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1.
Dev Med Child Neurol ; 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175662

RESUMO

Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi-Goutières syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy.

2.
Hum Mutat ; 40(5): 619-630, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30740813

RESUMO

The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.

3.
Hum Mutat ; 39(8): 1076-1080, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29782060

RESUMO

We describe progressive spastic paraparesis in two male siblings and the daughter of one of these individuals. Onset of disease occurred within the first decade, with stiffness and gait difficulties. Brisk deep tendon reflexes and extensor plantar responses were present, in the absence of intellectual disability or dermatological manifestations. Cerebral imaging identified intracranial calcification in all symptomatic family members. A marked upregulation of interferon-stimulated gene transcripts was recorded in all three affected individuals and in two clinically unaffected relatives. A heterozygous IFIH1 c.2544T>G missense variant (p.Asp848Glu) segregated with interferon status. Although not highly conserved (CADD score 10.08 vs. MSC-CADD score of 19.33) and predicted as benign by in silico algorithms, this variant is not present on publically available databases of control alleles, and expression of the D848E construct in HEK293T cells indicated that it confers a gain-of-function. This report illustrates, for the first time, the occurrence of autosomal-dominant spastic paraplegia with intracranial calcifications due to an IFIH1-related type 1 interferonopathy.

4.
Neuropediatrics ; 49(2): 118-122, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29253910

RESUMO

Alexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the GFAP gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no GFAP mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white-gray junction. Initial mutation screening of the GFAP gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the GFAP gene. Mutations in the GFAP gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in GFAP. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease.

6.
Neuropediatrics ; 47(6): 355-360, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27643693

RESUMO

The Aicardi-Goutières syndrome (AGS) was first described in 1984, and over the following years was defined by the clinical and radiological features of an early onset, severe, neurologic disorder with intracranial calcification, leukoencephalopathy, and cerebral atrophy, usually associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF interferon α activity. It is now recognized that mutations in any of the following seven genes may result in the classical AGS phenotype: TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7). All of these genes encode proteins involved in nucleotide metabolism and/or sensing. Mutations in these genes result in the induction of type 1 interferon production and an upregulation of interferon stimulated genes. As more patients harboring mutations in these genes have been described, in particular facilitated by the advent of whole exome sequencing, a remarkably broad spectrum of associated neurologic phenotypes has been revealed, which we summarize here. We propose that the term AGS has continued clinical utility in the designation of a characteristic phenotype, which suggests relevant diagnostic investigations and can inform outcome predictions. However, we also suggest that the use of the term "type 1 interferonopathy" is appropriate for the wider spectrum of disease consequent upon dysfunction of these genes and proteins since it implies the possibility of a common "anti-interferon" approach to therapy as such treatments become available.


Assuntos
Doenças Autoimunes do Sistema Nervoso/genética , Mutação/genética , Malformações do Sistema Nervoso/genética , Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Exodesoxirribonucleases/genética , Estudos de Associação Genética , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Interferons/líquido cefalorraquidiano , Imagem por Ressonância Magnética , Proteínas Monoméricas de Ligação ao GTP/genética , Malformações do Sistema Nervoso/líquido cefalorraquidiano , Malformações do Sistema Nervoso/diagnóstico por imagem , Fosfoproteínas/genética , Proteínas de Ligação a RNA/genética , Ribonuclease H/genética , Proteína 1 com Domínio SAM e Domínio HD
7.
Eur J Paediatr Neurol ; 20(4): 604-10, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27091087

RESUMO

BACKGROUND: Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutières syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged. PATIENTS AND METHODS: We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS. RESULTS: All patients were found to carry biallelic mutations of RNASET2. CONCLUSIONS: Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2-related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation.


