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1.
Front Pediatr ; 10: 892445, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35601411

RESUMO

Background: Moyamoya is a rare progressive cerebral arteriopathy, occurring as an isolated phenomenon (moyamoya disease, MMD) or associated with other conditions (moyamoya syndrome, MMS), responsible for 6-10% of all childhood strokes and transient ischemic attacks (TIAs). Methods: We conducted a retrospective multicenter study on pediatric-onset MMD/MMS in Italy in order to characterize disease presentation, course, management, neuroradiology, and outcome in a European country. Results: A total of 65 patients (34/65 women) with MMD (27/65) or MMS (38/65) were included. About 18% (12/65) of patients were asymptomatic and diagnosed incidentally during investigations performed for an underlying condition (incMMS), whereas 82% (53/65) of patients with MMD or MMS were diagnosed due to the presence of neurological symptoms (symptMMD/MMS). Of these latter, before diagnosis, 66% (43/65) of patients suffered from cerebrovascular events with or without other manifestations (ischemic stroke 42%, 27/65; TIA 32%, 21/65; and no hemorrhagic strokes), 18% (12/65) of them reported headache (in 4/12 headache was not associated with any other manifestation), and 26% (17/65) of them experienced multiple phenotypes (≥2 among: stroke/TIA/seizures/headache/others). Neuroradiology disclosed ≥1 ischemic lesion in 67% (39/58) of patients and posterior circulation involvement in 51% (30/58) of them. About 73% (47/64) of patients underwent surgery, and 69% (45/65) of them received aspirin, but after diagnosis, further stroke events occurred in 20% (12/61) of them, including operated patients (11%, 5/47). Between symptom onset and last follow-up, the overall patient/year incidence of stroke was 10.26% (IC 95% 7.58-13.88%). At last follow-up (median 4 years after diagnosis, range 0.5-15), 43% (26/61) of patients had motor deficits, 31% (19/61) of them had intellectual disability, 13% (8/61) of them had epilepsy, 11% (7/61) of them had behavioral problems, and 25% (13/52) of them had mRS > 2. The proportion of final mRS > 2 was significantly higher in patients with symptMMD/MMS than in patients with incMMS (p = 0.021). Onset age <4 years and stroke before diagnosis were significantly associated with increased risk of intellectual disability (p = 0.0010 and p = 0.0071, respectively) and mRS > 2 at follow-up (p = 0.0106 and p = 0.0009, respectively). Conclusions: Moyamoya is a severe condition that may affect young children and frequently cause cerebrovascular events throughout the disease course, but may also manifest with multiple and non-cerebrovascular clinical phenotypes including headache (isolated or associated with other manifestations), seizures, and movement disorder. Younger onset age and stroke before diagnosis may associate with increased risk of worse outcome (final mRS > 2).

2.
Joint Bone Spine ; 84(3): 353-356, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28034820

RESUMO

OBJECTIVE: To report our single centre experience in treating 4 children affected by childhood primary central nervous system vasculitis (cPACNS) using mycophenolate mofetil (MMF). METHODS: From December 2011 to August 2015, 4 patients (3 males; age range: 9 months-13 years) affected by cPACNS were collected. Enrolled children received the following treatment protocol: acetylsalicylic acid and/or anticoagulant therapy with low molecular weight heparin (LMWH) 100 U/k BID replaced by acenocoumarol; methyl-prednisolone (30mg/kg/day for 3-5 days) followed by prednisone (2mg/kg/day), tapered and discontinued over 7-8 months; MMF used for induction therapy and subsequent maintenance phase (750-1000mg/m2 BID, half-dose for the first 10-15 days followed by full-dose). RESULTS: In all children, no relapse of cerebral vasculitis occurred during the whole follow-up period and all of them improved while in MMF treatment. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), performed at 6, 9 or 12 months intervals, showed no progression or even improvement of the typical radiological findings. Medium period of MMF treatment was 29 months (range: 10-42 months). No major drug-related adverse events were documented. CONCLUSION: We report for the first time on the efficacy and safety of MMF in the induction and maintenance of clinical remission in cPACNS. Our single centre experience of MMF use in treating cPACNS seems represent an appealing, alternative and safe option in this clinical setting over a long-term follow-up.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ácido Micofenólico/uso terapêutico , Vasculite do Sistema Nervoso Central/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Vasculite do Sistema Nervoso Central/complicações , Vasculite do Sistema Nervoso Central/diagnóstico por imagem
3.
Eur J Hum Genet ; 20(3): 357-60, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22189266

RESUMO

Although mutations in mitochondrial tRNAs constitute the most common mtDNA defect, the presence of pathological variants in mitochondrial tRNA(Asn) is extremely rare. We were able to identify a novel mtDNA tRNA(Asn) gene pathogenic mutation associated with a myopathic phenotype and a previously unreported respiratory impairment. Our proband is an adult woman with ophthalmoparesis and respiratory impairment. Her muscle biopsy presented several cytochrome c oxidase-negative (COX-) fibres and signs of mitochondrial proliferation (ragged red fibres). Sequence analysis of the muscle-derived mtDNA revealed an m.5709T>C substitution, affecting mitochondrial tRNA(Asn) gene. Restriction-fragment length polymorphism analysis of the mutation in isolated muscle fibres showed that a threshold of at least 91.9% mutated mtDNA results in the COX deficiency phenotype. The new phenotype further increases the clinical spectrum of mitochondrial diseases caused by mutations in the tRNA(Asn) gene.


