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1.
J Inherit Metab Dis ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31930735

RESUMO

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.

2.
J Neuromuscul Dis ; 7(1): 41-46, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31744015

RESUMO

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

3.
Neuropediatrics ; 50(5): 280-293, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31340400

RESUMO

Neonatal seizures are the most prevalent and distinctive sign of neurologic dysfunction in early life and pose an immense challenge for clinicians. Improvements in neonatal care have increased the survival rate of extremely premature infants, considerably changing the spectrum of underlying etiologies, and instigating a gradual shift from mortality to morbidity. Recognizing neonatal seizures can be challenging due to variability in presentation but clinical features can often provide valuable clues about etiology. Yet, the majority of neonatal seizures are subclinical. Even though conventional electroencephalography (EEG) with simultaneous video detection of seizures still represents the diagnostic gold standard, continuous monitoring using a one- to two-channel amplitude-integrated EEG with concurrent unprocessed EEG can be crucial for early recognition and intervention. Furthermore, tremendous progress has been made in neuroimaging, and all infants with seizures should have a magnetic resonance imaging (MRI) to help identify the underlying etiology. While the majority of neonatal seizures are caused by hypoxic-ischemic events, stroke, hemorrhage, or infection, approximately 15% of patients will require more sophisticated algorithms for diagnostic workup, including metabolic and genetic screening. These recent developments have led to renew interest in the classification of neonatal seizures, which aim to help identify etiology and guide appropriate therapeutic and prognostic decisions. In this review, we outline recent progress made in the etiology, diagnosis, and treatment of neonatal seizures and highlight areas that deserve further research.

4.
Brain ; 142(6): 1561-1572, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31135052

RESUMO

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.

5.
Genet Med ; 21(9): 2043-2058, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30842647

RESUMO

PURPOSE: Microcephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly. METHODS: We performed clinical assessment, high-resolution chromosomal microarray analysis, exome sequencing, and functional studies in 62 patients (58% with primary microcephaly [PM], 27% with secondary microcephaly [SM], and 15% of unknown onset). RESULTS: We found severity of developmental delay/intellectual disability correlating with severity of microcephaly in PM, but not SM. We detected causative variants in 48.4% of patients and found divergent inheritance and variant pattern for PM (mainly recessive and likely gene-disrupting [LGD]) versus SM (all dominant de novo and evenly LGD or missense). While centrosome-related pathways were solely identified in PM, transcriptional regulation was the most frequently affected pathway in both SM and PM. Unexpectedly, we found causative variants in different mitochondria-related genes accounting for ~5% of patients, which emphasizes their role even in syndromic PM. Additionally, we delineated novel candidate genes involved in centrosome-related pathway (SPAG5, TEDC1), Wnt signaling (VPS26A, ZNRF3), and RNA trafficking (DDX1). CONCLUSION: Our findings enable improved evaluation and genetic counseling of PM and SM patients and further elucidate microcephaly pathways.

6.
Mol Med ; 25(1): 6, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30813884

RESUMO

BACKGROUND: Deleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood. METHODS: To further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling. RESULTS: The two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings. CONCLUSIONS: Our findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Nav1.2 gating changes. Moreover, structural modeling was able to predict the severity of the variant impact, supporting a potential role of structural modeling as a prognostic tool. Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants.


Assuntos
Epilepsia Neonatal Benigna/genética , Síndromes Epilépticas/genética , Deficiência Intelectual/genética , Canal de Sódio Disparado por Voltagem NAV1.2/fisiologia , Adolescente , Criança , Epilepsia Neonatal Benigna/fisiopatologia , Síndromes Epilépticas/fisiopatologia , Estudos de Associação Genética , Células HEK293 , Humanos , Deficiência Intelectual/fisiopatologia , Fenótipo , Adulto Jovem
7.
J Inherit Metab Dis ; 42(4): 620-628, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30767241

