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1.
Am J Hum Genet ; 100(3): 523-536, 2017 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-28190456

RESUMO

Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Downregulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease.


Assuntos
Catarata/genética , Disfunção Cognitiva/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Anormalidades Musculoesqueléticas/genética , Monoéster Fosfórico Hidrolases/genética , Adolescente , Adulto , Alelos , Animais , Encéfalo/patologia , Criança , Pré-Escolar , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/patologia , Mutação , Linhagem , Adulto Jovem , Peixe-Zebra/embriologia , Peixe-Zebra/genética
2.
Ann Neurol ; 86(2): 310-315, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31187502

RESUMO

Distinct clinical syndromes have been associated with pathogenic MT-ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty-one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT-ATP6-related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310-315.


Assuntos
Variação Genética/genética , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico , Reino Unido/epidemiologia , Adulto Jovem
3.
Mov Disord ; 35(8): 1357-1368, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32472658

RESUMO

BACKGROUND: Juvenile forms of parkinsonism are rare conditions with onset of bradykinesia, tremor and rigidity before the age of 21 years. These atypical presentations commonly have a genetic aetiology, highlighting important insights into underlying pathophysiology. Genetic defects may affect key proteins of the endocytic pathway and clathrin-mediated endocytosis (CME), as in DNAJC6-related juvenile parkinsonism. OBJECTIVE: To report on a new patient cohort with juvenile-onset DNAJC6 parkinsonism-dystonia and determine the functional consequences on auxilin and dopamine homeostasis. METHODS: Twenty-five children with juvenile parkinsonism were identified from a research cohort of patients with undiagnosed pediatric movement disorders. Molecular genetic investigations included autozygosity mapping studies and whole-exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G-associated kinase and synaptic proteins. RESULTS: We identified 6 patients harboring previously unreported, homozygous nonsense DNAJC6 mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. 123 I-FP-CIT SPECT (DaTScan) was performed in 3 patients and demonstrated reduced or absent tracer uptake in the basal ganglia. CSF neurotransmitter analysis revealed an isolated reduction of homovanillic acid. Auxilin levels were significantly reduced in both patient fibroblasts and CSF. Cyclin G-associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced. CONCLUSIONS: DNAJC6 is an emerging cause of recessive juvenile parkinsonism-dystonia. DNAJC6 encodes the cochaperone protein auxilin, involved in CME of synaptic vesicles. The observed dopamine dyshomeostasis in patients is likely to be multifactorial, secondary to auxilin deficiency and/or neurodegeneration. Increased patient CSF cyclin G-associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G-associated kinase, as observed in the auxilin knockout mouse. DNAJC6 parkinsonism-dystonia should be considered as a differential diagnosis for pediatric neurotransmitter disorders associated with low homovanillic acid levels. Future research in elucidating disease pathogenesis will aid the development of better treatments for this pharmacoresistant disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Distonia , Transtornos Parkinsonianos , Criança , Dopamina , Distonia/diagnóstico por imagem , Distonia/genética , Proteínas de Choque Térmico HSP40/genética , Homeostase , Humanos , Mutação/genética , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/genética
4.
Brain ; 142(6): 1547-1560, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31081514

RESUMO

Next generation sequencing techniques were recently used to show mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Animal studies showed COL13A1, a synaptic extracellular-matrix protein, is involved in the formation and maintenance of the neuromuscular synapse that appears independent of the Agrin-LRP4-MuSK-DOK7 acetylcholine receptor clustering pathway. Here, we report the phenotypic spectrum of 16 patients from 11 kinships harbouring homozygous or heteroallelic mutations in COL13A1. Clinical presentation was mostly at birth with hypotonia and breathing and feeding difficulties often requiring ventilation and artificial feeding. Respiratory crisis related to recurrent apnoeas, sometimes triggered by chest infections, were common early in life but resolved over time. The predominant pattern of muscle weakness included bilateral ptosis (non-fatigable in adulthood), myopathic facies and marked axial weakness, especially of neck flexion, while limb muscles were less involved. Other features included facial dysmorphism, skeletal abnormalities and mild learning difficulties. All patients tested had results consistent with abnormal neuromuscular transmission. Muscle biopsies were within normal limits or showed non-specific changes. Muscle MRI and serum creatine kinase levels were normal. In keeping with COL13A1 mutations affecting both synaptic structure and presynaptic function, treatment with 3,4-diaminopyridine and salbutamol resulted in motor and respiratory function improvement. In non-treated cases, disease severity and muscle strength improved gradually over time and several adults recovered normal muscle strength in the limbs. In summary, patients with COL13A1 mutations present mostly with severe early-onset myasthenic syndrome with feeding and breathing difficulties. Axial weakness is greater than limb weakness. Disease course improves gradually over time, which could be consistent with the less prominent role of COL13A1 once the neuromuscular junction is mature. This report emphasizes the role of collagens at the human muscle endplate and should facilitate the recognition of this disorder, which can benefit from pharmacological treatment.


