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1.
Am J Hum Genet ; 111(8): 1673-1699, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39084224

RESUMO

Understanding the impact of splicing and nonsense variants on RNA is crucial for the resolution of variant classification as well as their suitability for precision medicine interventions. This is primarily enabled through RNA studies involving transcriptomics followed by targeted assays using RNA isolated from clinically accessible tissues (CATs) such as blood or skin of affected individuals. Insufficient disease gene expression in CATs does however pose a major barrier to RNA based investigations, which we show is relevant to 1,436 Mendelian disease genes. We term these "silent" Mendelian genes (SMGs), the largest portion (36%) of which are associated with neurological disorders. We developed two approaches to induce SMG expression in human dermal fibroblasts (HDFs) to overcome this limitation, including CRISPR-activation-based gene transactivation and fibroblast-to-neuron transdifferentiation. Initial transactivation screens involving 40 SMGs stimulated our development of a highly multiplexed transactivation system culminating in the 6- to 90,000-fold induction of expression of 20/20 (100%) SMGs tested in HDFs. Transdifferentiation of HDFs directly to neurons led to expression of 193/516 (37.4%) of SMGs implicated in neurological disease. The magnitude and isoform diversity of SMG expression following either transactivation or transdifferentiation was comparable to clinically relevant tissues. We apply transdifferentiation and/or gene transactivation combined with short- and long-read RNA sequencing to investigate the impact that variants in USH2A, SCN1A, DMD, and PAK3 have on RNA using HDFs derived from affected individuals. Transactivation and transdifferentiation represent rapid, scalable functional genomic solutions to investigate variants impacting SMGs in the patient cell and genomic context.


Assuntos
Transdiferenciação Celular , Fibroblastos , Neurônios , Ativação Transcricional , Humanos , Transdiferenciação Celular/genética , Fibroblastos/metabolismo , Fibroblastos/citologia , Neurônios/metabolismo , Neurônios/citologia , RNA/genética , RNA/metabolismo , Sistemas CRISPR-Cas
2.
Am J Hum Genet ; 108(10): 2006-2016, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34626583

RESUMO

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.


Assuntos
Paralisia Cerebral/patologia , Epilepsia/patologia , Predisposição Genética para Doença , Variação Genética , Perda Auditiva/patologia , Deficiência Intelectual/patologia , Espasticidade Muscular/patologia , ATPases Associadas a Diversas Atividades Celulares/genética , Adolescente , Adulto , Alelos , Animais , Paralisia Cerebral/etiologia , Paralisia Cerebral/metabolismo , Pré-Escolar , Epilepsia/etiologia , Epilepsia/metabolismo , Feminino , Perda Auditiva/etiologia , Perda Auditiva/metabolismo , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/etiologia , Deficiência Intelectual/metabolismo , Masculino , Espasticidade Muscular/etiologia , Espasticidade Muscular/metabolismo , Ratos , Adulto Jovem
3.
Brain ; 145(9): 3274-3287, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-35769015

RESUMO

Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a 'reeling' gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance = 1). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging.


Assuntos
Lisencefalia , Proteína Reelina , Adulto , Cerebelo/anormalidades , Criança , Deficiências do Desenvolvimento/genética , Humanos , Lisencefalia/complicações , Mutação , Malformações do Sistema Nervoso , Proteína Reelina/genética
4.
Dev Med Child Neurol ; 65(1): 126-135, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35661998