RESUMO

Deficiency of antiquitin (ATQ), an enzyme involved in lysine degradation, is the major cause of vitamin B6 -dependent epilepsy. Accumulation of the potentially neurotoxic α-aminoadipic semialdehyde (AASA) may contribute to frequently associated developmental delay. AASA is formed by α-aminoadipic semialdehyde synthase (AASS) via the saccharopine pathway of lysine degradation, or, as has been postulated, by the pipecolic acid (PA) pathway, and then converted to α-aminoadipic acid by ATQ. The PA pathway has been considered to be the predominant pathway of lysine degradation in mammalian brain; however, this was refuted by recent studies in mouse. Consequently, inhibition of AASS was proposed as a potential new treatment option for ATQ deficiency. It is therefore of utmost importance to determine whether the saccharopine pathway is also predominant in human brain cells. The route of lysine degradation was analyzed by isotopic tracing studies in cultured human astrocytes, ReNcell CX human neuronal progenitor cells and human fibroblasts, and expression of enzymes of the two lysine degradation pathways was determined by Western blot. Lysine degradation was only detected through the saccharopine pathway in all cell types studied. The enrichment of 15 N-glutamate as a side product of AASA formation through AASS furthermore demonstrated activity of the saccharopine pathway. We provide first evidence that the saccharopine pathway is the major route of lysine degradation in cultured human brain cells. These results support inhibition of the saccharopine pathway as a new treatment option for ATQ deficiency.

8.
J Inherit Metab Dis ; 42(4): 629-646, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30671974

RESUMO

Vitamin B6 is present in our diet in many forms, however, only pyridoxal 5'-phosphate (PLP) can function as a cofactor for enzymes. The intestine absorbs nonphosphorylated B6 vitamers, which are converted by specific enzymes to the active PLP form. The role of PLP is enabled by its reactive aldehyde group. Pathways reliant on PLP include amino acid and neurotransmitter metabolism, folate and 1-carbon metabolism, protein and polyamine synthesis, carbohydrate and lipid metabolism, mitochondrial function and erythropoiesis. Besides the role of PLP as a cofactor B6 vitamers also play other cellular roles, for example, as antioxidants, modifying expression and action of steroid hormone receptors, affecting immune function, as chaperones and as an antagonist of Adenosine-5'-triphosphate (ATP) at P2 purinoceptors. Because of the vital role of PLP in neurotransmitter metabolism, particularly synthesis of the inhibitory transmitter γ-aminobutyric acid, it is not surprising that various inborn errors leading to PLP deficiency manifest as B6 -responsive epilepsy, usually of early onset. This includes pyridox(am)ine phosphate oxidase deficiency (a disorder affecting PLP synthesis and recycling), disorders affecting PLP import into the brain (hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects), a disorder of an intracellular PLP-binding protein (PLPBP, previously named PROSC) and disorders where metabolites accumulate that inactivate PLP, for example, ALDH7A1 deficiency and hyperprolinaemia type II. Patients with these disorders can show rapid control of seizures in response to either pyridoxine and/or PLP with a lifelong dependency on supraphysiological vitamin B6 supply. The clinical and biochemical features of disorders leading to B6 -responsive seizures and the treatment of these disorders are described in this review.

9.
Eur J Hum Genet ; 27(5): 747-759, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30664714

RESUMO

CYFIP2, encoding the evolutionary highly conserved cytoplasmic FMRP interacting protein 2, has previously been proposed as a candidate gene for intellectual disability and autism because of its important role linking FMRP-dependent transcription regulation and actin polymerization via the WAVE regulatory complex (WRC). Recently, de novo variants affecting the amino acid p.Arg87 of CYFIP2 were reported in four individuals with epileptic encephalopathy. We here report 12 independent patients harboring a variety of de novo variants in CYFIP2 broadening the molecular and clinical spectrum of a novel CYFIP2-related neurodevelopmental disorder. Using trio whole-exome or -genome sequencing, we identified 12 independent patients carrying a total of eight distinct de novo variants in CYFIP2 with a shared phenotype of intellectual disability, seizures, and muscular hypotonia. We detected seven different missense variants, of which two occurred recurrently (p.(Arg87Cys) and p.(Ile664Met)), and a splice donor variant in the last intron for which we showed exon skipping in the transcript. The latter is expected to escape nonsense-mediated mRNA decay resulting in a truncated protein. Despite the large spacing in the primary structure, the variants spatially cluster in the tertiary structure and are all predicted to weaken the interaction with WAVE1 or NCKAP1 of the actin polymerization regulating WRC-complex. Preliminary genotype-phenotype correlation indicates a profound phenotype in p.Arg87 substitutions and a more variable phenotype in other alterations. This study evidenced a variety of de novo variants in CYFIP2 as a novel cause of mostly severe intellectual disability with seizures and muscular hypotonia.

