitoreo Fisiológico/métodosRESUMEN
OBJECTIVE AND IMPORTANCE: Whereas posthemorrhagic hydrocephalus is well known after preterm birth, its association with syringomyelia has been reported only once. Here, we describe two additional patients showing this rare constellation. CLINICAL PRESENTATION: The children had been born after 27 and 28 completed weeks of gestation, respectively. Both had developed neonatal cerebral hemorrhages. At the age of 4 years, patient 1 presented with progressive ataxia leading to the diagnosis of internal hydrocephalus and extensive syringomyelia. In patient 2, progressive ventriculomegaly and syringomyelia were diagnosed at the age of 4 weeks. INTERVENTION: In both children, ventriculoperitoneal shunting resulted in clinical improvement, decrease of the ventricular size, and regression of the syringomyelia. After surgery, patient 1 developed a subdural hematoma and patient 2 parenchymatous cerebral hemorrhages. CONCLUSION: The combination of syringomyelia and posthemorrhagic hydrocephalus may be more frequent than commonly assumed. Therefore, neurological deterioration may mandate spinal MRI in addition to cerebral MRI. Syringomyelia seems to result from impaired ventricular cerebrospinal fluid drainage as it regresses after ventriculoperitoneal shunting. Bleeding may complicate the postsurgical relaxation of distended brain parenchyma.
Asunto(s)
Hidrocefalia/etiología , Hemorragias Intracraneales/complicaciones , Siringomielia/complicaciones , Ataxia/etiología , Preescolar , Femenino , Lateralidad Funcional/fisiología , Humanos , Hidrocefalia/patología , Hidrocefalia/cirugía , Recién Nacido , Hemorragias Intracraneales/patología , Hemorragias Intracraneales/cirugía , Imagen por Resonancia Magnética , Masculino , Procedimientos Neuroquirúrgicos , Siringomielia/patología , Siringomielia/cirugía , Derivación Ventriculoperitoneal , VentriculostomíaRESUMEN
Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine. To date, only 11 individuals have been reported suffering from a complete DHP deficiency. Here, we report on the clinical, biochemical and molecular findings of 17 newly identified DHP deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological and gastrointestinal abnormalities and markedly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine. Analysis of DPYS, encoding DHP, showed nine missense mutations, two nonsense mutations, two deletions and one splice-site mutation. Seventy-one percent of the mutations were located at exons 5-8, representing 41% of the coding sequence. Heterologous expression of 11 mutant enzymes in Escherichia coli showed that all but two missense mutations yielded mutant DHP proteins without significant activity. Only DHP enzymes containing the mutations p.R302Q and p.T343A possessed a residual activity of 3.9% and 49%, respectively. The crystal structure of human DHP indicated that the point mutations p.R490C, p.R302Q and p.V364M affect the oligomerization of the enzyme. In contrast, p.M70T, p.D81G, p.L337P and p.T343A affect regions near the di-zinc centre and the substrate binding site. The p.S379R and p.L7V mutations were likely to cause structural destabilization and protein misfolding. Four mutations were identified in multiple unrelated DHP patients, indicating that DHP deficiency may be more common than anticipated.
Asunto(s)
Amidohidrolasas/química , Amidohidrolasas/genética , Enfermedades Metabólicas/genética , Adolescente , Adulto , Amidohidrolasas/deficiencia , Amidohidrolasas/metabolismo , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades Metabólicas/enzimología , Modelos Biológicos , Modelos Moleculares , Fenotipo , Estabilidad Proteica , Estructura Secundaria de Proteína , Relación Estructura-Actividad , Adulto JovenRESUMEN
OBJECTIVE: Psychomotor impairment has been described in hypertyrosinemia types II and III (HT III). Only recently cognitive deficits have also been reported in hypertyrosinemia type I (HT I). The pathogenic mechanisms responsible are unknown. Since implementation of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, Nitisinone (Swedish Orphan International)) in the treatment of HT I, plasma tyrosine elevation is a common finding as known from the other hypertyrosinemias. PATIENTS AND METHODS: With elevated tyrosine as suspected pathogenic factor in the development of cognitive deficits, we here investigated tyrosine in the cerebrospinal fluid (CSF) and serotonergic and dopaminergic neurotransmitter levels in three patients with HT I during long-term treatment with Nitisinone. In addition, Nitisinone concentrations in plasma and CSF were measured. We also assessed psychomotor and cognitive development by standardized test systems and brain morphology by magnetic resonance imaging. RESULTS: All patients presented with high tyrosine concentrations in CSF correlating with increased plasma tyrosine levels and a reduced CSF serotonin turnover. MRI revealed no structural abnormalities in the brain. All patients presented with either impaired cognitive development or behavioural abnormalities. CONCLUSIONS: We here outline the need to further study the exact pathogenic mechanisms responsible for the neurotransmitter changes observed in HT type I in order to possibly prevent cognitive dysfunction. Nitisinone has significantly improved outcome and quality of life in HT type I; however, it is also accompanied by elevated plasma and CSF tyrosine. Further studies are essential to identify the necessary dietary tyrosine restriction and the optimal Nitisinone dose.