Assuntos
Colágeno Tipo XIII/genética , Proteínas Musculares/genética , Síndromes Miastênicas Congênitas/genética , Junção Neuromuscular/metabolismo , Transmissão Sináptica/genética , Adolescente , Adulto , Criança , Feminino , Homozigoto , Humanos , Masculino , Músculo Esquelético/patologia , Mutação/genética , Síndromes Miastênicas Congênitas/diagnóstico , Junção Neuromuscular/genética , Sinapses/genética , Adulto Jovem
5.
Dev Med Child Neurol ; 60(3): 275-282, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29238964

RESUMO

AIM: Difficulties in reading comprehension can arise from either word reading or listening comprehension difficulties, or a combination of the two. We sought to determine whether children with rolandic epilepsy had poor reading comprehension relative to typically developing comparison children, and whether such difficulties were associated with word reading and/or general language comprehension difficulties. METHOD: In this cross-sectional study, children with rolandic epilepsy (n=25; 16 males, 9 females; mean age 9y 1mo, SD 1y 7mo) and a comparison group (n=39; 25 males, 14 females; mean age 9y 1mo, SD 1y 3mo) completed assessments of reading comprehension, listening comprehension, word/non-word reading, speech articulation, and Non-verbal IQ. RESULTS: Reading comprehension and word reading were worse in children with rolandic epilepsy (F1,61 =6.89, p=0.011, ηp2=0.10 and F1,61 =6.84, p=0.011, ηp2=0.10 respectively), with listening comprehension being marginal (F1,61 =3.81, p=0.055, ηp2=0.06). Word reading and listening comprehension made large and independent contributions to reading comprehension, explaining 70% of the variance. INTERPRETATION: Children with rolandic epilepsy may be at risk of reading comprehension difficulties. Thorough assessment of individual children is required to ascertain whether the difficulties lie with decoding text, or with general comprehension skills, or both. WHAT THIS PAPER ADDS: Children with rolandic epilepsy may be at risk of poor reading comprehension. This was related to poor word reading, poor listening comprehension, or both. Reading comprehension interventions should be tailored to the profile of difficulties.


Assuntos
Transtornos Cognitivos/etiologia , Compreensão/fisiologia , Dislexia/etiologia , Epilepsia Rolândica/complicações , Epilepsia Rolândica/psicologia , Estimulação Acústica , Análise de Variância , Criança , Transtornos Cognitivos/diagnóstico , Estudos Transversais , Dislexia/diagnóstico , Feminino , Humanos , Testes de Linguagem , Masculino , Estudos Retrospectivos
6.
Neuropediatrics ; 48(3): 166-184, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28561207

RESUMO

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Interferon Tipo I/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Proteínas de Ligação a RNA/genética , Adolescente , Adulto , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Biomarcadores/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Fenótipo , Adulto Jovem
7.
Arch Dis Child Educ Pract Ed ; 102(6): 319-327, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28751535

RESUMO

In paediatrics, one of our main aims in the diagnostic process is to identify any treatable conditions. The copper metabolism disorder Wilson's disease (WD) is one such condition that is caused by mutations in the ATP7B gene. Delay in treatment could result in irreversible disability or even death. Although liver disease is the most common presenting feature in children, some children may initially present with a subtle neurological presentation only. In patients presenting with dystonia, tremor, dysarthria or with a deterioration in school performance, there should be a high index of suspicion for WD. However, the differential of these clinical presentations is wide and exclusion of WD is difficult. No single diagnostic test can exclude WD and each of the biochemical tests has limitations. In this article, we discuss copper metabolism disorders including WD and Menke's disease. We then discuss the available diagnostic tests and how to investigate children for these rare disorders.