10.
J Inherit Metab Dis ; 42(2): 264-275, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30689204

RESUMO

Mitochondrial aconitase is the second enzyme in the tricarboxylic acid (TCA) cycle catalyzing the interconversion of citrate into isocitrate and encoded by the nuclear gene ACO2. A homozygous pathogenic variant in the ACO2 gene was initially described in 2012 resulting in a novel disorder termed "infantile cerebellar retinal degeneration" (ICRD, OMIM#614559). Subsequently, additional studies reported patients with pathogenic ACO2 variants, further expanding the genetic and clinical spectrum of this disorder to include milder and later onset manifestations. Here, we report an international multicenter cohort of 16 patients (of whom 7 are newly diagnosed) with biallelic pathogenic variants in ACO2 gene. Most patients present in early infancy with severe truncal hypotonia, truncal ataxia, variable seizures, evolving microcephaly, and ophthalmological abnormalities of which the most dominant are esotropia and optic atrophy with later development of retinal dystrophy. Most patients remain nonambulatory and do no acquire any language, but a subgroup of patients share a more favorable course. Brain magnetic resonance imaging (MRI) is typically normal within the first months but global atrophy gradually develops affecting predominantly the cerebellum. Ten of our patients were homozygous to the previously reported c.336C>G founder mutation while the other six patients were all compound heterozygotes displaying 10 novel mutations of whom 2 were nonsense predicting a deleterious effect on enzyme function. Structural protein modeling predicted significant impairment in aconitase substrate binding in the additional missense mutations. This study provides the most extensive cohort of patients and further delineates the clinical, radiological, biochemical, and molecular features of ACO2 deficiency.

11.
Eur J Hum Genet ; 27(3): 408-421, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30552426

RESUMO

Early-onset epileptic encephalopathy (EE) and combined developmental and epileptic encephalopathies (DEE) are clinically and genetically heterogeneous severely devastating conditions. Recent studies emphasized de novo variants as major underlying cause suggesting a generally low-recurrence risk. In order to better understand the full genetic landscape of EE and DEE, we performed high-resolution chromosomal microarray analysis in combination with whole-exome sequencing in 63 deeply phenotyped independent patients. After bioinformatic filtering for rare variants, diagnostic yield was improved for recessive disorders by manual data curation as well as molecular modeling of missense variants and untargeted plasma-metabolomics in selected patients. In total, we yielded a diagnosis in ∼42% of cases with causative copy number variants in 6 patients (∼10%) and causative sequence variants in 16 established disease genes in 20 patients (∼32%), including compound heterozygosity for causative sequence and copy number variants in one patient. In total, 38% of diagnosed cases were caused by recessive genes, of which two cases escaped automatic calling due to one allele occurring de novo. Notably, we found the recessive gene SPATA5 causative in as much as 3% of our cohort, indicating that it may have been underdiagnosed in previous studies. We further support candidacy for neurodevelopmental disorders of four previously described genes (PIK3AP1, GTF3C3, UFC1, and WRAP53), three of which also followed a recessive inheritance pattern. Our results therefore confirm the importance of de novo causative gene variants in EE/DEE, but additionally illustrate the major role of mostly compound heterozygous or hemizygous recessive inheritance and consequently high-recurrence risk.


Assuntos
Variações do Número de Cópias de DNA , Epilepsia/genética , Taxa de Mutação , Sequenciamento Completo do Exoma/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Epilepsia/diagnóstico , Exoma , Feminino , Genes Recessivos , Humanos , Lactente , Masculino
13.
J Inherit Metab Dis ; 41(3): 425-434, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29536202

RESUMO

Conventional workup of rare neurological disease is frequently hampered by diagnostic delay or lack of diagnosis. While biomarkers have been established for many neurometabolic disorders, improved methods are required for diagnosis of previously unidentified or underreported causes of rare neurological disease. This would result in a higher diagnostic yield and increased patient numbers required for interventional studies. Recent studies using next-generation sequencing and metabolomics have led to identification of novel disease-causing genes and biomarkers. This combined approach can assist in overcoming challenges associated with analyzing and interpreting the large amount of data obtained from each technique. In particular, metabolomics can support the pathogenicity of sequence variants in genes encoding enzymes or transporters involved in metabolic pathways. Moreover, metabolomics can show the broader perturbation caused by inborn errors of metabolism and identify a metabolic fingerprint of metabolic disorders. As such, using "omics" has great potential to meet the current needs for improved diagnosis and elucidation of rare neurological disease.


