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1.
World Neurosurg ; 123: 464-468.e1, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30496930

RESUMO

BACKGROUND: Hypertrophic olivary degeneration (HOD) is a rare neurological condition of trans-synaptic degeneration caused by disruption of the dentatorubro-olivary pathway. We present new radiologic findings of HOD in 2 cases of brainstem lymphoma. CASE DESCRIPTION: A 35-year-old woman (Case 1) and a 69-year-old man (Case 2) presented with remarkably similar clinical courses. The primary lesion was located at the dorsal pons extending to the midbrain. Pathologic diagnosis of diffuse large B-cell lymphoma was obtained after surgical resection. Complete remission of the primary lesion was achieved by treatment with 3 courses of high-dose methotrexate and radiotherapy. Arterial spin-labeling and T2-weighted imagings showed high signal intensity in the inferior olive (IO) at some time after the operation. Slight contrast enhancement in the IO was also found in Case 1. These radiologic findings nearly misled us into a diagnosis of recurrence of lymphoma. Signal intensity in the IO on arterial spin-labeling imaging changed with time. Normalized regional cerebral blood flow (rCBF) in the IO was defined as a percentage of rCBF to the global cerebral blood flow calculated using automated software. Chronologic change in normalized rCBF in the IO revealed a large peak in Case 1, but only a mild increase in Case 2. Neurological findings demonstrated severe oculopalatal tremor in Case 1 and mild palatal tremor in Case 2. CONCLUSIONS: Hyperperfusion and contrast enhancement in the IO were found in 2 patients with HOD. These findings may be confused with recurrence of malignant tumor.


Assuntos
Neoplasias do Tronco Encefálico/complicações , Linfoma/complicações , Núcleo Olivar/patologia , Atrofias Olivopontocerebelares/diagnóstico por imagem , Atrofias Olivopontocerebelares/etiologia , Adulto , Idoso , Feminino , Humanos , Imageamento Tridimensional , Imagem por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Marcadores de Spin
2.
Muscle Nerve ; 59(1): 137-141, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30025162

RESUMO

INTRODUCTION: Mutations in the EXOSC3 gene are responsible for type 1 pontocerebellar hypoplasia, an autosomal recessive congenital disorder characterized by cerebellar atrophy, developmental delay, and anterior horn motor neuron degeneration. Muscle biopsies of these patients often show characteristics resembling classic spinal muscle atrophy, but to date, no distinct features have been identified. METHODS: Clinical data and muscle biopsy findings of 3 unrelated patients with EXOSC3 mutations are described. RESULTS: All patients presented as a severe congenital cognitive and neuromuscular phenotype with short survival, harboring the same point mutation (c.92G>C; p.Gly31Ala). Muscle biopsies consistently showed variable degrees of sarcomeric disorganization with myofibrillar remnants, Z-line thickening, and small nemaline bodies. CONCLUSIONS: In this uniform genetic cohort of patients with EXOSC3 mutations, sarcomeric disruption and rod structures were prominent features of muscle biopsies. In the context of neonatal hypotonia, ultrastructural studies might provide early clues for the diagnosis of EXOSC3-related pontocerebellar hypoplasia. Muscle Nerve 59:137-141, 2019.


Assuntos
Complexo Multienzimático de Ribonucleases do Exossomo/genética , Músculo Esquelético/patologia , Mutação/genética , Atrofias Olivopontocerebelares/genética , Atrofias Olivopontocerebelares/patologia , Proteínas de Ligação a RNA/genética , Sarcoma/patologia , Biópsia , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Músculo Esquelético/ultraestrutura , Miopatias da Nemalina , Sarcoma/ultraestrutura
3.
J Neuropathol Exp Neurol ; 77(11): 1005-1016, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30203094