Assuntos
Degeneração Hepatolenticular/diagnóstico , Síndrome dos Cabelos Torcidos/diagnóstico , Adolescente , Algoritmos , Proteína C-Reativa/metabolismo , Ceruloplasmina/metabolismo , Criança , Pré-Escolar , Cobre/metabolismo , Feminino , Testes Genéticos , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/metabolismo , Humanos , Lactente , Testes de Função Hepática , Masculino , Síndrome dos Cabelos Torcidos/complicações , Síndrome dos Cabelos Torcidos/metabolismo , Adulto Jovem
8.
Am J Med Genet A ; 167A(2): 296-312, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25604658

RESUMO

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , RNA Helicases DEAD-box/genética , Exodesoxirribonucleases/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Fenótipo , Fosfoproteínas/genética , Ribonuclease H/genética , Estudos de Associação Genética , Genótipo , Humanos , Helicase IFIH1 Induzida por Interferon , Interferons/sangue , Interferons/líquido cefalorraquidiano , Pterinas/líquido cefalorraquidiano , Proteína 1 com Domínio SAM e Domínio HD
9.
J Med Genet ; 51(2): 76-82, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24262145

RESUMO

BACKGROUND: We recently observed mutations in ADAR1 to cause a phenotype of bilateral striatal necrosis (BSN) in a child with the type I interferonopathy Aicardi-Goutières syndrome (AGS). We therefore decided to screen patients with apparently non-syndromic BSN for ADAR1 mutations, and for an upregulation of interferon-stimulated genes (ISGs). METHODS: We performed Sanger sequencing of ADAR1 in a series of patients with BSN presenting to us during our routine clinical practice. We then undertook detailed clinical and neuroradiological phenotyping in nine mutation-positive children. We also measured the expression of ISGs in peripheral blood from these patients, and in children with BSN who did not have ADAR1 mutations. RESULTS: Nine ADAR1 mutation-positive patients from seven families demonstrated an acute (five cases) or subacute (four cases) onset of refractory, four-limb dystonia starting between 8 months and 5 years of age. Eight patients were developmentally normal at initial presentation. In seven cases, the disease was inherited as an autosomal recessive trait, while two related patients were found to have a heterozygous (dominant) ADAR1 mutation. All seven mutation-positive patients assayed showed an upregulation of ISGs (median: 12.50, IQR: 6.43-36.36) compared to controls (median: 0.93, IQR: 0.57-1.30), a so-called interferon signature, present many years after disease onset. No interferon signature was present in four children with BSN negative for mutations in ADAR1 (median: 0.63, IQR: 0.47-1.10). CONCLUSIONS: ADAR1-related disease should be considered in the differential diagnosis of apparently non-syndromic BSN with severe dystonia of varying evolution. The finding of an interferon signature provides a useful screening test for the presence of ADAR1 mutations in this context, and may suggest novel treatment approaches.


Assuntos
Adenosina Desaminase/genética , Interferon Tipo I/fisiologia , Degeneração Estriatonigral/congênito , Estudos de Casos e Controles , Pré-Escolar , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Técnicas de Diagnóstico Molecular , Mutação de Sentido Incorreto , Proteínas de Ligação a RNA , Degeneração Estriatonigral/enzimologia , Degeneração Estriatonigral/genética
10.
Mol Genet Metab ; 113(4): 301-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25458521

RESUMO

Thiamine pyrophosphokinase (TPK) produces thiamine pyrophosphate, a cofactor for a number of enzymes, including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. Episodic encephalopathy type thiamine metabolism dysfunction (OMIM 614458) due to TPK1 mutations is a recently described rare disorder. The mechanism of the disease, its phenotype and treatment are not entirely clear. We present two patients with novel homozygous TPK1 mutations (Patient 1 with p.Ser160Leu and Patient 2 with p.Asp222His). Unlike the previously described phenotype, Patient 2 presented with a Leigh syndrome like non-episodic early-onset global developmental delay, thus extending the phenotypic spectrum of the disorder. We, therefore, propose that TPK deficiency may be a better name for the condition. The two cases help to further refine the neuroradiological features of TPK deficiency and show that MRI changes can be either fleeting or progressive and can affect either white or gray matter. We also show that in some cases lactic acidosis can be absent and 2-ketoglutaric aciduria may be the only biochemical marker. Furthermore, we have established the assays for TPK enzyme activity measurement and thiamine pyrophosphate quantification in frozen muscle and blood. These tests will help to diagnose or confirm the diagnosis of TPK deficiency in a clinical setting. Early thiamine supplementation prevented encephalopathic episodes and improved developmental progression of Patient 1, emphasizing the importance of early diagnosis and treatment of TPK deficiency. We present evidence suggesting that thiamine supplementation may rescue TPK enzyme activity. Lastly, in silico protein structural analysis shows that the p.Ser160Leu mutation is predicted to interfere with TPK dimerization, which may be a novel mechanism for the disease.