RESUMO

AIM: To improve delivery of acute therapies for acute ischaemic stroke (AIS). METHOD: We identified factors influencing the speed of diagnosis and delivery of acute therapies in a prospective cohort of 21 children with suspected AIS (eight with AIS, 13 stroke mimics) and explored them in a retrospective cohort with confirmed AIS. RESULTS: Approximately half of the prospective and total AIS cohorts presented with acute, sustained hemiparesis, and were diagnosed relatively quickly. AIS was suspected and diagnosed more slowly in the half presenting with symptoms other than sustained hemiparesis. Thirty-one out of 51 patients with AIS (19 females, 32 males, mean age 8 years 6 months, SD 5 years 4 months) had arterial abnormalities identified by computed tomography angiography (CTA) or magnetic resonance angiography (MRA): 11 with large vessel occlusion, six with dissection, five with moyamoya disease, nine with other arteriopathies. Among these patients, those initially imaged with CTA were diagnosed more quickly than those with initial magnetic resonance imaging/angiography, which facilitated thrombectomy and thrombolytic therapy. Twenty out of 51 had AIS without arterial abnormalities on CTA or MRA: eight with lenticulostriate vasculopathy and 12 with other small-vessel AIS. Among these patients, 80% were ineligible for thrombolysis for reasons beyond delay to diagnosis, and all showed good outcomes with supportive treatments alone. INTERPRETATION: Clinical features at presentation influence rapidity with which childhood AIS is suspected and diagnosed. Readily available CTA can direct thrombectomy in patients with large vessel occlusion and thrombolysis in most, but not all, eligible patients. WHAT THIS PAPER ADDS: Children with acute ischaemic stroke (AIS) commonly present with symptoms other than sustained hemiparesis. Stroke is more slowly recognized in these patients, which limits potential therapies. Computed tomography angiography (CTA) accurately identifies AIS with large vessel occlusion, enabling timely endovascular thrombectomy. CTA is sufficient to direct thrombolytic therapy in most eligible children. Most childhood AIS without arterial abnormalities identified by CTA had good outcomes.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Masculino , Feminino , Humanos , Criança , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/terapia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/terapia , Angiografia por Tomografia Computadorizada , Estudos Retrospectivos , Estudos Prospectivos , Angiografia por Ressonância Magnética , Paresia
5.
J Inherit Metab Dis ; 44(4): 1001-1012, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33734437

RESUMO

Pathogenic variants in ALG13 (ALG13 UDP-N-acetylglucosaminyltransferase subunit) cause an X-linked congenital disorder of glycosylation (ALG13-CDG) where individuals have variable clinical phenotypes that include developmental delay, intellectual disability, infantile spasms, and epileptic encephalopathy. Girls with a recurrent de novo c.3013C>T; p.(Asn107Ser) variant have normal transferrin glycosylation. Using a highly sensitive, semi-quantitative flow injection-electrospray ionization-quadrupole time-of-flight mass spectrometry (ESI-QTOF/MS) N-glycan assay, we report subtle abnormalities in N-glycans that normally account for <0.3% of the total plasma glycans that may increase up to 0.5% in females with the p.(Asn107Ser) variant. Among our 11 unrelated ALG13-CDG individuals, one male had abnormal serum transferrin glycosylation. We describe seven previously unreported subjects including three novel variants in ALG13 and report a milder neurodevelopmental course. We also summarize the molecular, biochemical, and clinical data for the 53 previously reported ALG13-CDG individuals. We provide evidence that ALG13 pathogenic variants may mildly alter N-linked protein glycosylation in both female and male subjects, but the underlying mechanism remains unclear.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Deficiência Intelectual/fisiopatologia , N-Acetilglucosaminiltransferases/genética , Defeitos Congênitos da Glicosilação/fisiopatologia , Feminino , Variação Genética , Glicosilação , Humanos , Deficiência Intelectual/genética , Masculino , Fenótipo , Transferrina/metabolismo
6.
J Inherit Metab Dis ; 43(6): 1333-1348, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32681751

RESUMO

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.


Assuntos
Defeitos Congênitos da Glicosilação/genética , N-Acetilglucosaminiltransferases/deficiência , N-Acetilglucosaminiltransferases/genética , Espasmos Infantis/genética , Biomarcadores , Pré-Escolar , Defeitos Congênitos da Glicosilação/diagnóstico , Dieta Cetogênica , Feminino , Glicosilação , Humanos , Lactente , Masculino , Mutação , N-Acetilglucosaminiltransferases/química , Espasmos Infantis/diagnóstico , Transferrina/metabolismo
7.
Seizure ; 115: 1-13, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38160512