RESUMO

We aimed to determine patterns of α-synuclein (α-syn) pathology in multiple system atrophy (MSA) using 70-µm-thick sections of 20 regions of the central nervous system of 37 cases with striato-nigral degeneration (SND) and 10 cases with olivo-ponto-cerebellar atrophy (OPCA). In SND cases with the shortest disease duration (phase 1), α-syn pathology was observed in striatum, lentiform nucleus, substantia nigra, brainstem white matter tracts, cerebellar subcortical white matter as well as motor cortex, midfrontal cortex, and sensory cortex. SND with increasing duration of disease (phase 2) was characterized by involvement of spinal cord and thalamus, while phase 3 was characterized by involvement of hippocampus and amygdala. Cases with the longest disease duration (phase 4) showed involvement of the visual cortex. We observed an increasing overlap of α-syn pathology with increasing duration of disease between SND and OPCA, and noted increasingly similar regional distribution patterns of α-syn pathology. The GBA variant, p.Thr408Met, was found to have an allele frequency of 6.94% in SND cases which was significantly higher compared with normal (0%) and other neurodegenerative disease pathologies (0.74%), suggesting that it is associated with MSA. Our findings indicate that SND and OPCA show distinct early foci of α-syn aggregations, but increasingly converge with longer disease duration to show overlapping patterns of α-syn pathology.


Assuntos
Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/metabolismo , Atrofia de Múltiplos Sistemas/patologia , Atrofias Olivopontocerebelares/etiologia , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Feminino , Testes Genéticos , Glucosilceramidase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/genética , Medula Espinal/metabolismo , Medula Espinal/patologia
5.
Am J Med Genet A ; 176(12): 2623-2629, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30151950

RESUMO

KIF26B is a member of the kinesin superfamily with evolutionarily conserved functions in controlling aspects of embryogenesis, including the development of the nervous system, though its function is incompletely understood. We describe an infant with progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis secondary to the involvement of anterior horn cells and ventral (motor) nerves. We performed whole exome sequencing on the trio and identified a de novo KIF26B missense variant, p.Gly546Ser, in the proband. This variant alters a highly conserved amino acid residue that is part of the phosphate-binding loop motif and motor-like domain and is deemed pathogenic by several in silico methods. Functional analysis of the variant protein in cultured cells revealed a reduction in the KIF26B protein's ability to promote cell adhesion, a defect that potentially contributes to its pathogenicity. Overall, KIF26B may play a critical role in the brain development and, when mutated, cause pontocerebellar hypoplasia with arthrogryposis.


Assuntos
Cinesina/genética , Atrofias Olivopontocerebelares/genética , Atrofias Musculares Espinais da Infância/diagnóstico , Atrofias Musculares Espinais da Infância/genética , Sequência de Aminoácidos , Animais , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Adesão Celular , Modelos Animais de Doenças , Expressão Gênica , Humanos , Cinesina/química , Imagem por Ressonância Magnética/métodos , Camundongos , Modelos Moleculares , Conformação Proteica , Sequenciamento Completo do Exoma
6.
ACS Chem Biol ; 13(10): 3000-3010, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30141626

RESUMO

Mutations of EXOSC3 have been linked to the rare neurological disorder known as Pontocerebellar Hypoplasia type 1B (PCH1B). EXOSC3 is one of three putative RNA-binding structural cap proteins that guide RNA into the RNA exosome, the cellular machinery that degrades RNA. Using RNAcompete, we identified a G-rich RNA motif binding to EXOSC3. Surface plasmon resonance (SPR) and microscale thermophoresis (MST) indicated an affinity in the low micromolar range of EXOSC3 for long and short G-rich RNA sequences. Although several PCH1B-causing mutations in EXOSC3 did not engage a specific RNA motif as shown by RNAcompete, they exhibited lower binding affinity to G-rich RNA as demonstrated by MST. To test the hypothesis that modification of the RNA-protein interface in EXOSC3 mutants may be phenocopied by small molecules, we performed an in-silico screen of 50 000 small molecules and used enzyme-linked immunosorbant assays (ELISAs) and MST to assess the ability of the molecules to inhibit RNA-binding by EXOSC3. We identified a small molecule, EXOSC3-RNA disrupting (ERD) compound 3 (ERD03), which ( i) bound specifically to EXOSC3 in saturation transfer difference nuclear magnetic resonance (STD-NMR), ( ii) disrupted the EXOSC3-RNA interaction in a concentration-dependent manner, and ( iii) produced a PCH1B-like phenotype with a 50% reduction in the cerebellum and an abnormally curved spine in zebrafish embryos. This compound also induced modification of zebrafish RNA expression levels similar to that observed with a morpholino against EXOSC3. To our knowledge, this is the first example of a small molecule obtained by rational design that models the abnormal developmental effects of a neurodegenerative disease in a whole organism.