Assuntos
Mutação , Doenças do Sistema Nervoso/genética , Tiamina Pirofosfoquinase/deficiência , Tiamina Pirofosfoquinase/genética , Acidose Láctica , Sequência de Aminoácidos , Criança , Pré-Escolar , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Modelos Moleculares , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Fenótipo , Conformação Proteica , Multimerização Proteica , Tiamina Pirofosfoquinase/química , Tiamina Pirofosfoquinase/metabolismo , Tiamina/administração & dosagem , Tiamina/uso terapêutico , Tiamina Pirofosfato/metabolismo
11.
J Neurol Neurosurg Psychiatry ; 85(4): 456-61, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24133290

RESUMO

BACKGROUND: Autoantibodies to glial, myelin and neuronal antigens have been reported in a range of central demyelination syndromes and autoimmune encephalopathies in children, but there has not been a systematic evaluation across the range of central nervous system (CNS) autoantibodies in childhood-acquired demyelinating syndromes (ADS). METHODS: Children under the age of 16 years with first-episode ADS were identified from a national prospective surveillance study; serum from 65 patients had been sent for a variety of diagnostic tests. Antibodies to astrocyte, myelin and neuronal antigens were tested or retested in all samples. RESULTS: Fifteen patients (23%) were positive for at least one antibody (Ab): AQ4-Ab was detected in three; two presenting with neuromyelitis optica (NMO) and one with isolated optic neuritis (ON). Myelin oligodendrocyte glycoprotein (MOG)-Ab was detected in seven; two with acute disseminated encephalomyelitis (ADEM), two with ON, one with transverse myelitis (TM) and two with clinically isolated syndrome (CIS). N-Methyl-D-Aspartate receptor (NMDAR)-Ab was found in two; one presenting with ADEM and one with ON. Voltage-gated potassium channel (VGKC)-complex antibodies were positive in three; one presenting with ADEM, one with ON and one with CIS. GlyR-Ab was detected in one patient with TM. All patients were negative for the VGKC-complex-associated proteins LGI1, CASPR2 and contactin-2. CONCLUSIONS: A range of CNS-directed autoantibodies were found in association with childhood ADS. Although these antibodies are clinically relevant when associated with the specific neurological syndromes that have been described, further studies are required to evaluate their roles and clinical relevance in demyelinating diseases.


Assuntos
Autoanticorpos/imunologia , Doenças Desmielinizantes/imunologia , Proteínas do Tecido Nervoso/imunologia , Adolescente , Autoanticorpos/sangue , Biomarcadores/sangue , Criança , Estudos de Coortes , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico , Feminino , Humanos , Masculino , Neuroimagem , Reino Unido
12.
Brain ; 136(Pt 12): 3634-44, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24176978

RESUMO

Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjögren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expression.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Mutação/genética , Degenerações Espinocerebelares/genética , Adolescente , Linfócitos B , Encéfalo/patologia , Encéfalo/ultraestrutura , Células Cultivadas , Análise Mutacional de DNA , Saúde da Família , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Estudos Retrospectivos , Degenerações Espinocerebelares/patologia , Degenerações Espinocerebelares/fisiopatologia
13.
Cochrane Database Syst Rev ; (9): CD006779, 2014 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-25190506