Assuntos
Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Encéfalo/fisiopatologia , Cistos/fisiopatologia , Leucoencefalopatias/fisiopatologia , Malformações do Sistema Nervoso/fisiopatologia , Adolescente , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/genética , Encéfalo/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Criança , Pré-Escolar , Cistos/diagnóstico por imagem , Cistos/genética , Infecções por Citomegalovirus/congênito , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Fenótipo , Ribonucleases/genética , Tomografia Computadorizada por Raios X , Proteínas Supressoras de Tumor/genética , Adulto Jovem
9.
J Clin Immunol ; 36(3): 220-34, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26951490

RESUMO

PURPOSE: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. METHODS: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. RESULTS: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. CONCLUSIONS: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.


Assuntos
Doenças Autoimunes/genética , Deficiência Intelectual/genética , Lúpus Eritematoso Sistêmico/genética , Mutação , Osteocondrodisplasias/genética , Púrpura Trombocitopênica Idiopática/genética , Fosfatase Ácida Resistente a Tartarato/genética , Adolescente , Adulto , Alelos , Autoanticorpos/biossíntese , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Osso e Ossos/imunologia , Osso e Ossos/patologia , Encéfalo/imunologia , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Expressão Gênica , Genótipo , Humanos , Deficiência Intelectual/imunologia , Deficiência Intelectual/patologia , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Masculino , Osteocondrodisplasias/imunologia , Osteocondrodisplasias/patologia , Linhagem , Fenótipo , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/patologia , Fosfatase Ácida Resistente a Tartarato/deficiência , Fosfatase Ácida Resistente a Tartarato/imunologia
10.
Hum Mutat ; 36(5): 489-95, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25726928

RESUMO

Primary familial brain calcification (PFBC) is a heterogeneous neuropsychiatric disorder, with affected individuals presenting a wide variety of motor and cognitive impairments, such as migraine, parkinsonism, psychosis, dementia, and mood swings. Calcifications are usually symmetrical, bilateral, and found predominantly in the basal ganglia, thalamus, and cerebellum. So far, variants in three genes have been linked to PFBC: SLC20A2, PDGFRB, and PDGFB. Variants in SLC20A2 are responsible for most cases identified so far and, therefore, the present review is a comprehensive worldwide summary of all reported variants to date. SLC20A2 encodes an inorganic phosphate transporter, PiT-2, widely expressed in various tissues, including brain, and is part of a major family of solute carrier membrane transporters. Fifty variants reported in 55 unrelated patients so far have been identified in families of diverse ethnicities and only few are recurrent. Various types of variants were detected (missense, nonsense, frameshift) including full or partial SLC20A2 deletions. The recently reported SLC20A2 knockout mouse will enhance our understanding of disease mechanism and allow for screening of therapeutic compounds. In the present review, we also discuss the implications of these recent exciting findings and consider the possibility of treatments based on manipulation of inorganic phosphate homeostasis.


Assuntos
Encefalopatias/genética , Encefalopatias/patologia , Calcinose/genética , Mutação , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Alelos , Substituição de Aminoácidos , Encefalopatias/diagnóstico , Análise Mutacional de DNA , Éxons , Estudos de Associação Genética , Variação Genética , Humanos , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo
11.
J Child Neurol ; 30(10): 1343-8, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25535058

RESUMO

Aicardi-Goutières syndrome is an inherited leukodystrophy with calcifying microangiopathy and abnormal central nervous system myelination. As fewer diagnostic computed tomographic (CT) scans are being performed due to increased availability of magnetic resonance imaging (MRI), there is a potential for missed diagnoses on the basis of calcifications. We review a series of patients with MRIs selected from IRB-approved leukodystrophy biorepositories to identify MRI patterns for recognition of early-onset Aicardi-Goutières syndrome and scored for a panel of radiologic predictors. Each individual predictor was tested against disease status using exact logistic regression. Features for pattern recognition of Aicardi-Goutières syndrome are temporal lobe swelling followed by atrophy with temporal horn dilatation, early global cerebral atrophy and visible calcifications, as evidenced by 94.44% of cases of Aicardi-Goutières syndrome correctly classified with a sensitivity of 90.9% and specificity of 96.9%. We identify a panel of MRI features predictive of Aicardi-Goutières syndrome in young patients that would differentiate it from other leukoencephalopathies.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/patologia , Encéfalo/patologia , Imagem por Ressonância Magnética , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/patologia , Idade de Início , Pré-Escolar , Humanos , Lactente , Modelos Logísticos , Imagem por Ressonância Magnética/métodos , Tamanho do Órgão , Sensibilidade e Especificidade
12.
Pediatr Neurol ; 51(6): 843-5, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25301227

