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2.
Rev Assoc Med Bras (1992) ; 66(3): 375-379, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32520161

RESUMO

BACKGROUND: Symptomatic Chiari Type I Malformation (CM) is treated with posterior fossa decompression with or without duroplasty. We have noticed some cases with concomitant severe cerebellar ataxia due to cerebellar atrophy. The aim of this study is to review the literature of CM associated with severe cerebellar atrophy and discuss its potential physiopathology. METHODS: A systematic literature review in the Pubmed Database was performed using the following key-terms: "cerebellar atrophy Chiari", and "cerebellar degeneration Chiari". Articles reporting the presence of cerebellar degeneration/atrophy associated with CM were included. RESULTS: We found only six studies directly discussing the association of cerebellar atrophy with CM, with a total of seven cases. We added one case of our own practice for additional discussion. Only speculative causes were described to justify cerebellar atrophy. The potential causes of cerebellar atrophy were diffuse cerebellar ischemia from chronic compression of small vessels (the most mentioned speculative cause), chronic raised intracranial pressure due to CSF block, chronic venous hypertension, and association with platybasia with ventral compression of the brainstem resulting in injury of the inferior olivary nuclei leading to mutual trophic effects in the cerebellum. Additionally, it is not impossible to rule out a degenerative cause for cerebellar atrophy without a causative reason. CONCLUSIONS: Severe cerebellar atrophy is found in some patients with CM. Although chronic ischemia due to compression is the most presumed cause, other etiologies were proposed. The real reasons for cerebellar degeneration are not known. Further studies are necessary.


Assuntos
Malformação de Arnold-Chiari/fisiopatologia , Doenças Cerebelares/fisiopatologia , Malformação de Arnold-Chiari/diagnóstico por imagem , Atrofia , Doenças Cerebelares/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/fisiopatologia , Cerebelo/cirurgia , Descompressão Cirúrgica , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino
3.
BMC Med Genet ; 21(1): 96, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381069

RESUMO

BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Morte Súbita/patologia , Epilepsia/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Adulto , Cerebelo/patologia , Criança , Morte Súbita/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/mortalidade , Deficiências do Desenvolvimento/patologia , Epilepsia/mortalidade , Epilepsia/patologia , Anormalidades do Olho/mortalidade , Anormalidades do Olho/patologia , Feminino , Heterozigoto , Humanos , Mutação INDEL , Doenças Renais Císticas/mortalidade , Doenças Renais Císticas/patologia , Masculino , Neuro-Hipófise/metabolismo , Neuro-Hipófise/patologia , Retina/patologia , Sequenciamento Completo do Genoma , Adulto Jovem
4.
J Vet Diagn Invest ; 32(3): 463-466, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32404029

RESUMO

A juvenile raccoon (Procyon lotor) was submitted dead to the Minnesota Veterinary Diagnostic Laboratory for rabies testing without history. The animal had marked hypoplasia of the cerebellum. Histology demonstrated that most folia lacked granule cells and had randomly misplaced Purkinje cells. Immunohistochemistry revealed the presence of parvoviral antigen in a few neurons and cell processes. PCR targeting feline and canine parvovirus yielded a positive signal. Sequencing analyses from a fragment of the nonstructural protein 1 (NS1) gene and a portion of the viral capsid protein 2 (VP2) gene confirmed the presence of DNA of a recent canine parvovirus variant (CPV-2a-like virus) in the cerebellum. Our study provides evidence that (canine) parvovirus may be associated with cerebellar hypoplasia and dysplasia in raccoons, similar to the disease that occurs naturally and has been reproduced experimentally by feline parvoviral infection of pregnant cats, with subsequent intrauterine or neonatal infections of the offspring.