RESUMO

BACKGROUND: Benign Epilepsy with Centro Temporal Spikes (BECTS) is a common epilepsy syndrome with onset in childhood which almost always remits by adolescence. It is characterised by focal seizures associated with motor signs and somatosensory symptoms, at times progressing to become generalised. The characteristic interictal EEG shows normal background activity with centrotemporal spikes which are more prominent in sleep. The prognosis is good though subtle cognitive impairment has been implicated. Antiepileptic drug (AED) treatment is used if seizures are frequent or occurring in the daytime. OBJECTIVES: To evaluate whether or not treatment with AEDs changes the short- or long-term outcome of children with BECTS or both. SEARCH METHODS: We searched the following databases: the Cochrane Epilepsy Group Specialized Register (30 April 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2013, Issue 4: (April 2013)), MEDLINE (Ovid, 1946 to 30 April 2013), SCOPUS (30 April 2013), ClinicalTrials.gov (30 April 2013) and the WHO International Clinical Trials Registry Platform ICTRP (30 April 2013). We also handsearched the reference lists of articles that were considered for inclusion in the review. SELECTION CRITERIA: All randomised controlled trials (RCTs) that compared the use of different AEDs, or compared the use of AEDs with no treatment, or placebo in children with BECTS. DATA COLLECTION AND ANALYSIS: Data were independently extracted by all four of the review authors and discrepancies were resolved by discussion. Analysis included assessment of risk of bias, quality of evidence of individual studies, heterogeneity, and statistical analysis of the effects on seizure remission and cognition. MAIN RESULTS: There were six eligible studies but only four had sufficient data at the time of this review. The four RCTs included in this review reported on a total of 262 participants. One study, a placebo-controlled trial with a low risk of bias, found that individuals on sulthiame were significantly more likely to remain in seizure remission during the three and six months from commencement of treatment than those on placebo (3 months: RR 2.26, 95% CI 1.48 to 3.44; 6 months: RR 2.63, 95% CI 1.43 to 4.86, 66 participants, moderate quality evidence). The other three trials, all open-labelled studies, had a high risk of bias and did not show any significant differences in terms of seizure remission between AEDs. One compared levetiracetam with oxcarbazepine (3 months: RR 1.13, 95% CI of 0.93 - 1.36; 12 months: RR of 1.29 with 95% CI of 0.89 - 1.86, 39 participants, low to very low quality evidence), one clobazam with carbamazepine (4-40 weeks: RR of 1.04, 95% CI of 0.67 - 1.62; last 9 months: RR of 1.06 with 95% CI of 0.84, 1.34, 45 participants, low quality evidence), and one carbamazepine with topiramate (28 weeks: RR 1.02 with 95% CI of 0.8 - 1.3, 112 participants, low quality evidence).Other outcome measures assessed included time to first seizure after randomisation which was only obtained in the sulthiame versus placebo study as a hazard ratio of 7.8 (95% CI 2.66 - 22.87). There were no significant differences between the proportion of participants who had adverse events, apart from a higher incidence of rash in the carbamazepine group (14.8%) when compared with topiramate (1.7%), or the proportion who withdrew from treatment due to adverse events, when this was reported. Two trials (carbamazepine versus topiramate, and clobazam versus carbamazepine) evaluated the effects on cognition. The studies were of low to very low quality evidence showing no clear difference in cognition at the end of the study periods between the AEDs compared. A meta-analysis was not performed as the RCTs evaluated different therapies. AUTHORS' CONCLUSIONS: There is evidence from one trial reviewed that sulthiame is effective for seizure remission in the short term in children with BECTS although the precision of the effect estimate is uncertain due to its small sample size. There were no significant differences in the proportion of adverse events between treatment groups studied, including those resulting in withdrawal of treatment. There is insufficient evidence about the medium to longer term effects on seizure control, the optimum antiepileptic drug treatment and the effects of AED treatment on cognition. There is a need for more good quality randomised controlled trials to address these questions to aid the management of children with BECTS.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Conduta Expectante , Benzodiazepinas/uso terapêutico , Carbamazepina/análogos & derivados , Carbamazepina/uso terapêutico , Criança , Clobazam , Epilepsia/fisiopatologia , Frutose/análogos & derivados , Frutose/uso terapêutico , Humanos , Quimioterapia de Indução/métodos , Levetiracetam , Oxcarbazepina , Piracetam/análogos & derivados , Piracetam/uso terapêutico , Placebos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiazinas/uso terapêutico , Topiramato
14.
Eur J Paediatr Neurol ; 52: 52-58, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39025036