Assuntos
Genômica/métodos , Metabolômica/métodos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/terapia , Biomarcadores/metabolismo , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Redes e Vias Metabólicas/genética , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/metabolismo , Doenças Raras/terapia
14.
Neuropediatrics ; 49(2): 154-157, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29401530

RESUMO

Antiquitin deficiency is the most prevalent form of pyridoxine-dependent epilepsy. While most patients present with neonatal onset of therapy-resistant seizures, a few cases with late-onset during infancy have been described. Here, we describe the juvenile onset of epilepsy at the age of 17 years due to antiquitin deficiency in an Indian female with homozygosity for the most prevalent ALDH7A1 missense mutation, c.1279G > C; p.Glu427Gln in exon 14. The diagnosis was established along familial cosegregation analysis for an affected offspring, that had neonatal pyridoxine responsive seizures and had been found to be compound heterozygous for c.1279G > C; p.Glu427Gln in exon 14 and a nonsense mutation c.796C > T; p.Arg266* in exon 9. While seizures in the mother had been incompletely controlled by levetiracetam, she remained seizure-free on pyridoxine monotherapy, 200 mg/day. Her fourth pregnancy resulted in a female affected offspring, who was treated prospectively and never developed seizures with a normal outcome at age 2 years while on pyridoxine. This report illustrates that the phenotypic spectrum of antiquitin deficiency is still underestimated and that this treatable inborn error of metabolism has to be considered in case of therapy-resistant seizures even at older age. It furthermore supports prospective in utero treatment with pyridoxine in forthcoming pregnancies at risk.


Assuntos
Aldeído Desidrogenase/deficiência , Epilepsia/etiologia , Epilepsia/genética , Doenças Metabólicas/complicações , Doenças Metabólicas/genética , Idade de Início , Aldeído Desidrogenase/genética , Epilepsia/sangue , Epilepsia/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/diagnóstico por imagem , Ácidos Pipecólicos/sangue , Adulto Jovem
15.
BMC Pediatr ; 18(1): 67, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29452600

RESUMO

BACKGROUND: Paediatric end-of-life care is challenging and requires a high level of professional expertise. It is important that healthcare teams have a thorough understanding of paediatric subspecialties and related knowledge of disease-specific aspects of paediatric end-of-life care. The aim of this study was to comprehensively describe, explore and compare current practices in paediatric end-of-life care in four distinct diagnostic groups across healthcare settings including all relevant levels of healthcare providers in Switzerland. METHODS: In this nationwide retrospective chart review study, data from paediatric patients who died in the years 2011 or 2012 due to a cardiac, neurological or oncological condition, or during the neonatal period were collected in 13 hospitals, two long-term institutions and 10 community-based healthcare service providers throughout Switzerland. RESULTS: Ninety-three (62%) of the 149 reviewed patients died in intensive care units, 78 (84%) of them following withdrawal of life-sustaining treatment. Reliance on invasive medical interventions was prevalent, and the use of medication was high, with a median count of 12 different drugs during the last week of life. Patients experienced an average number of 6.42 symptoms. The prevalence of various types of symptoms differed significantly among the four diagnostic groups. Overall, our study patients stayed in the hospital for a median of six days during their last four weeks of life. Seventy-two patients (48%) stayed at home for at least one day and only half of those received community-based healthcare. CONCLUSIONS: The study provides a wide-ranging overview of current end-of-life care practices in a real-life setting of different healthcare providers. The inclusion of patients with all major diagnoses leading to disease- and prematurity-related childhood deaths, as well as comparisons across the diagnostic groups, provides additional insight and understanding for healthcare professionals. The provision of specialised palliative and end-of-life care services in Switzerland, including the capacity of community healthcare services, need to be expanded to meet the specific needs of seriously ill children and their families.