Assuntos
Modelos Animais de Doenças , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Isoquinolinas/farmacologia , Isoquinolinas/toxicidade , Atrofias Olivopontocerebelares/genética , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Peixe-Zebra/anormalidades , Animais , Atrofia , Cerebelo/patologia , Regulação para Baixo , Complexo Multienzimático de Ribonucleases do Exossomo/química , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Técnicas de Silenciamento de Genes , Humanos , Isoquinolinas/metabolismo , Simulação de Acoplamento Molecular , Mutação , Atrofias Olivopontocerebelares/induzido quimicamente , Atrofias Olivopontocerebelares/patologia , Fenótipo , Ligação Proteica , Domínios Proteicos , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Curvaturas da Coluna Vertebral/induzido quimicamente , Transcriptoma/efeitos dos fármacos , Regulação para Cima
7.
J Biol Chem ; 293(35): 13604-13615, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-30006346

RESUMO

Human mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are key enzymes in the mitochondrial protein translation system and catalyze the charging of amino acids on their cognate tRNAs. Mutations in their nuclear genes are associated with pathologies having a broad spectrum of clinical phenotypes, but with no clear molecular mechanism(s). For example, mutations in the nuclear genes encoding mt-AspRS and mt-ArgRS are correlated with the moderate neurodegenerative disorder leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) and with the severe neurodevelopmental disorder pontocerebellar hypoplasia type 6 (PCH6), respectively. Previous studies have shown no or only minor impacts of these mutations on the canonical properties of these enzymes, indicating that the role of the mt-aaRSs in protein synthesis is mostly not affected by these mutations, but their effects on the mitochondrial localizations of aaRSs remain unclear. Here, we demonstrate that three human aaRSs, mt-AspRS, mt-ArgRS, and LysRS, each have a specific sub-mitochondrial distribution, with mt-ArgRS being exclusively localized in the membrane, LysRS exclusively in the soluble fraction, and mt-AspRS being present in both. Chemical treatments revealed that mt-AspRs is anchored in the mitochondrial membrane through electrostatic interactions, whereas mt-ArgRS uses hydrophobic interactions. We also report that novel mutations in mt-AspRS and mt-ArgRS genes from individuals with LBSL and PCH6, respectively, had no significant impact on the mitochondrial localizations of mt-AspRS and mt-ArgRS. The variable sub-mitochondrial locations for these three mt-aaRSs strongly suggest the existence of additional enzyme properties, requiring further investigation to unravel the mechanisms underlying the two neurodegenerative disorders.


Assuntos
Arginina-tRNA Ligase/análise , Aspartato-tRNA Ligase/análise , Lisina-tRNA Ligase/análise , Mitocôndrias/química , Arginina-tRNA Ligase/genética , Aspartato-tRNA Ligase/genética , Feminino , Células HEK293 , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Lisina-tRNA Ligase/genética , Mitocôndrias/genética , Mitocôndrias/patologia , Mutação , Atrofias Olivopontocerebelares/genética , Atrofias Olivopontocerebelares/patologia
8.
J Neuropathol Exp Neurol ; 77(7): 598-607, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29850876

