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1.
Am J Med Genet A ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31710777

RESUMO

Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

3.
Brain ; 142(8): 2230-2237, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31332433

RESUMO

Superoxide dismutase 1 (SOD1) is the principal cytoplasmic superoxide dismutase in humans and plays a major role in redox potential regulation. It catalyses the transformation of the superoxide anion (O2•-) into hydrogen peroxide. Heterozygous variants in SOD1 are a common cause of familial amyotrophic lateral sclerosis. In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity. The resulting phenotype is severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms. Heterozygous carriers have a markedly reduced enzyme activity when compared to wild-type controls but show no overt neurologic phenotype. These results are in contrast with the previously proposed theory that a loss of function is the underlying mechanism in SOD1-related motor neuron disease and should be considered before application of previously proposed SOD1 silencing as a treatment option for amyotrophic lateral sclerosis.

5.
6.
Neuropediatrics ; 50(3): 209-210, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30939598
7.
Neuropediatrics ; 50(3): 206, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30847875
8.
Neuropediatrics ; 50(3): 207, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30875699
9.
Neuropediatrics ; 50(3): 208, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30913568
10.
Eur J Paediatr Neurol ; 23(3): 537-540, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30799093

RESUMO

Mitochondrial DNA depletion syndromes (MDS) are a group of clinically and genetically heterogeneous autosomal recessive disorders characterized by a reduction of mtDNA. We report two siblings of Armenian origin with early onset neurodegenerative disease characterized by encephalopathy, severe hypotonia, facial dyskinetic movements, abnormal eye movements, severe failure to thrive, and abnormal renal and hepatic function. Sanger sequencing confirmed two variants in the C10orf2 gene (TWNK) and indicated a diagnosis of MDS. Our recent observation confirms that nephrocalcinosis and proximal tubulopathy can be a part of a clinical picture of MDS associated with TWNK mutations and document peculiar ocular and orobuccolingual dyskinesias. Wrist myoclonia and tongue tremor were new clinical features in our patients. We suggest that the above-mentioned clinical constellation could potentially provide the basis for the diagnosis of MDS.


Assuntos
DNA Helicases/genética , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Proteínas Mitocondriais/genética , Doenças Musculares/genética , Doenças Musculares/patologia , Humanos , Nefropatias/genética , Hepatopatias/genética , Masculino , Mutação , Doenças Neurodegenerativas/genética , Fenótipo , Irmãos , Síndrome
11.
Pediatr Neurol ; 94: 21-31, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30797593

RESUMO

INTRODUCTION: The area postrema in the caudal fourth ventricular floor is highly vascular without blood-brain or blood-cerebrospinal fluid barrier. In addition to its function as vomiting center, several others are part of the circumventricular organs for vasomotor/angiotensin II regulation, role in neuromyelitis optica related to aquaporin-4, and somatic growth and appetite regulation. Functions are immature at birth. The purpose was to demonstrate neuronal, synaptic, glial, or ependymal maturation in the area postrema of normal fetuses. We describe three area postrema tumors. METHODS: Sections of caudal fourth ventricle of 12 normal human fetal brains at autopsy aged six to 40 weeks and three infants aged three to 18 months were examined. Immunocytochemical neuronal and glial markers were applied to paraffin sections. Two infants with area postrema tumors and another with neurocutaneous melanocytosis and pernicious vomiting also studied. RESULTS: Area postrema neurons exhibited cytologic maturity and synaptic circuitry by 14 weeks'. Astrocytes coexpressed vimentin, glial fibrillary acidic protein, and S-100ß protein. The ependyma is thin over area postrema, with fetal ependymocytic basal processes. A glial layer separates area postrema from medullary tegmentum. Melanocytes infiltrated area postrema in the toddler with pernicious vomiting; two children had primary area postrema pilocytic astrocytomas. CONCLUSIONS: Although area postrema is cytologically mature by 14 weeks, growth increases and functions mature during postnatal months. We recommend neuroimaging for patients with unexplained vomiting and that area postrema neuropathology includes synaptophysin and microtubule-associated protein-2 in patients with suspected dysfunction.