Assuntos
Mutação , Oftalmoplegia/genética , RNA de Transferência de Asparagina/genética , RNA/genética , Sequência de Bases , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Humanos , Pessoa de Meia-Idade , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Fibras Musculares Esqueléticas/enzimologia , Oftalmoplegia/diagnóstico , Fenótipo , RNA Mitocondrial , Alinhamento de Sequência
4.
J Neurol Sci ; 315(1-2): 146-9, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22197506

RESUMO

Autosomal Dominant Optic Atrophy (ADOA) is characterized by the selective degeneration of retinal ganglion cells. The occurrence of mutations in the gene encoding the dynamin-like GTPase protein Optic Atrophy 1 (OPA1) has been observed in about 60-70% of ADOA cases. A subset of missense mutations, mostly within the GTPase domain, has recently been associated with a syndromic ADOA form called "OPA1 plus" phenotype presenting, at muscle level, mitochondrial DNA (mtDNA) instability. In this study we disclosed two OPA1 gene mutations in independent probands from two families affected by OPA1 plus phenotype: the previously reported c.985-2A>G substitution and a novel microdeletion (c.2819-1_2821del). The correlation between genotype and phenotype and the effects of these variants at the transcript level and in the muscle tissue were investigated, confirming the broad complexity in the phenotypic spectrum associated with these OPA1 mutations.


Assuntos
GTP Fosfo-Hidrolases/genética , Mutação/genética , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Fenótipo , Adolescente , Substituição de Aminoácidos/genética , Criança , Feminino , Deleção de Genes , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Linhagem
5.
Biochem Biophys Res Commun ; 412(2): 245-8, 2011 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-21819970

RESUMO

Leigh syndrome (LS) is an incurable, nearly always fatal, neurodegenerative, pediatric disorder that results from respiratory chain failure. The most common mitochondrial DNA (mtDNA) mutations that result in LS are m.8993T→C/G and m.9176T→C/G, which were previously found in several patients with early-onset Leigh syndrome. Here, we describe clinical and molecular features of a novel pedigree, where LS developed in two siblings. The proband was a young woman with an unusual adult-onset LS. She harbored a homoplasmic m.9176T→C mutation, based on analysis of a muscle biopsy. In contrast, the brother died at a young age. This novel case report and literature review highlights the variability of phenotypic expression of the m.9176T→C mutation.


Assuntos
DNA Mitocondrial/genética , Genes Mitocondriais , Doença de Leigh/genética , Adulto , Idade de Início , Feminino , Humanos , Doença de Leigh/patologia , Músculo Esquelético/patologia , Mutação , Linhagem
6.
BMC Neurol ; 11: 85, 2011 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-21749722

RESUMO

BACKGROUND: Leigh Syndrome (LS) is a severe neurodegenerative disorder characterized by bilateral symmetrical necrotic lesions in the basal ganglia and brainstem. Onset is in early infancy and prognosis is poor. Causative mutations have been disclosed in mitochondrial DNA and nuclear genes affecting respiratory chain subunits and assembly factors. CASE PRESENTATION: Here we report the clinical and molecular features of a 15-month-old female LS patient. Direct sequencing of her muscle-derived mtDNA revealed the presence of two apparently homoplasmic variants: the novel m.14792C>G and the already known m.14459G>A resulting in p.His16Asp change in cytochrome b (MT-CYB) and p.Ala72Val substitution in ND6 subunit, respectively. The m.14459G>A was heteroplasmic in the mother's blood-derived DNA. CONCLUSIONS: The m.14459G>A might lead to LS, complicated LS or Leber Optic Hereditary Neuropathy. A comprehensive re-evaluation of previously described 14459G>A-mutated patients does not explain this large clinical heterogeneity.


Assuntos
DNA Mitocondrial/genética , Doença de Leigh/genética , Doença de Leigh/patologia , Mutação Puntual , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Doença de Leigh/fisiopatologia
7.
J Neurol Sci ; 308(1-2): 173-6, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21689831

RESUMO

Maintenance and replication of mitochondrial DNA require the concerted action of several factors encoded by nuclear genome. The mitochondrial helicase Twinkle is a key player of replisome machinery. Heterozygous mutations in its coding gene, PEO1, are associated with progressive external ophthalmoplegia (PEO) characterised by ptosis and ophthalmoparesis, with cytochrome c oxidase (COX)-deficient fibres, ragged-red fibres (RRF) and multiple mtDNA deletions in muscle. Here we describe clinical, histological and molecular features of two patients presenting with mitochondrial myopathy associated with PEO. PEO1 sequencing disclosed two novel mutations in exons 1 and 4 of the gene, respectively. Although mutations in PEO1 exon 1 have already been described, this is the first report of mutation occurring in exon 4.


Assuntos
DNA Helicases/genética , Mutação/genética , Oftalmoplegia Externa Progressiva Crônica/diagnóstico , Oftalmoplegia Externa Progressiva Crônica/genética , Adulto , Sequência de Aminoácidos , DNA Mitocondrial/genética , Éxons/genética , Feminino , Humanos , Proteínas Mitocondriais , Dados de Sequência Molecular
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