RESUMO

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterized by aggregation of α-synuclein in oligodendrocytes to form glial cytoplasmic inclusions. According to the distribution of neurodegeneration, MSA is subtyped as striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), or as combination of these 2 (mixed MSA). In the current study, we aimed to investigate regional microglial populations and gene expression in the 3 different MSA subtypes. Microscopy with microglial marker Iba-1 combined with either proinflammatory marker CD68 or anti-inflammatory marker Arginase-1 was analyzed in control, SND, and OPCA cases (n = 5) using paraffin embedded sections. Western immunoblotting and cytokine array were used to determine protein expression in MSA and control brain regions. Gene expression was investigated using the NanoString nCounter Human Inflammation panel v2 mRNA Expression Assay. Analysis of neuropathological subtypes of MSA demonstrated a significant increase in microglia in the substantia nigra of OPCA cases. There was no difference in the microglial activation state in any region. Cytokine expression in MSA was comparable with controls. Decreased expression of CX3CL1 precursor protein and significantly greater CX3CR1 protein was found in MSA. NanoString analysis revealed the >2-fold greater expression of ARG1, MASP1, NOX4, PTGDR2, and C6 in MSA.


Assuntos
Encéfalo/patologia , Inflamação/genética , Inflamação/patologia , Atrofia de Múltiplos Sistemas/genética , Atrofia de Múltiplos Sistemas/patologia , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/biossíntese , Antígenos de Diferenciação Mielomonocítica/genética , Arginase/biossíntese , Arginase/genética , Proteínas de Ligação ao Cálcio , Quimiocinas/análise , Quimiocinas/biossíntese , Corpo Estriado/patologia , Citocinas/análise , Citocinas/biossíntese , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Proteínas dos Microfilamentos , Microglia/patologia , Atrofias Olivopontocerebelares/patologia , Substância Negra/patologia
9.
Wiad Lek ; 71(3 pt 1): 603-606, 2018.
Artigo em Russo | MEDLINE | ID: mdl-29783233

RESUMO

Features of the onset, the course of the disease causes difficulties in the early diagnosis and formulation of the correct diagnosis. Olivopontocerebellar atrophy is characterized by a broad polymorphism of clinical manifestations. There is a need to develop new methods of symptomatic and neuroprotective treatment, as well as the optimization of non-drug therapy.


Assuntos
Atrofias Olivopontocerebelares/diagnóstico , Humanos , Pessoa de Meia-Idade , Atrofias Olivopontocerebelares/diagnóstico por imagem
10.
Eur J Paediatr Neurol ; 22(4): 674-681, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29656927

RESUMO

Pontocerebellar hypoplasia type 1 (PCH1) is a major cause of non-5q spinal muscular atrophy (SMA). We screened 128 SMN1-negative SMA patients from Bulgaria for a frequent mutation -p.G31A in EXOSC3, and performed a literature review of all genetically verified PCH1 cases. Homozygous p.G31A/EXOSC3 mutation was identified in 14 Roma patients, representing three fourths of all our SMN1-negative Roma SMA cases. The phenotype of the p.G31A/EXOSC3 homozygotes was compared to the clinical presentation of all reported to date genetically verified PCH1 cases. Signs of antenatal onset of disease present at birth were common in all PCH1 sub-types except in the homozygous p.D132A/EXOSC3 patients. The PCH1sub-types with early death (between ages 1 day and 17 months), seen in patients with p.G31A/EXOSC3 or SLC25A46 mutations have a SMA type 1-like clinical presentation but with global developmental delay, visual and hearing impairment, with or without microcephaly, nystagmus and optic atrophy. Mutations with milder presentation (homozygous p.D132A/EXOSC3 or VRK1) may display additionally signs of upper motor neuron impairment, dystonia or ataxia and die at age between 5 and 18 years. Other EXOSC3 mutations and EXOSC8 cases are intermediate - SMA type 1-like presentation, spasticity (mostly in EXOSC8) and death between 3 months and 5 years. There is no correlation between neurological onset and duration of life. We add marble-like skin and congenital laryngeal stridor as features of PCH1. We show that imaging signs of cerebellar and pontine hypoplasia may be missing early in infancy. EMG signs of anterior horn neuronopathy may be missing in PCH1 patients with SLC25A46 mutations. Thus, there is considerable phenotypic variability in PCH1, with some cases being more SMA-like, than PCH-like. Detailed clinical evaluation and ethnicity background may guide genetic testing and subsequent genetic counseling.