12.
Eur Radiol ; 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30066250

RESUMO

OBJECTIVES: To describe the spectrum of brainstem malformations associated to mutations in the tubulin genes taking advantage of magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). METHODS: Fifteen patients (six males; median age, 1.25 years; range, 1 month to 31 years) with mutations in the tubulin genes (TUBA1A = 8, TUBB2B = 4, TUBB3 = 3) studied with MRI and DTI were included in the study. Brain MR exams were reviewed to describe the malformative aspects of the brainstem. Malformations of the supratentorial brain and cerebellum were also recorded. Tractography was performed in seven selected cases. RESULTS: Fourteen patients (93%) showed complex malformations of the brainstem. Most common findings, apparent on anatomical MR sequences, were brainstem asymmetry (12 cases, 5 of which with a crossed pattern characterised by a hypertrophic right medulla oblongata and hypertrophic left pons), short and small pons on midline (10 cases) and anterior brainstem clefting (6 cases). DTI revealed abnormal transverse pontine fibres (13 cases), fusion of corticospinal tracts and medial lemnisci (9 cases) and a small decussation of the superior cerebellar peduncles (7 cases). CONCLUSIONS: Conventional/anatomical MRI and DTI reveal a complex pattern of brainstem malformations associated with tubulin genes mutations. KEY POINTS: • Brainstem malformations affect 93% patients with mutated tubulin genes • MRI shows homolateral and crossed brainstem asymmetries, clefts and pons hypoplasia • DTI demonstrates irregular representation of transverse pontine fibres and fusion of corticospinal tracts.

13.
Handb Clin Neurol ; 155: 371-377, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891072

RESUMO

There are no approved disease-modifying therapies for any of the inherited cerebellar ataxias. Drug treatment in childhood ataxia is still very limited. Effective treatments are available for only a few rare metabolic hereditary disorders. Symptomatic management of associated tremor, spasticity, dystonia, or chorea can follow the medication recommendations in general usage. The foundation of management of cerebellar ataxia in adults or children remains rehabilitation.


Assuntos
Ataxia Cerebelar/tratamento farmacológico , Tratamento Farmacológico/métodos , Fatores Etários , Ataxia Cerebelar/reabilitação , Humanos
14.
Handb Clin Neurol ; 155: 91-103, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891079

RESUMO

The terminology of nonprogressive congenital ataxia (NPCA) refers to a clinically and genetically heterogeneous group of disorders characterized by congenital or early-onset ataxia, but no progression or even improvement on follow-up. Ataxia is preceded by muscular hypotonia and delayed motor (and usually language) milestones. We exclude children with prenatal, perinatal, and postnatal acquired diseases, malformations other than cerebellar hypoplasia, and defined syndromic disorders. Patients with NPCA have a high prevalence of cognitive and language impairments, in addition to increased occurrence of seizures, ocular signs (nystagmus, strabismus), behavior changes, and microcephaly. Neuroimaging is variable, ranging from normal cerebellar anatomy to reduced cerebellar volume (hypoplasia in the proper sense), and enlarged interfolial spaces, potentially mimicking atrophy. The latter appearance is often called "hypoplasia" as well, in view of the static clinical course. Some patients had progressive enlargement of cerebellar fissures, but a nonprogressive course. There is no imaging-clinical-genetic correlation. Dominant, recessive, and X-linked inheritance is documented for NPCA. Here, we focus on the still rather short list of dominant and recessive genes associated with NPCA, identified in the last few years. With future advances in genetics, we expect a rapid expansion of knowledge in this field.