RESUMO

BACKGROUND: Beta-propeller protein-associated neurodegeneration is a newly described X-linked dominant condition due to heterozygous mutations in WDR45. The condition is associated with characteristic changes on brain magnetic resonance imaging. Previous literature relating to this disorder has not specifically referred to intracranial calcification. METHODS: A female patient presented with significant developmental delay in early childhood and subsequently demonstrated neurodegeneration with progressive dystonia and dementia in her third decade. Brain magnetic resonance imaging revealed low signal in the substantia nigra and both globus pallidi on T2-weighted imaging, with no eye-of-the-tiger sign. Computed tomography revealed bilateral dense calcification of the globus pallidus. We performed Sanger sequencing of the WDR45 gene in the patient and her parents. RESULTS: We identified a heterozygous c.488del C p.Pro163Argfs*34 variant in exon 8 of WDR45. Neither parent carried the same mutation, indicating that the molecular change had occurred de novo. CONCLUSIONS: Although the characteristic features of beta-propeller protein-associated neurodegeneration were present in our patient, the observation of basal ganglia calcification was considered atypical. Previous descriptions of basal ganglia calcification in individuals with neuronal brain iron accumulation led us to review the frequency of calcification in these disorders.


Assuntos
Gânglios da Base/patologia , Calcinose/patologia , Distúrbios do Metabolismo do Ferro/patologia , Distrofias Neuroaxonais/patologia , Adulto , Proteínas de Transporte/genética , Feminino , Humanos , Distúrbios do Metabolismo do Ferro/classificação , Distúrbios do Metabolismo do Ferro/genética , Distrofias Neuroaxonais/classificação , Distrofias Neuroaxonais/genética
13.
Neuropediatrics ; 45(6): 386-93, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25243380

RESUMO

BACKGROUND: Hereditary spastic paraplegia is a neurodegenerative phenotype characterized by a progressive loss of corticospinal motor tract function. In a majority of affected individuals the pathogenesis remains undetermined. METHODS: We identified a series of patients with a phenotype of nonsyndromic spastic paraplegia in whom no diagnosis had been reached before exome sequencing. We measured the expression of interferon stimulated genes (ISGs) in peripheral blood from these patients. RESULTS: Five patients from four families with previously unexplained spastic paraplegia were identified with mutations in either ADAR1 (one patient), IFIH1 (one patient), or RNASEH2B (three patients from two families). All patients were developmentally normal before the onset of features beginning in the second year of life. All patients remain of normal intellect. Four patients demonstrated normal neuroimaging, while a single patient had features of nonspecific dysmyelination. The patients with ADAR1 and IFIH1-related disease showed a robust interferon signature. The patients with mutations in RNASEH2B demonstrated no (two patients) or a minimal (one patient) upregulation of ISGs compared with controls. CONCLUSIONS: Mutations in ADAR1, IFIH1, and RNASEH2B can cause a phenotype of spastic paraplegia with normal neuroimaging, or in association with nonspecific dysmyelination. Although the presence of an interferon signature can be helpful in interpreting the significance of gene variants in this context, patients with pathogenic mutations in RNASEH2B may demonstrate no upregulation of ISGs in peripheral blood. However, it remains possible that type I interferons act as a neurotoxin in the context of all genotypes.


Assuntos
Adenosina Desaminase/genética , RNA Helicases DEAD-box/genética , Mutação , Proteínas de Ligação a RNA/genética , Ribonuclease H/genética , Paraplegia Espástica Hereditária/genética , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Interferon Tipo I/metabolismo , Helicase IFIH1 Induzida por Interferon , Masculino , Irmãos , Paraplegia Espástica Hereditária/sangue
14.
Nat Genet ; 46(5): 503-509, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24686847

RESUMO

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.