RESUMO

OBJECTIVES: To determine: i) seizure recurrence; ii) developmental disability; iii) co-morbidities and risk factors in self-limited familial neonatal and/or infantile epilepsy (SeLFE) in a multigenerational study. METHODS: Families were retrospectively recruited from epilepsy databases (2021-2022) in 2 paediatric hospitals, Sydney, Australia. Eligible families had 2 first degree relatives with seizures and underwent genetic testing. Demographics/clinical data were collected from interviews and medical records. Vineland Adaptive Behaviour Scales-Third Edition measured adaptive function. RESULTS: Fifteen families participated. Fourteen had a genetic diagnosis (93%): 11 pathogenic; PRRT2 (n=4), KCNQ2 (n=3), SCN2A (n=4), 3 likely pathogenic; KCNQ2 (n=1), SCN8A (n=2). Seizures affected 73 individuals (ages 1-76 years); 30 children and 20 adults had in-depth phenotyping. Ten of 50 individuals (20%) had seizure recurrence, aged 8-65 years. Median time from last neonatal/infantile seizure was 11.8/12.8 years. Predictors of recurrence were high seizure number (p=0.05) and longer treatment duration (p=0.03). Seven children had global developmental delay (GDD): mild (n=4), moderate (n=1) and severe (n=2). Vineland-3 identified 3 had low-average and 3 had mild-moderately impaired functioning. The majority (82%) were average. GDD was associated with older age at last seizure (p=0.03), longer epilepsy duration (p=0.02), and higher number of anti-seizure medications (p=0.05). Four children had speech delay, 5 (10%) had Autism Spectrum Disorder. Paroxysmal kinesiogenic dyskinesia (n=5) occurred in 4 families and hemiplegic migraine (n=8) in 3 families. CONCLUSIONS: Individuals with SeLFE have a small risk of recurrent seizures (20%) and neurodevelopmental disability. Significant predictors are higher seizure number and longer epilepsy duration. Developmental surveillance is imperative.


Assuntos
Transtorno do Espectro Autista , Epilepsia Neonatal Benigna , Epilepsia , Síndromes Epilépticas , Criança , Recém-Nascido , Adulto , Humanos , Epilepsia Neonatal Benigna/genética , Estudos Retrospectivos , Mutação , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Austrália/epidemiologia , Epilepsia/epidemiologia , Epilepsia/genética , Convulsões/epidemiologia , Convulsões/genética
8.
Neurology ; 102(5): e208112, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38335499

RESUMO

BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. DISCUSSION: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03439670. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.


Assuntos
Distrofia Muscular de Duchenne , Pregnadienodiois , Humanos , Masculino , Biomarcadores , Distrofia Muscular de Duchenne/tratamento farmacológico , Prednisona/efeitos adversos , Pregnadienodiois/efeitos adversos , Pré-Escolar , Criança
9.
Brain Commun ; 2(2): fcaa178, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33629063

RESUMO

Bilateral basal ganglia abnormalities on MRI are observed in a wide variety of childhood disorders. MRI pattern recognition can enable rationalization of investigations and also complement clinical and molecular findings, particularly confirming genomic findings and also enabling new gene discovery. A pattern recognition approach in children with bilateral basal ganglia abnormalities on brain MRI was undertaken in this international multicentre cohort study. Three hundred and five MRI scans belonging to 201 children with 34 different disorders were rated using a standard radiological scoring proforma. In addition, literature review on MRI patterns was undertaken in these 34 disorders and 59 additional disorders reported with bilateral basal ganglia MRI abnormalities. Cluster analysis on first MRI findings from the study cohort grouped them into four clusters: Cluster 1-T2-weighted hyperintensities in the putamen; Cluster 2-T2-weighted hyperintensities or increased MRI susceptibility in the globus pallidus; Cluster 3-T2-weighted hyperintensities in the globus pallidus, brainstem and cerebellum with diffusion restriction; Cluster 4-T1-weighted hyperintensities in the basal ganglia. The 34 diagnostic categories included in this study showed dominant clustering in one of the above four clusters. Inflammatory disorders grouped together in Cluster 1. Mitochondrial and other neurometabolic disorders were distributed across clusters 1, 2 and 3, according to lesions dominantly affecting the striatum (Cluster 1: glutaric aciduria type 1, propionic acidaemia, 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome and thiamine responsive basal ganglia disease associated with SLC19A3), pallidum (Cluster 2: methylmalonic acidaemia, Kearns Sayre syndrome, pyruvate dehydrogenase complex deficiency and succinic semialdehyde dehydrogenase deficiency) or pallidum, brainstem and cerebellum (Cluster 3: vigabatrin toxicity, Krabbe disease). The Cluster 4 pattern was exemplified by distinct T1-weighted hyperintensities in the basal ganglia and other brain regions in genetically determined hypermanganesemia due to SLC39A14 and SLC30A10. Within the clusters, distinctive basal ganglia MRI patterns were noted in acquired disorders such as cerebral palsy due to hypoxic ischaemic encephalopathy in full-term babies, kernicterus and vigabatrin toxicity and in rare genetic disorders such as 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome, thiamine responsive basal ganglia disease, pantothenate kinase-associated neurodegeneration, TUBB4A and hypermanganesemia. Integrated findings from the study cohort and literature review were used to propose a diagnostic algorithm to approach bilateral basal ganglia abnormalities on MRI. After integrating clinical summaries and MRI findings from the literature review, we developed a prototypic decision-making electronic tool to be tested using further cohorts and clinical practice.