Assuntos
Atrofias Olivopontocerebelares/diagnóstico , Atrofias Olivopontocerebelares/genética , Atrofias Musculares Espinais da Infância/genética , Adolescente , Bulgária , Criança , Pré-Escolar , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Feminino , Estudos de Associação Genética , Homozigoto , Humanos , Masculino , Mutação , Atrofias Olivopontocerebelares/patologia , Fenótipo , Proteínas de Ligação a RNA/genética , Roma/genética
11.
Birth Defects Res ; 110(6): 538-542, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29316359

RESUMO

BACKGROUND: Bainbridge-Ropers syndrome (BRPS) is a recently identified severe disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay, caused by de novo dominant loss of function mutation in the ASXL3 gene. CASE: We report here the first case of prenatal BRPS in a fetus presenting with arthrogryposis on ultrasound and for pontocerebellar hypoplasia type 1 (PCH1) following neuropathological examination. The diagnosis was done by whole exome sequencing that identified a novel de novo ASXL3 mutation. We review 29 previous published cases. DISCUSSION: The fetopathological examination allowed to extend the phenotype to central nervous system and the genetic study highlights ASXL3 as a dominant gene responsible for PCH1 phenotype. Recognizing heterozygous ASXL3 mutation as a cause of prenatal PCH1 is essential for both large scale molecular analysis in the NGS era and genetic counseling.


Assuntos
Feto/patologia , Atrofias Olivopontocerebelares/diagnóstico , Atrofias Olivopontocerebelares/genética , Sequenciamento Completo do Exoma , Adulto , Diagnóstico Diferencial , Humanos , Fenótipo , Síndrome
12.
Auton Neurosci ; 211: 39-42, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29269241

RESUMO

Multiple system atrophy (MSA) is a rare, progressive and ultimately fatal neurodegenerative disease with no known cause and no available disease modifying treatment. Known previously by various names including Shy-Drager Syndrome, olivopontocerebellar atrophy (OPCA) and striatonigral degeneration, MSA can be classified simultaneously as a movement disorder, an autonomic disorder, a cerebellar ataxia and an atypical parkinsonian disorder. Despite scholarly attempts to better describe the disease, awareness among medical practitioners about multiple system atrophy as a diagnostic possibility has been slow to catch on. As a result, patients often go undiagnosed for many years or are largely misdiagnosed as Parkinson's disease. The non-homogeneous clinical presentation of MSA and years of confusing nomenclature have all contributed to a lack of awareness of the disease among healthcare professionals as well as the public. This lack of awareness has amplified the unmet needs of MSA patients and other stakeholders. Since the 1980s there has been a growing advocacy effort directed at this rare disease from advocacy groups, grassroots supporters, healthcare professionals and research networks. These stakeholders are beginning to unite their efforts and attack the disease from a global perspective in the hopes of improving outcomes for MSA patients in the future.


Assuntos
Doenças do Sistema Nervoso Autônomo/terapia , Atrofia de Múltiplos Sistemas/terapia , Doença de Parkinson/terapia , Síndrome de Shy-Drager/terapia , Doenças do Sistema Nervoso Autônomo/diagnóstico , Humanos , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofias Olivopontocerebelares/diagnóstico , Atrofias Olivopontocerebelares/terapia , Doença de Parkinson/diagnóstico , Síndrome de Shy-Drager/diagnóstico , Substância Negra/efeitos dos fármacos
13.
World Neurosurg ; 110: 294-300, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29061458