RESUMO

OBJECTIVES: We aimed to study the risks of relapse and long term disability in children with non-MS acquired demyelinating syndromes (ADS). METHODS: In this prospective, multi-centre study, from the 14 UK pediatric neurology centres, children (<16 years) experiencing a first episode of ADS were recruited from 2010 to 2014. Case report forms were collected prospectively. RESULTS: A total of 269 children were recruited and followed up for a median of 7.2 years. Median age at onset was 9y (IQR 9.5-14.5, 126 females). At last follow-up, 46 (18 %) had MS, 4 AQP4-Ab NMOSD and 206 (80 %) had other ADS, of which 27 (13 %) relapsed. Relapsing MOGAD was the diagnosis in 12/27, 6 were seronegative and 9 did not have antibodies tested. Frequency of relapse differed according to first presentation in non-MS ADS, being least likely in transverse myelitis (p = 0.025). In the non-MS group, MOG-Ab was predictive of relapse (HR = 8.42; p < 0.001) occurring 8 times as often decreasing over time. Long-term difficulties did not differ between children with monophasic vs relapsing diseases. CONCLUSION: The risk of relapse in non-MS ADS depends on initial diagnosis, and MOG-Ab positivity. Long-term difficulties are observed regardless of relapses and are determined by presenting phenotype.


Assuntos
Recidiva , Humanos , Feminino , Criança , Masculino , Adolescente , Estudos Prospectivos , Doenças Desmielinizantes/diagnóstico , Seguimentos , Glicoproteína Mielina-Oligodendrócito/imunologia , Autoanticorpos/sangue , Pré-Escolar
15.
Mult Scler ; 19(1): 76-86, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22516794

RESUMO

OBJECTIVE: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. METHODS: We conducted a population active surveillance study. All paediatricians, and ophthalmologists (n = 4095) were sent monthly reporting cards (September 2009-September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. RESULTS: Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3-15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years (n = 63) was 1.52:1 (p = 0.045). The incidence of first onset ADS in children aged 1-15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18-11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria. CONCLUSIONS: We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/epidemiologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino
16.
Epilepsy Res ; 192: 107136, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37068422

RESUMO

Although Childhood Epilepsy with Centro-Temporal Spikes (CECTS) is considered a 'benign' form of epilepsy, word reading, listening comprehension, and reading comprehension difficulties have been reported. We examined two core skills for text comprehension, coherence monitoring and inference generation, in children with CECTS and compared performance with typically developing controls. Children with CECTS (n = 23; 9 females; mean age 9 y 0 m) and the comparison group (n = 38; 14 females; mean age 9 y 1 m) completed two tasks. For coherence monitoring they heard 24 narrative texts, 16 containing two inconsistent sentences, and responded to a yes/no question to assess identification of the inconsistency after each text; for inference making they heard 16 texts designed to elicit a target inference by integrating information in two sentences and responded to a yes/no question to assess generation of the inference. In both tasks there was a near condition, in which critical sentences were adjacent, and a far condition in which these sentences were separated by filler sentences. Accuracy to the question and the processing time for critical sentences in the text were measured. We used listening comprehension tasks to control for variation in word reading ability. Mixed effects analyses for each task revealed that children with CECTS show comparable levels of accuracy to age-matched peers in these tasks tapping two core text integration skills: detection of inconsistencies and generation of inferences. However, they take longer to process texts indicating a likely source of their listening and reading comprehension difficulties.


Assuntos
Cognição , Compreensão , Feminino , Humanos , Criança , Leitura , Idioma , Percepção Auditiva
17.
Brain Commun ; 5(5): fcad222, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37794925

RESUMO

LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy and nonspecific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in 11 families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified 12 distinct homozygous loss-of-function variants in 16 individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor ('ear-of-the-lynx' sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the 'ear-of-the-lynx' sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction.