11.
Neurology ; 92(2): e96-e107, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30541864

RESUMO

OBJECTIVE: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. METHODS: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. RESULTS: We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). CONCLUSIONS: SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.


Assuntos
Deficiências do Desenvolvimento/genética , Mutação/genética , Espasmos Infantis/genética , Proteínas Ativadoras de ras GTPase/genética , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Encefalopatias/complicações , Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico por imagem , Eletroencefalografia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Espasmos Infantis/complicações , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/tratamento farmacológico , Adulto Jovem
12.
Neuromuscul Disord ; 18(1): 52-8, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17825555

RESUMO

Pontocerebellar hypoplasia type 2, an autosomal recessive neurodegeneration with prenatal onset, is characterised by progressive microcephaly and chorea/dystonia and has not previously been associated with muscular involvement. The gene associated with PCH-2 is unknown. An episode of rhabdomyolysis is reported in two non-related children with PCH-2, fatal in one, precipitated by intercurrent disease. Muscle biopsies in two other PCH-2 patients, and in one rhabdomyolysis patient whose biopsy antedated this complication showed areas of myofibrillar disruption or necrosis. Postmortem muscle sampled in another case without neuromuscular symptoms revealed focal necrosis, regenerating small fibres and upregulation of HLA-ABC. Random serum creatine kinase values in six other PCH-2 patients without clinical signs of neuromuscular involvement were increased in four. Collected data provide preliminary evidence of a subclinical myopathy associated with PCH-2.


Assuntos
Cerebelo/anormalidades , Músculo Esquelético/patologia , Atrofias Olivopontocerebelares/complicações , Ponte/anormalidades , Rabdomiólise/patologia , Adulto , Pré-Escolar , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Transtornos Cromossômicos/fisiopatologia , Creatina Quinase/sangue , Feminino , Genes Recessivos/genética , Antígenos HLA/análise , Antígenos HLA/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Microscopia Eletrônica de Transmissão , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Necrose/genética , Necrose/patologia , Necrose/fisiopatologia , Atrofias Olivopontocerebelares/patologia , Atrofias Olivopontocerebelares/fisiopatologia , Rabdomiólise/genética , Rabdomiólise/fisiopatologia
13.
J Child Neurol ; 23(1): 32-8, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18184941

RESUMO

Chronic disorders are known to have a wide-ranging impact on overall health and family dynamics. The objective of this study was to assess child health and well-being and parental stress in a cohort of school-age children diagnosed before school entry with either global developmental delay or developmental language impairment. In total, 65 children with preschool developmental delay were assessed at school age (mean +/- SD age: 7.3 +/- 0.7 years) with the Child Health Questionnaire and Parenting Stress Index, with a mean interval between assessment of 3.9 years. Almost all children who completed testing (60/62) continued to show developmental impairments across domains. On the Child Health Questionnaire, children showed the greatest impairment on the mental health scale (median z score: -0.9). The median Child Health Questionnaire psychosocial health score (40.7) was almost 1 SD below established normative values ( P < .001). More than 40% of parents had a Parenting Stress Index above the 85th percentile (clinically significant parenting stress). Using multiple linear regression analysis, high levels of parenting stress were best predicted by a child's Child Health Questionnaire psychosocial health score (r2 = 0.49, P < .001). Thus, 4 years after a preschool-age diagnosis of developmental delay, poor psychosocial health was a common comorbidity. Almost half the parents showed clinically significant levels of parenting stress. There is a need to both recognize and provide ongoing social and emotional support for young children diagnosed with developmental disability and their families.