Assuntos
Padrões de Prática Médica/estatística & dados numéricos , Assistência Terminal/métodos , Adolescente , Criança , Pré-Escolar , Serviços de Saúde Comunitária/estatística & dados numéricos , Estudos Transversais , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Cuidados Paliativos/estatística & dados numéricos , Pediatria , Estudos Retrospectivos , Suíça , Assistência Terminal/estatística & dados numéricos
16.
Eur J Paediatr Neurol ; 22(1): 46-55, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29122497

RESUMO

Iron-Sulfur Cluster (ISC) biogenesis is a vital cellular process required to produce various ISC-containing proteins. These ISC proteins are responsible for essential functions such as glycine cleavage and the formation of lipoic acid, an essential cofactor of respiratory chain complexes. Defects in ISC biogenesis lead to multiple mitochondrial dysfunction syndromes including: ISCA2 with infantile onset leukodystrophy. Recently, a founder mutation, c.229G > A, p.Gly77Ser in ISCA2 was reported to cause Multiple Mitochondrial Dysfunction Syndrome type 4. In a retrospective review of children diagnosed with the ISCA2 defect, we were able to identify ten new patients who were not reported previously with the identical founder mutation. High CSF glycine levels and elevated glycine peaks on MR spectroscopy were demonstrated in all tested probands. All patients were between 3 and 7 months of age with a triad of neurodevelopmental regression, nystagmus and optic atrophy and leukodystrophy. MRI findings were typical in the patients with diffuse, abnormal white matter signal in the cerebrum, cerebellum, brain stem and spinal cord. The patients ended up in a vegetative state, and often premature death due to respiratory infections. We alert clinicians to consider the ISCA2 defect as a differential diagnosis of infantile onset leukodystrophies affecting the brain as well as the spinal cord, especially in the presence of elevated CSF glycine or elevated glycine peaks in MR spectroscopy.


Assuntos
Encéfalo/patologia , Proteínas com Ferro-Enxofre/genética , Doenças Mitocondriais/patologia , Medula Espinal/patologia , Substância Branca/patologia , Feminino , Humanos , Lactente , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/patologia , Imagem por Ressonância Magnética , Masculino , Doenças Mitocondriais/genética , Fenótipo , Estudos Retrospectivos
17.
Fetal Diagn Ther ; 44(3): 210-220, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28950252

RESUMO

OBJECTIVE: In order to provide aid for prenatal counseling in fetal isolated ventriculomegaly (IVM) on ultrasound, we recorded the latest long-term clinical and imaging outcomes of children with a mean age of 7.2 years (range 2.1-14.6). METHODS: In 72 fetuses with IVM, diagnosed between 1999 and 2011, the measurement quality of atrial diameter was reviewed in the axial plane. We assessed the association of characteristics of IVM with outcome parameters in the cohort and in subgroups. Prognostic values of significant associations were reported by receiver operating characteristic curve analysis. RESULTS: Cerebral anomalies were diagnosed postnatally in 42% and genetic disorders in 12% of 45 live births. Significant associations of outcome parameters were found between the degree of IVM and genetic disorders (p = 0.017) with an area under the curve (AUC) of 0.866, and between progression of IVM and motor impairment (p = 0.024) with an AUC of 0.789. No significant correlation was found with the other assessed outcome parameters. Furthermore, our subgroup analysis clearly showed that, if cerebral or genetic anomalies are not found postnatally, a favorable outcome may be expected. DISCUSSION: Diameter and progression in IVM are not significantly associated with most outcome parameters. Cerebral anomalies and genetic disorders may contribute to an unfavorable outcome.


Assuntos
Hidrocefalia/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/etiologia , Diagnóstico Pré-Natal , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Hidrocefalia/complicações , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Gravidez , Prognóstico , Ultrassonografia Pré-Natal
18.
Neurology ; 89(17): 1821-1828, 2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-28931644

RESUMO

OBJECTIVE: To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations. METHODS: We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression. RESULTS: Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all 16 patients. All patients shared a common haplotype, indicative of a founder effect. Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%-25%. Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines. CONCLUSIONS: UFM1 encodes ubiquitin-fold modifier 1 (UFM1), a member of the ubiquitin-like family involved in posttranslational modification of proteins. Its exact biological role is unclear. This study associates a UFM1 gene defect with a disease and sheds new light on possible UFM1 functional networks.