Assuntos
Cerebelo/anormalidades , Malformações do Sistema Nervoso/veterinária , Infecções por Parvoviridae/veterinária , Parvovirus Canino/isolamento & purificação , Guaxinins/virologia , Animais , Cerebelo/patologia , Cerebelo/virologia , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/virologia , Feminino , Imuno-Histoquímica , Malformações do Sistema Nervoso/patologia , Malformações do Sistema Nervoso/virologia , Infecções por Parvoviridae/virologia , Parvovirus Canino/genética , Reação em Cadeia da Polimerase/veterinária
5.
J Headache Pain ; 21(1): 39, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32334532

RESUMO

BACKGROUND: Migraine is a common neurological disorder characterized by a complex physiopathology. We assessed brain morphologic differences in migraine and the possible pathogenetic mechanism underlying this disease. METHODS: We analyzed brain morphologic images of migraine patients, 14 with aura (MwA) [the mean (SD) age was 42.36 (2.95) years (range, 37-47)] and 14 without aura (MwoA) [the mean (SD) age was 43.5 (3.25) years (range, 39-50)] during episodic attack compared with health subjects balanced (HS) [the mean (SD) age was 42.5 (5.17) years (range, 34-51)]. All subjects underwent a Magnetic Resonance Imaging (MRI) examination with a scanner operating at 3.0 T and voxel based morphometry (VBM) approach was used to examine the gray matter volume (GMV). The statistical analysis to compare clinicl characteristics was performed using unpaired t-test an one-way Anova. RESULTS: Total cerebral GMV showed a significant difference between MwA and HS (p = 0.02), and between MwoA and HS (p = 0.003). In addition, not significative differences were found between MwA and MwoA groups (p = 0.17). We found three clusters of regions which showed significant GMV reduction in MwA compared with MwoA. MwA subjects showed a less of GMV in 4 clusters if compared with HS, and MwoA subjects showed a less of GMV in 3 clusters if compared with HS. We observed that MwA and MwoA patients had a significant reduction of GMV in the frontal and temporal lobe and the cerebellum, if compared to HS. The bilateral fusiform gyrus and the cingulate gyrus were increase in MwoA patients compared with HS. CONCLUSION: Our findings could provide a approach to understand possible differences in the pathogenesis of two type of migraine.


Assuntos
Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Enxaqueca com Aura/diagnóstico por imagem , Adulto , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Feminino , Substância Cinzenta/anormalidades , Substância Cinzenta/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 509-513, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335874

RESUMO

OBJECTIVE: To identify pathogenic variants in two families with patients suspected for Joubert syndrome(UBST) by cerebellar vermis hypoplasia. METHODS: Clinical data and peripheral venous blood and skin tissue samples were collected for the extraction of genomic DNA. Potential variants were screened by using targeted capture and next generation sequencing. Suspected variants were validated by PCR and Sanger sequencing. The frequency of the variants in the population was calculated. Pathogenicity of the variants was predicted by following the guidelines of the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was provided to these families upon subsequent pregnancy. RESULTS: The proband of family 1 was found to harbor homozygous c.2072delT (p.F691S*fs19) frameshift variant of the AHI1 gene, which may cause premature termination of translation of the Abelson helper integration site 1 after the 691st amino acid. The proband of family 2 was found to harbor compound heterozygous variants of the CPLANE1 gene, namely c.7243dupA (p.T2415Nfs*7) and c.8001delG (p.K2667Nfs*31), which can respectively lead to premature termination of translation of ciliogenesis and planar polarity effector 1 after the 2145th and 2667th amino acids. All of the three variants were previously unreported, and were predicted to be pathogenic by bioinformatic analysis. CONCLUSION: The AHI1 c.2072delT and CPLANE1 c.7243dupA and c.8001delG variants probably underlay JBTS3 in family 1 and JBTS17 in family 2, respectively. Based on above results, prenatal diagnosis may be offered to the affected families upon their subsequent pregnancies.


Assuntos
Anormalidades Múltiplas , Proteínas Adaptadoras de Transporte Vesicular , Cerebelo/anormalidades , Anormalidades do Olho , Testes Genéticos , Doenças Renais Císticas , Proteínas de Membrana , Diagnóstico Pré-Natal , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Variação Genética , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Mutação , Gravidez
7.
Nucleic Acids Res ; 48(7): 3678-3691, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123907