Assuntos
Sintomas Afetivos/epidemiologia , Cuidadores/psicologia , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/psicologia , Pais/psicologia , Estresse Psicológico/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Avaliação da Deficiência , Feminino , Seguimentos , Humanos , Transtornos do Desenvolvimento da Linguagem/epidemiologia , Transtornos do Desenvolvimento da Linguagem/psicologia , Masculino , Testes Neuropsicológicos , Prevalência , Psicologia , Qualidade de Vida/psicologia , Inquéritos e Questionários
14.
J Child Neurol ; 23(2): 155-62, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18056690

RESUMO

Duchenne and Becker muscular dystrophy are allelic X-linked disorders causing progressive muscle weakness in males. Duchenne muscular dystrophy is caused by absence of dystrophin in muscle and brain; boys with Duchenne muscular dystrophy have a static cognitive impairment with mean Full Scale IQ approximately 1 standard deviation below the mean. Less is known of the cognitive profile of males with Becker muscular dystrophy, which is associated with variable alterations in the amount or size of the dystrophin protein. The aim of this study was to describe the cognitive and psychological profile of males with Becker muscular dystrophy. This was a prospective cohort study. Clinical data collected included age at diagnosis and assessment, socioeconomic status, serum creatine kinase level, and site of gene deletion/mutation (by exon number). The following psychological tests were used to assess general intellectual functioning, academic achievement, incidence and nature of behavioral problems: The Wechsler Intelligence Scales, The Wide Range Achievement Test-Revised, The Developmental Test of Visual-Motor Integration, The Child Behavior Checklist, and The Conner's Parent Rating Scale. Twenty-four males were enrolled. The Wechsler Full Scale IQ was normally distributed with a mean of 95.6 (SD 23.3), which did not differ significantly from the population mean. The frequency of learning difficulties for reading was 21%, for spelling was 32%, and for arithmetic was 26%, significantly higher than the frequency in the general population. The frequency of total behavioral problems in the clinical range was 67%, and the frequency of autism was 8.3%. Patients with Becker muscular dystrophy demonstrate a less homogeneous cognitive phenotype than that seen in Duchenne muscular dystrophy. Males with Becker muscular dystrophy have a high incidence of learning difficulties. Autism and behavioral and attention problems are also more common in Becker muscular dystrophy than in the general population.


Assuntos
Transtorno Autístico/complicações , Inteligência , Deficiências da Aprendizagem/complicações , Transtornos Mentais/complicações , Distrofia Muscular de Duchenne/psicologia , Adolescente , Adulto , Atenção , Transtorno Autístico/diagnóstico , Criança , Estudos de Coortes , Creatina Quinase/sangue , Escolaridade , Humanos , Deficiências da Aprendizagem/diagnóstico , Masculino , Transtornos Mentais/diagnóstico , Distrofia Muscular de Duchenne/sangue , Distrofia Muscular de Duchenne/complicações , Estudos Prospectivos , Estatísticas não Paramétricas , Escalas de Wechsler
15.
Pediatr Infect Dis J ; 36(11): 1021-1026, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28654561

RESUMO

BACKGROUND: Influenza-associated encephalitis/encephalopathy (IAE) is an important cause of acute encephalitis syndrome in children. IAE includes a series of clinicoradiologic syndromes or acute encephalopathy syndromes that have been infrequently reported outside East Asia. We aimed to describe cases of IAE identified by the Australian Childhood Encephalitis study. METHODS: Children ≤ 14 years of age with suspected encephalitis were prospectively identified in 5 hospitals in Australia. Demographic, clinical, laboratory, imaging, and outcome at discharge data were reviewed by an expert panel and cases were categorized by using predetermined case definitions. We extracted cases associated with laboratory identification of influenza virus for this analysis; among these cases, specific IAE syndromes were identified where clinical and radiologic features were consistent with descriptions in the published literature. RESULTS: We identified 13 cases of IAE during 3 southern hemisphere influenza seasons at 5 tertiary children's hospitals in Australia; 8 children with specific acute encephalopathy syndromes including: acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures and late diffusion restriction, mild encephalopathy with reversible splenial lesion, and hemiconvulsion-hemiplegia syndrome. Use of influenza-specific antiviral therapy and prior influenza vaccination were infrequent. In contrast, death or significant neurologic morbidity occurred in 7 of the 13 children (54%). CONCLUSIONS: The conditions comprising IAE are heterogeneous with varied clinical features, magnetic resonance imaging changes, and outcomes. Overall, outcome of IAE is poor emphasizing the need for optimized prevention, early recognition, and empiric management.