18.
Arch Dis Child ; 107(2): 160-165, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34244165

RESUMO

OBJECTIVE: To describe age and time at key stages in the Duchenne muscular dystrophy (DMD) prediagnosis pathway at selected centres to identify opportunities for service improvement. DESIGN: A multicentre retrospective national audit. SETTING: Nine tertiary neuromuscular centres across the UK and Ireland. A prior single-centre UK audit of 20 patients with no DMD family history provided benchmark criteria. PATIENTS: Patients with a definitive diagnosis of DMD documented within 3 years prior to December 2018 (n=122). MAIN OUTCOME MEASURES: Mean age (months) at four key stages in the DMD diagnostic pathway and mean time (months) of presentational and diagnostic delay, and time from first reported symptoms to definitive diagnosis. Type of symptoms was also recorded. RESULTS: Overall, mean age at definitive diagnosis, age at first engagement with healthcare professional (HCP) and age at first reported symptoms were 53.9±29.7, 49.9±28.9 and 36.4±26.8 months, respectively. The presentational delay and time to diagnosis were 21.1 (±21.1) and 4.6 (±7.9) months, respectively. The mean time from first reported symptoms to definitive diagnosis was 24.2±20.9. The percentages of patients with motor and/or non-motor symptoms recorded were 88% (n=106/121) and 47% (n=57/121), respectively. CONCLUSIONS: Majority of data mirrored the benchmark audit. However, while the time to diagnosis was shorter, a presentational delay was observed. Failure to recognise early symptoms of DMD could be a contributing factor and represents an unmet need in the diagnosis pathway. Methods determining how to improve this need to be explored.


Assuntos
Distrofia Muscular de Duchenne/diagnóstico , Idade de Início , Benchmarking , Pré-Escolar , Procedimentos Clínicos , Progressão da Doença , Humanos , Distrofia Muscular de Duchenne/patologia , Estudos Retrospectivos
19.
Brain ; 133(Pt 3): 655-70, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20129935

RESUMO

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos , Transportador de Glucose Tipo 1/deficiência , Transportador de Glucose Tipo 1/genética , Adolescente , Adulto , Idade de Início , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Erros Inatos do Metabolismo dos Carboidratos/genética , Erros Inatos do Metabolismo dos Carboidratos/terapia , Criança , Pré-Escolar , Dieta Cetogênica , Discinesias/diagnóstico , Discinesias/genética , Discinesias/terapia , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/terapia , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/terapia , Masculino , Mutação , Fenótipo , Estudos Retrospectivos , Síndrome , Adulto Jovem
20.
BMC Pediatr ; 11: 68, 2011 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-21798048

RESUMO

BACKGROUND: There is evidence that at least 5% of Multiple sclerosis (MS) cases manifest in childhood. Children with MS present with a demyelinating episode involving single or multiple symptoms prior to developing a second event (usually within two years) to then meet criteria for diagnosis. There is evidence from adult cohorts that the incidence and sex ratios of MS are changing and that children of immigrants have a higher risk for developing MS. A paediatric population should reflect the vanguard of such changes and may reflect trends yet to be observed in adult cohorts. Studying a paediatric population from the first demyelinating event will allow us to test these hypotheses, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS. METHODS/DESIGN: The Paediatric UK Demyelinating Disease Longitudinal Study (PUDDLS) is a prospective longitudinal observational study which aims to determine the natural history, predictors and outcomes of childhood CNS inflammatory demyelinating diseases. PUDDLS will involve centres in the UK, and will establish a cohort of children affected with a first CNS inflammatory demyelinating event for long-term follow up by recruiting for approximately 5 years. PUDDLS will also establish a biological sample archive (CSF, serum, and DNA), allowing future hypothesis driven research. For example, the future discovery of a biomarker will allow validation within this dataset for the evaluation of novel biomarkers. Patients will also be requested to consent to be contacted in the future. A secondary aim is to collaborate internationally with the International Paediatric Multiple Sclerosis Study Group when future collaborative studies are proposed, whilst sharing a minimal anonymised dataset. PUDDLS is the second of two jointly funded studies. The first (UCID-SS) is an epidemiological surveillance study that already received ethical approvals, and started on the 1st September 2009. There is no direct patient involvement, and UCID-SS aims to determine the UK and Ireland incidence of CNS inflammatory demyelinating disorders in children under 16 years. DISCUSSION: A paediatric population should reflect the vanguard of MS epidemiological changes and may reflect trends yet to be observed in adult MS cohorts. The restricted window between clinical expression of disease and exposure to environmental factors in children offers a unique research opportunity. Studying a paediatric population from the first demyelinating event will allow us to investigate the changing epidemiology of MS, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS.


Assuntos
Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes/fisiopatologia , Esclerose Múltipla/fisiopatologia , Biomarcadores/análise , Criança , Efeitos Psicossociais da Doença , Doenças Desmielinizantes/complicações , Doenças Desmielinizantes/tratamento farmacológico , Diagnóstico Diferencial , Progressão da Doença , Diagnóstico Precoce , Humanos , Estudos Longitudinais , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/etiologia , Estudos Prospectivos , Qualidade de Vida , Reino Unido/epidemiologia
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