Assuntos
Doenças Autoimunes do Sistema Nervoso/genética , RNA Helicases DEAD-box/genética , Interferon Tipo I/imunologia , Modelos Moleculares , Mutação/genética , Malformações do Sistema Nervoso/genética , Fenótipo , Transdução de Sinais/genética , Análise de Variância , Doenças Autoimunes do Sistema Nervoso/imunologia , Sequência de Bases , RNA Helicases DEAD-box/química , Ensaio de Desvio de Mobilidade Eletroforética , Exoma/genética , Células HEK293 , Humanos , Helicase IFIH1 Induzida por Interferon , Repetições de Microssatélites/genética , Dados de Sequência Molecular , Malformações do Sistema Nervoso/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Análise Espectral
15.
Brain ; 137(Pt 5): 1350-60, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24645144

RESUMO

The first described patients with pyridox(am)ine 5'-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5'-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5'-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5'-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5'-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5'-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5'-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin mononucleotide or pyridoxal 5'-phosphate and many of them showed residual enzyme activity. One sequence change (R116Q), predicted to affect flavin mononucleotide binding and binding of the two PNPO dimers, and with high residual activity was found in Groups (ii) and (iii). This sequence change has been reported in the 1000 Genomes project suggesting it could be a polymorphism but alternatively it could be a common mutation, perhaps responsible for the susceptibility locus for genetic generalized epilepsy on 17q21.32 (close to rs72823592). We believe the reduction in PNPO activity and B6-responsive epilepsy in the patients reported here indicates that it contributes to the pathogenesis of epilepsy.


Assuntos
Meio Ambiente , Epilepsia/genética , Mutação/genética , Piridoxaminafosfato Oxidase/genética , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/terapia , Feminino , Células HeLa , Humanos , Lactente , Masculino , Mutagênese Sítio-Dirigida/métodos , Fosfato de Piridoxal/uso terapêutico , Piridoxaminafosfato Oxidase/metabolismo , Transfecção , Adulto Jovem
16.
Neuropediatrics ; 45(3): 175-82, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24407470

RESUMO

OBJECTIVE: With the identification of mutations in the conserved telomere maintenance component 1 (CTC1) gene as the cause of Coats plus (CP) disease, it has become evident that leukoencephalopathy with calcifications and cysts (LCC) is a distinct genetic entity. PATIENTS AND METHODS: A total of 15 patients with LCC were identified from our database of patients with intracranial calcification. The clinical and radiological features are described. RESULTS: The median age (range) at presentation was 10 months (range, 2 days-54 years). Of the 15 patients, 9 presented with epileptic seizures, 5 with motor abnormalities, and 1 with developmental delay. Motor abnormalities developed in 14 patients and cognitive problems in 13 patients. Dense calcification occurred in the basal ganglia, thalami, dentate nucleus, brain stem, deep gyri, deep white matter, and in a pericystic distribution. Diffuse leukoencephalopathy was present in all patients, and it was usually symmetrical involving periventricular, deep, and sometimes subcortical, regions. Cysts developed in the basal ganglia, thalamus, deep white matter, cerebellum, or brain stem. In unaffected areas, normal myelination was present. No patient demonstrated cerebral atrophy. CONCLUSION: LCC shares the neuroradiological features of CP. However, LCC is a purely neurological disorder distinguished genetically by the absence of mutations in CTC1. The molecular cause(s) of LCC has (have) not yet been determined.