RESUMO

BACKGROUND: Hypertrophic olivary degeneration (HOD) is a rare phenomenon in the dento-rubro-olivary pathway caused by lesion or disruption of the fibers of the Guillain-Mollaret triangle. Hemorrhage of pontine and midbrain cavernous angiomas can rarely lead to HOD portending neurologic deterioration and possible concomitant life-threatening complications; for this reason, it may define a poignant consideration in planning intervention. CASE DESCRIPTION: The patient was a 57-year-old woman with known midbrain-pontine cavernous angioma. For several years, the lesion had been stable, as shown by imaging follow-up, until 10 months before the patient presented with falls, dysarthria, and headache. Imaging showed some decrease in size as well as blood product around the cavernous angioma, suggesting interim period hemorrhage and interval development of HOD. CONCLUSIONS: The literature regarding imaging recommendations for stable cavernous angioma in the midbrain-pontine junction is reviewed. The implication of HOD for patient outcome is discussed and a comment is made on how the development of HOD may affect management of the cavernous angioma.


Assuntos
Neoplasias do Tronco Encefálico/complicações , Hemangioma Cavernoso/complicações , Atrofias Olivopontocerebelares/etiologia , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Feminino , Hemangioma Cavernoso/diagnóstico por imagem , Humanos , Hipertrofia/complicações , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Degeneração Neural , Atrofias Olivopontocerebelares/diagnóstico por imagem , Atrofias Olivopontocerebelares/cirurgia , Tomografia Computadorizada por Raios X
14.
Clin Genet ; 93(2): 255-265, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28653766

RESUMO

Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestations in late childhood and survival into the fifties. Here we report on 4 patients from 2 families diagnosed with PCH who died within the first month of life from respiratory insufficiency. Patients from 1 family had pathoanatomically proven spinal motor neuron degeneration (PCH1). Using exome sequencing, we identified biallelic disease-segregating loss-of-function mutations in SLC25A46 in both families. Our study adds to the definition of the SLC25A46-associated phenotypic spectrum that includes neonatal fatalities due to PCH as the severe extreme.


Assuntos
Proteínas Mitocondriais/genética , Doença dos Neurônios Motores/genética , Atrofias Olivopontocerebelares/genética , Proteínas de Transporte de Fosfato/genética , Alelos , Feminino , Humanos , Lactente , Recém-Nascido , Mutação com Perda de Função/genética , Masculino , Dinâmica Mitocondrial/genética , Doença dos Neurônios Motores/mortalidade , Doença dos Neurônios Motores/fisiopatologia , Mutação , Atrofias Olivopontocerebelares/mortalidade , Atrofias Olivopontocerebelares/fisiopatologia , Fenótipo
15.
Pediatr Neurol ; 74: 87-91.e2, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28662915

RESUMO

BACKGROUND: Likely pathogenic variants in SLC17A5 results in allelic disorders of free sialic acid metabolism including (1) infantile free sialic acid storage disease with severe global developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; (2) intermediate severe Salla disease with moderate to severe global developmental delay, hypotonia, and hypomyelination with or without coarse facial features, and (3) Salla disease with normal appearance, mild cognitive dysfunction, and spasticity. PATIENT DESCRIPTION: This five-year-old girl presented with infantile-onset severe global developmental delay, truncal hypotonia, and generalized dystonia following normal development during her first six months of life. Brain magnetic resonance imaging showed marked hypomyelination and a thin corpus callosum at age 19 months, both unchanged on follow-up at age 28 months. Urine free sialic acid was moderately elevated. Cerebrospinal fluid free sialic acid was marginally elevated. Sequencing of SLC17A5 revealed compound heterozygous likely pathogenic variants, namely, a known missense (c.291G>A) variant and a novel truncating (c.819+1G>A) variant, confirming the diagnosis of Salla disease at age 3.5 years. CONCLUSION: We report a new patient with intermediate severe Salla disease. Normal or marginally elevated urine or cerebrospinal fluid free sialic acid levels cannot exclude Salla disease. In patients with progressive global developmental delay and hypomyelination on brain magnetic resonance imaging, Salla disease should be included into the differential diagnosis.