Assuntos
Sistemas de Transporte de Aminoácidos Acídicos/deficiência , Antiporters/deficiência , Gânglios da Base/patologia , Cerebelo/patologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Mitocondriais/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , Transtornos Psicomotores/genética , Adolescente , Adulto , Sistemas de Transporte de Aminoácidos Acídicos/genética , Antiporters/genética , Atrofia/etiologia , Gânglios da Base/diagnóstico por imagem , Linhagem Celular Tumoral/patologia , Cerebelo/diagnóstico por imagem , Criança , Pré-Escolar , Análise Mutacional de DNA , Saúde da Família , Feminino , Células HeLa , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/complicações , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Itália , Imagem por Ressonância Magnética , Masculino , Doenças Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico por imagem , Transtornos Psicomotores/complicações , Transtornos Psicomotores/diagnóstico por imagem , Transfecção , Tubulina (Proteína)/genética , Adulto Jovem
19.
Pediatr Rheumatol Online J ; 15(1): 67, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28830446

RESUMO

BACKGROUND: Loss-of-function CECR1 mutations cause polyarteritis nodosa (PAN) with childhood onset, an autoinflammatory disorder without significant signs of autoimmunity. Herein we describe the unusual presentation of an autoimmune phenotype with constitutive type I interferon activation in siblings with adenosine deaminase 2 (ADA2) deficiency. CASE PRESENTATION: We describe two siblings with early-onset recurrent strokes, arthritis, oral ulcers, discoid rash, peripheral vascular occlusive disease and high antinuclear antibody titers. Assessment of interferon signatures in blood revealed constitutive type I interferon activation. Aicardi-Goutières syndrome (AGS) was suspected, but no mutation in the known AGS genes were detected. Whole exome sequencing identified compound heterozygosity for a known and a novel mutation in the CECR1 gene. Functional consequences of the mutations were demonstrated by marked reduction in ADA2 catalytic activity. CONCLUSIONS: Our findings demonstrate that ADA2 deficiency can cause an unusual autoimmune phenotype extending the phenotypic spectrum of PAN. Constitutive interferon I activation in patient blood suggests a possible role of type I interferon in disease pathogenesis which may have therapeutic implications.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Interferon Tipo I/metabolismo , Poliarterite Nodosa/genética , Imunodeficiência Combinada Severa/genética , Adenosina Desaminase/genética , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Criança , Pré-Escolar , Humanos , Lactente , Interferon Tipo I/genética , Masculino , Mutação , Linhagem , Fenótipo , Poliarterite Nodosa/complicações , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/diagnóstico
20.
PLoS One ; 12(5): e0176363, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28463998

RESUMO

Mitochondrial respiratory chain dysfunction has been identified in a number of neurodegenerative disorders. Infantile cerebellar-retinal degeneration associated with mutations in the mitochondrial aconitase 2 gene (ACO2) has been recently described as a neurodegenerative disease of autosomal recessive inheritance. To date there is no biomarker for ACO2 deficiency and diagnosis relies on genetic analysis. Here we report global metabolic profiling in eight patients with ACO2 deficiency. Using an LC-MS-based metabolomics platform we have identified several metabolites with affected plasma concentrations including the tricarboxylic acid cycle metabolites cis-aconitate, isocitrate and alpha-ketoglutarate, as well as phosphoenolpyruvate and hydroxybutyrate. Taken together we report a diagnostic metabolic fingerprint for mitochondrial aconitase 2 deficiency.


Assuntos
Aconitato Hidratase/deficiência , Aconitato Hidratase/genética , Ácido Aconítico/sangue , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Transtornos Heredodegenerativos do Sistema Nervoso/sangue , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Humanos , Hidroxibutiratos/sangue , Isocitratos/sangue , Ácidos Cetoglutáricos/sangue , Masculino , Metabolômica/métodos , Fosfoenolpiruvato/sangue
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