Assuntos
Ataxia , Cerebelo/anormalidades , Transtornos Cognitivos/etiologia , Ataxia/diagnóstico por imagem , Ataxia/genética , Ataxia/fisiopatologia , Cerebelo/diagnóstico por imagem , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/genética , Humanos , Neuroimagem
16.
Handb Clin Neurol ; 154: 287-298, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29903445

RESUMO

This chapter deals with chemical and hematologic investigations which are often considered in the diagnostic workup of subacute to chronic cerebellar ataxias. Relevant investigations in blood (serum, plasma), urine, and cerebrospinal fluid are discussed. Particular attention is paid to early diagnosis of treatable metabolic ataxias (such as abetalipoproteinemia, coenzyme Q10 deficiency, cerebrotendinous xanthomatosis, glucose transporter type 1 deficiency, Refsum disease, and vitamin E deficiency), but autoimmune ataxias, other vitamin deficiencies, and endocrine disorders should also be kept in mind. Adequate interpretation of test results has to consider age-specific reference values. The selection of investigations should mainly be driven by the overall clinical context, considering gender, history, age, and mode of presentation, cerebellar and other neurologic as well as extraneurologic findings.


Assuntos
Ataxia Cerebelar/diagnóstico , Ciência de Laboratório Médico/métodos , Ataxia Cerebelar/metabolismo , Humanos
17.
Neuropediatrics ; 49(4): 298, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29852511
18.
Neuropediatrics ; 49(4): 262-268, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29791933

RESUMO

Basal ganglia infarction in young children, mostly after mild head trauma, has been repeatedly reported. The pathogenesis and the risk factors are not fully understood. Lenticulostriate vasculopathy, usually referred to as basal ganglia calcification, is discussed as one of them. We describe five young (7-13 months old on presentation) male children who suffered from hemiparesis due to ischemic stroke of the basal ganglia, four of them after minor head trauma. All of them had calcification in the basal ganglia visible on computed tomography or cranial ultrasound but not on magnetic resonance imaging. Follow-up care was remarkable for recurrent infarction in three patients. One patient had a second symptomatic stroke on the contralateral side, and two patients showed new asymptomatic infarctions in the contralateral basal ganglia on imaging. In view of the scant literature, this clinic-radiologic entity seems under recognized. We review the published cases and hypothesize that male sex and iron deficiency anemia are risk factors for basal ganglia stroke after minor trauma in the context of basal ganglia calcification in infants. We suggest to perform appropriate targeted neuroimaging in case of infantile basal ganglia stroke, and to consider prophylactic medical treatment, although its value in this context is not proven.

19.
Radiographics ; 38(3): 912-931, 2018 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29757724

RESUMO

Although individual cases of inherited metabolic disorders are rare, overall they account for a substantial number of disorders affecting the central nervous system. Organic acidemias and aminoacidopathies include a variety of inborn errors of metabolism that are caused by defects in the intermediary metabolic pathways of carbohydrates, amino acids, and fatty acid oxidation. These defects can lead to the abnormal accumulation of organic acids and amino acids in multiple organs, including the brain. Early diagnosis is mandatory to initiate therapy and prevent permanent long-term neurologic impairments or death. Neuroimaging findings can be nonspecific, and metabolism- and genetics-based laboratory investigations are needed to confirm the diagnosis. However, neuroimaging has a key role in guiding the diagnostic workup. The findings at conventional and advanced magnetic resonance imaging may suggest the correct diagnosis, help narrow the differential diagnosis, and consequently facilitate early initiation of targeted metabolism- and genetics-based laboratory investigations and treatment. Neuroimaging may be especially helpful for distinguishing organic acidemias and aminoacidopathies from other more common diseases with similar manifestations, such as hypoxic-ischemic injury and neonatal sepsis. Therefore, it is important that radiologists, neuroradiologists, pediatric neuroradiologists, and clinicians are familiar with the neuroimaging findings of organic acidemias and aminoacidopathies. ©RSNA, 2018.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Neuroimagem/métodos , Criança , Pré-Escolar , Diagnóstico Diferencial , Diagnóstico Precoce , Humanos , Lactente , Recém-Nascido
20.
Neuropediatrics ; 49(3): 227-228, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29482253
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