Assuntos
Encefalopatias/virologia , Encefalite Viral/virologia , Influenza Humana/virologia , Adolescente , Austrália/epidemiologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Influenza Humana/complicações , Masculino , Estudos Prospectivos
16.
Pediatr Neurol ; 34(3): 212-8, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16504791

RESUMO

To identify the clinical and etiologic profile of children with spastic diplegia, the medical records of patients with spastic diplegia in a single practice over a 12-year period were systematically and retrospectively reviewed. Clinical factors and possible etiology based on investigations were identified. Univariate and binomial logistical regression analyses were undertaken to identify factors correlating with an etiologic determination. Chart review identified 54 children with spastic diplegia. There were 31 (57.4%) preterm children and 23 (42.6%) term children. Periventricular leukomalacia was diagnosed in 24 (44.4%) children (26.1% of term children, 58.1% of preterm children). An etiology was not identified in 25 (46.3%) children: 14 (60.9%) term children and 11 (35.5%) preterm children. Periventricular leukomalacia among all children correlated with a birth weight less than 2000 gm (P = 0.037), history of neonatal resuscitation (P = 0.004), and gestation less than 33 weeks (P = 0.001). Factors specifically associated with periventricular leukomalacia in term children were a problematic perinatal history (P = 0.011), a history of neonatal resuscitation (P = 0.011), and a history of neonatal respiratory distress (P = 0.046). Regression analysis revealed a correlation between an abnormal perinatal history and an etiology of periventricular leukomalacia among term children (odds ratio 8.67, 95% confidence interval 2.51-29.97, P = 0.001). Approximately half of all children with spastic diplegia encountered in clinical practice will have an etiology identified.


Assuntos
Paralisia Cerebral/diagnóstico , Adolescente , Causalidade , Paralisia Cerebral/epidemiologia , Paralisia Cerebral/etiologia , Criança , Pré-Escolar , Comorbidade , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/epidemiologia , Doenças do Prematuro/etiologia , Recém-Nascido de muito Baixo Peso , Leucomalácia Periventricular/diagnóstico , Leucomalácia Periventricular/epidemiologia , Leucomalácia Periventricular/etiologia , Modelos Logísticos , Masculino , Exame Neurológico , Quebeque , Estudos Retrospectivos , Fatores de Risco , Estatística como Assunto
17.
Neurology ; 86(19): 1794-800, 2016 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-27029630

RESUMO

OBJECTIVE: The primary objective of this research was to characterize the movement disorders associated with FOXG1 mutations. METHODS: We identified patients with FOXG1 mutations who were referred to either a tertiary movement disorder clinic or tertiary epilepsy service and retrospectively reviewed medical records, clinical investigations, neuroimaging, and available video footage. We administered a telephone-based questionnaire regarding the functional impact of the movement disorders and perceived efficacy of treatment to the caregivers of one cohort of participants. RESULTS: We identified 28 patients with FOXG1 mutations, of whom 6 had previously unreported mutations. A wide variety of movement disorders were identified, with dystonia, choreoathetosis, and orolingual/facial dyskinesias most commonly present. Ninety-three percent of patients had a mixed movement disorder phenotype. In contrast to the phenotype classically described with FOXG1 mutations, 4 patients with missense mutations had a milder phenotype, with independent ambulation, spoken language, and normocephaly. Hyperkinetic involuntary movements were a major clinical feature in these patients. Of the symptomatic treatments targeted to control abnormal involuntary movements, most did not emerge as clearly beneficial, although 4 patients had a caregiver-reported response to levodopa. CONCLUSIONS: Abnormal involuntary movements are a major feature of FOXG1 mutations. Our study delineates the spectrum of movement disorders and confirms an expanding clinical phenotype. Symptomatic treatment may be considered for severe or disabling cases, although further research regarding potential treatment strategies is necessary.