Assuntos
Encefalopatias/diagnóstico , Calcinose/diagnóstico , Cistos/diagnóstico , Leucoencefalopatias/diagnóstico , Doenças do Sistema Nervoso/diagnóstico , Adolescente , Adulto , Encefalopatias/complicações , Calcinose/complicações , Criança , Pré-Escolar , Cistos/complicações , Humanos , Lactente , Recém-Nascido , Leucoencefalopatias/complicações , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Tomógrafos Computadorizados , Adulto Jovem
17.
Childs Nerv Syst ; 30(3): 375-85, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24452481

RESUMO

PURPOSE: Cerebellar mutism is a serious neurosurgical complication after posterior fossa surgery, but the cause, incidence and outcome remain incompletely defined. The aim of this paper was to identify and review all reports of this phenomenon to better delineate and improve the evidence base. METHODS: A systematic search and retrieval of databases was conducted using advanced search techniques. Review/outcomes criteria were developed, and study quality was determined. RESULTS: The retrieval identified 2,281 papers of which 96 were relevant, identifying 650 children with cerebellar mutism. Causative factors, clinical features and outcomes were reported variably; papers focussed on multiple areas, the majority reporting incidence in single or series of case studies with little or no analysis further than description. CONCLUSIONS: The complexity and variability of data reporting, likely contributing factors and outcomes make cerebellar mutism difficult to predict in incidence and the degree of impact that may ensue. A clear and accepted universal definition would help improve reporting, as would the application of agreed outcome measures. Clear and consistent reporting of surgical technique remains absent. Recommendations for practice are provided.


Assuntos
Doenças Cerebelares/complicações , Doenças Cerebelares/terapia , Mutismo/etiologia , Mutismo/terapia , Adolescente , Doenças Cerebelares/psicologia , Doenças Cerebelares/cirurgia , Criança , Pré-Escolar , Cognição/fisiologia , Interpretação Estatística de Dados , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutismo/psicologia , Mutismo/cirurgia , Procedimentos Neurocirúrgicos , Viés de Publicação , Fatores de Risco , Resultado do Tratamento
18.
Dev Med Child Neurol ; 56(7): 612-26, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24372060

RESUMO

Intracranial calcification (ICC) is a common finding on neuroimaging in paediatric neurology practice. In approximately half of all cases the calcification occurs in damaged, neoplastic, or malformed brain. For the large number of other disorders in which ICC occurs, no common pathogenetic mechanism can be suggested. Congenital infection, particularly with cytomegalovirus, accounts for a significant proportion of all cases. However, some genetic diseases, in particular Aicardi-Goutières syndrome, Band-like calcification, and RNASET2-related disease, may mimic congenital infection; therefore, a full consideration of the radiological and clinical features is necessary before concluding that congenital infection is the cause. In some disorders calcification is a universal finding, in others it is a frequent occurrence, and in some it is only an occasional finding. Characteristic patterns of calcification are seen in a number of conditions, and a systematic approach to the identification and description of radiological findings, taken together in the context of the clinical scenario, allows a diagnosis to be made in many cases. Nonetheless, there remain a number of presumed genetic disorders associated with ICC for which the underlying molecular cause has not yet been identified.


Assuntos
Encefalopatias/etiologia , Encéfalo/anormalidades , Calcinose/etiologia , Fenótipo , Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Calcinose/diagnóstico por imagem , Calcinose/genética , Criança , Humanos , Neuroimagem , Radiografia
19.
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
20.
Lancet Neurol ; 12(12): 1159-69, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24183309

RESUMO

BACKGROUND: Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. METHODS: In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. FINDINGS: 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. INTERPRETATION: AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. FUNDING: European Union's Seventh Framework Programme; European Research Council.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/metabolismo , Exodesoxirribonucleases/genética , Regulação da Expressão Gênica , Interferon Tipo I/fisiologia , Proteínas Monoméricas de Ligação ao GTP/genética , Malformações do Sistema Nervoso/metabolismo , Fosfoproteínas/genética , Ribonuclease H/genética , Adolescente , Adulto , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/genética , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Heterogeneidade Genética , Genótipo , Humanos , Lactente , Interferon Tipo I/sangue , Interferon Tipo I/líquido cefalorraquidiano , Interferon Tipo I/imunologia , Masculino , Mutação , Malformações do Sistema Nervoso/genética , Testes de Neutralização , Estudos Prospectivos , RNA Mensageiro/biossíntese , Proteínas de Ligação a RNA , Proteína 1 com Domínio SAM e Domínio HD , Regulação para Cima , Adulto Jovem
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