Assuntos
Doença do Armazenamento de Ácido Siálico/complicações , Doença do Armazenamento de Ácido Siálico/diagnóstico , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Bases de Dados Bibliográficas/estatística & dados numéricos , Feminino , Humanos , Imagem por Ressonância Magnética , Mutação/genética , Atrofias Olivopontocerebelares/complicações , Atrofias Olivopontocerebelares/diagnóstico por imagem , Transportadores de Ânions Orgânicos/genética , Doença do Armazenamento de Ácido Siálico/genética , Simportadores/genética
16.
Mitochondrion ; 37: 46-54, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28687512

RESUMO

Recessive mutations in EXOSC3, encoding a subunit of the human RNA exosome complex, cause pontocerebellar hypoplasia type 1b (PCH1B). We report a boy with severe muscular hypotonia, psychomotor retardation, progressive microcephaly, and cerebellar atrophy. Biochemical abnormalities comprised mitochondrial complex I and pyruvate dehydrogenase complex (PDHc) deficiency. Whole exome sequencing uncovered a known EXOSC3 mutation p.(D132A) as the underlying cause. In patient fibroblasts, a large portion of the EXOSC3 protein was trapped in the cytosol. MtDNA copy numbers in muscle were reduced to 35%, but mutations in the mtDNA and in nuclear mitochondrial genes were ruled out. RNA-Seq of patient muscle showed highly increased mRNA copy numbers, especially for genes encoding structural subunits of OXPHOS complexes I, III, and IV, possibly due to reduced degradation by a dysfunctional exosome complex. This is the first case of mitochondrial dysfunction associated with an EXOSC3 mutation, which expands the phenotypic spectrum of PCH1B. We discuss the links between exosome and mitochondrial dysfunction.


Assuntos
Complexo Multienzimático de Ribonucleases do Exossomo/genética , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Mutação , Atrofias Olivopontocerebelares/genética , Atrofias Olivopontocerebelares/patologia , Proteínas de Ligação a RNA/genética , Complexo I de Transporte de Elétrons/deficiência , Humanos , Lactente , Masculino , Doença da Deficiência do Complexo de Piruvato Desidrogenase
17.
RNA ; 23(4): 466-472, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28053271

RESUMO

The RNA exosome is a conserved multiprotein complex that achieves a large number of processive and degradative functions in eukaryotic cells. Recently, mutations have been mapped to the gene encoding one of the subunits of the exosome, EXOSC3 (yeast Rrp40p), which results in pontocerebellar hypoplasia with motor neuron degeneration in human patients. However, the molecular impact of these mutations in the pathology of these diseases is not well understood. To investigate the molecular consequences of mutations in EXOSC3 that lead to neurological diseases, we analyzed the effect of three of the mutations that affect conserved residues of EXOSC3/Rrp40p (G31A, G191C, and W238R; G8A, G148C, and W195R, respectively, in human and yeast) in S. cerevisiae We show that the severity of the phenotypes of these mutations in yeast correlate with that of the disease in human patients, with the W195R mutant showing the strongest growth and RNA processing phenotypes. Furthermore, we show that these mutations affect more severely pre-ribosomal RNA processing functions of the exosome rather than other nuclear processing or surveillance functions. These results suggest that delayed or defective pre-rRNA processing might be the primary defect responsible for the pathologies detected in patients with mutations affecting EXOSC3 function in residues conserved throughout eukaryotes.


Assuntos
Complexo Multienzimático de Ribonucleases do Exossomo/genética , Mutação , Precursores de RNA/genética , Processamento Pós-Transcricional do RNA , RNA Fúngico/genética , RNA Ribossômico/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Sítios de Ligação , Sequência Conservada , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Regulação Fúngica da Expressão Gênica , Humanos , Atrofias Olivopontocerebelares/genética , Atrofias Olivopontocerebelares/metabolismo , Atrofias Olivopontocerebelares/patologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Precursores de RNA/metabolismo , RNA Fúngico/metabolismo , RNA Ribossômico/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
18.
Orphanet J Rare Dis ; 11(1): 140, 2016 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-27769281