Assuntos
Fatores de Transcrição Forkhead/genética , Transtornos dos Movimentos/genética , Mutação , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Transtornos dos Movimentos/tratamento farmacológico , Fenótipo , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto Jovem
18.
J Child Neurol ; 20(11): 898-904, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16417860

RESUMO

To identify early predictive factors of outcome in childhood epilepsy, the case records of all children with new-onset epilepsy presenting to a single neurology practice over a 10-year interval were reviewed. Only children with more than 2 years of follow-up were included. Cox regression analysis was used to identify factors predictive of remission (successful cessation of medication). One hundred ninety-six children (mean age 7.6 +/- 3.7 years at first seizure, mean follow-up 55 +/- 30 months) were identified. Ninety-eight of 196 children (50%) had an idiopathic epilepsy, 63 of 196 (32.1%) had cryptogenic epilepsy, and 35 of 196 (17.9%) had remote symptomatic epilepsy. At final assessment, 52.6% were in remission, 12.8% had a poor outcome (recurrent seizures on therapeutic antiepileptic drug levels within 6 months prior to the final assessment), and 6.9% were intractable (more than one seizure/month over 1 year with failure of three or more anticonvulsants). One year after initiating treatment, factors associated with a lower probability of remission included seizure recurrence in the 6- to 12-month interval after therapy initiation (hazard ratio 0.24), multiple seizure types (hazard ratio 0.40), and mental retardation at onset (hazard ratio 0.19). Factors predictive of a poor outcome included seizure recurrence in the 6- to 12-month interval after therapy initiation (odds ratio 21.6), more than one seizure type (odds ratio 8.9), and global developmental delay at onset (odds ratio 8.9). Factors predictive of intractability included multiple seizure types (hazard ratio 6.5), mental retardation at onset (hazard ratio 7.2), and seizure recurrence in the first 6 to 12 months of treatment (hazard ratio 70). It appears that response in the first 6 to 12 months on antiepileptic medication is predictive of outcome. Clinical features of the underlying epilepsy and concurrent neurologic conditions were independently associated with intractability and a lower probability of remission.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/patologia , Adolescente , Idade de Início , Criança , Pré-Escolar , Comorbidade , Resistência a Medicamentos , Feminino , Seguimentos , Humanos , Deficiência Intelectual/complicações , Masculino , Prognóstico , Recidiva , Análise de Regressão , Estudos Retrospectivos , Convulsões/patologia , Resultado do Tratamento
19.
Pediatr Neurol ; 32(4): 264-9, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15797183

RESUMO

In a prospective study, preschool children diagnosed with developmental language impairment were systematically reassessed during the early school years with standardized developmental (Battelle Developmental Inventory) and functional measures (Vineland Adaptive Behavior Scale). Of an original cohort of 70 children assessed and diagnosed at a mean age of 3.6 +/- 0.7 years, 43 were reassessed at a mean age of 7.4 +/- 0.7 years. Group performance on the Battelle overall was 71.9 +/- 8.2 with the lowest sub-domain score in communication at 69.5 +/- 8.9. On the Battelle, 67% of children fell below the 1.5 standard deviation (S.D.) cutoff signifying significant developmental concerns. Between 36% (gross motor) and 83% (communication) of the cohort performed at least 1.5 S.D. below the normative mean on the individual domains of the Battelle. Seventy-four percent were impaired in two or more domains of the Battelle. The group mean on the Vineland overall was 81.1 +/- 16.9 with between 19% (socialization) to 48% (communication) of the cohort scoring more than 1.5 S.D. below the mean on each of the sub-domains. Almost half of the cohort (20/42, 48%) manifested functional impairment in at least two domains of the Vineland. Univariate and multivariate analysis of potential predictor variables identified only female sex as being predictive of significantly poorer performance on the Vineland communication sub-domain and the Vineland total score. Children with early developmental language impairment demonstrate persistent impairments in developmental and functional skills at school entry not limited to language. Deficits remain especially evident in the communication sub-domain. These results have implications with respect to later prognostication, family counseling, and devising a programmatic approach to this group of children.


Assuntos
Desenvolvimento Infantil , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Testes Neuropsicológicos , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos
20.
Nat Commun ; 6: 7623, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26151409

RESUMO

A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy.


Assuntos
RNA Polimerases Dirigidas por DNA/metabolismo , Genes Recessivos , Predisposição Genética para Doença , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , RNA Polimerase III/metabolismo , RNA Polimerases Dirigidas por DNA/genética , Regulação Enzimológica da Expressão Gênica/fisiologia , Homozigoto , Humanos , Mutação , RNA Polimerase III/genética
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