RESUMO

BACKGROUND: Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease caused by mutations in the RARS2 gene. RARS2 encodes mitochondrial arginyl transfer RNA synthetase, an enzyme involved in mitochondrial protein translation. A total of 27 patients from 14 families have been reported so far. Characteristic clinical features comprise neonatal lactic acidosis, severe encephalopathy, intractable seizures, feeding problems and profound developmental delay. Most patients show typical neuroradiologic abnormalities including cerebellar hypoplasia and progressive pontocerebellar atrophy. METHODS: We describe the clinical, biochemical and molecular features of 2 siblings with a novel homozygous mutation in RARS2. Both patients presented neonatally with lactic acidosis. While the older sibling had severe neurological symptoms with microcephaly, seizures and developmental delay, the younger patient was still neurologically asymptomatic at the age of 2 months. RESULTS: MRI studies in both children lacked pontocerebellar involvement. The expression of the OXPHOS complex proteins was decreased in both patients, whereas oxygen consumption was increased. CONCLUSIONS: Characteristic neuroradiological abnormalities of PCH6 such as vermis and cerebellar hypoplasia and progressive pontocerebellar atrophy may be missing in patients with RARS2 mutations. RARS2 testing should therefore also be performed in patients without pontocerebellar hypoplasia but otherwise typical clinical symptoms.


Assuntos
Arginina-tRNA Ligase/genética , Doenças Mitocondriais/genética , Mutação/genética , Atrofias Olivopontocerebelares/genética , Irmãos , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Doenças Mitocondriais/patologia , Atrofias Olivopontocerebelares/patologia
20.
Orphanet J Rare Dis ; 11(1): 100, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27430971

RESUMO

BACKGROUND: Pontocerebellar hypoplasia type 2 (PCH2) is caused by a defect in the TSEN54-gene and leads to severe and early disruption of brain development, especially of cerebellum and pons. The aim of this work was to quantify the infra- and supratentorial brain growth during postnatal brain development in children with PCH2. METHODS: MRI data of 24 children with PCH2 (age 0.02-17 years., 13 females) were analysed volumetrically and compared to images of 24 typically developing age- and gender-matched children. All children with PCH2 had the homozygous p.A307S mutation in the TSEN54-gene. In 5 patients follow-up MRI investigations were available. Images of the children with PCH2 were available either on film (n = 12) or in digital format (n = 21). Images on film were digitalized. Brain structures were manually masked and further adjusted semi-automatically using intensity thresholding to exclude CSF. Volumes of cerebellum, brain stem, and pons were measured, as well as supratentorial brain and frontal lobe volume. For validation of the method part of the digital images were processed as images on film. In addition, intra- and inter-rater variabilities were tested. RESULTS: Children with PCH2 showed reduced volumes of all measured brain structures compared to healthy controls. Severely hypoplastic cerebellum, pons and brain stem only slightly increased in size postnatally. Supratentorial brain volume also showed reduced growth compared to the healthy controls. Differences between patients and controls could already be seen at birth but became more significant during childhood. Validation of the method showed high precision and reproducibility. CONCLUSIONS: In a genetically very homogenous group of children with PCH2 severely hypoplastic infratentorial structures, the hallmark of the disease, showed only slight increase in volume postnatally. Supratentorial brain structures, which are considered normal at birth, also showed smaller volumes neonatally and a lower growth rate compared to controls, leading to severe microcephaly. Volume loss, however, could not be observed during the first years of life. This argues for a severe disruption of the cerebellar-cerebral networks during pre- and postnatal development caused by a primary cerebellar dysfunction, rather than postnatal neurodegeneration. The developmental progress in these children, although little, further supports this.


Assuntos
Encéfalo/patologia , Atrofias Olivopontocerebelares/patologia , Adolescente , Tronco Encefálico/patologia , Estudos de Casos e Controles , Cerebelo/patologia , Criança , Pré-Escolar , Feminino , Lobo Frontal/patologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/patologia , Imagem por Ressonância Magnética , Masculino , Microcefalia/patologia , Ponte/patologia
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