RESUMO

Genomic instability resulting from defective DNA damage responses or repair causes several abnormalities, including progressive cerebellar ataxia, for which the molecular mechanisms are not well understood. Here, we report a new murine model of cerebellar ataxia resulting from concomitant inactivation of POLB and ATM. POLB is one of key enzymes for the repair of damaged or chemically modified bases, including methylated cytosine, but selective inactivation of Polb during neurogenesis affects only a subpopulation of cortical interneurons despite the accumulation of DNA damage throughout the brain. However, dual inactivation of Polb and Atm resulted in ataxia without significant neuropathological defects in the cerebellum. ATM is a protein kinase that responds to DNA strand breaks, and mutations in ATM are responsible for Ataxia Telangiectasia, which is characterized by progressive cerebellar ataxia. In the cerebella of mice deficient for both Polb and Atm, the most downregulated gene was Itpr1, likely because of misregulated DNA methylation cycle. ITPR1 is known to mediate calcium homeostasis, and ITPR1 mutations result in genetic diseases with cerebellar ataxia. Our data suggest that dysregulation of ITPR1 in the cerebellum could be one of contributing factors to progressive ataxia observed in human genomic instability syndromes.


Assuntos
Ataxia Cerebelar/genética , Cerebelo/metabolismo , Metilação de DNA , DNA Polimerase beta/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Encéfalo/embriologia , Encéfalo/patologia , Cerebelo/anormalidades , Cerebelo/patologia , Citosina/metabolismo , Dano ao DNA , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Camundongos , Camundongos Knockout , Neurogênese/genética
9.
World Neurosurg ; 137: 292-295, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32068170

RESUMO

BACKGROUND: Lumbar puncture is a common procedure that can be safely performed in most patients. Certain populations may have increased risk for complications following lumbar puncture, but the significance of basilar invagination is often underappreciated. CASE DESCRIPTION: A 45-year-old woman with basilar invagination received multiple lumbar punctures in the workup of acute meningitis. Preprocedural computed tomography was obtained. Following lumbar puncture, the patient developed locked-in syndrome. Magnetic resonance imaging obtained several days later demonstrated severe compression and infarction of the medulla and inferior cerebellum by the odontoid process and ectopic cerebellar tonsils. The patient was transferred but at this point, surgical decompression was not possible. She did not regain significant neurologic function. CONCLUSIONS: Basilar invagination is a risk factor for devastating neurologic complications following lumbar puncture. Awareness of this complication and prompt recognition of its occurrence may prevent future morbidity of lumbar puncture in patients with basilar invagination.


Assuntos
Infartos do Tronco Encefálico/diagnóstico por imagem , Síndrome do Encarceramento/diagnóstico , Bulbo/irrigação sanguínea , Bulbo/diagnóstico por imagem , Meningite Pneumocócica/diagnóstico , Platibasia/diagnóstico por imagem , Complicações Pós-Operatórias/diagnóstico , Punção Espinal/efeitos adversos , Infartos do Tronco Encefálico/etiologia , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Feminino , Humanos , Síndrome de Klippel-Feil/complicações , Síndrome de Klippel-Feil/cirurgia , Síndrome do Encarceramento/diagnóstico por imagem , Síndrome do Encarceramento/etiologia , Imagem por Ressonância Magnética , Meningite Pneumocócica/complicações , Pessoa de Meia-Idade , Processo Odontoide/anormalidades , Processo Odontoide/diagnóstico por imagem , Platibasia/complicações , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Fusão Vertebral , Streptococcus pneumoniae , Tomografia Computadorizada por Raios X
10.
Am J Hum Genet ; 106(2): 256-263, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32004446

RESUMO

We report an inborn error of metabolism caused by TKFC deficiency in two unrelated families. Rapid trio genome sequencing in family 1 and exome sequencing in family 2 excluded known genetic etiologies, and further variant analysis identified rare homozygous variants in TKFC. TKFC encodes a bifunctional enzyme involved in fructose metabolism through its glyceraldehyde kinase activity and in the generation of riboflavin cyclic 4',5'-phosphate (cyclic FMN) through an FMN lyase domain. The TKFC homozygous variants reported here are located within the FMN lyase domain. Functional assays in yeast support the deleterious effect of these variants on protein function. Shared phenotypes between affected individuals with TKFC deficiency include cataracts and developmental delay, associated with cerebellar hypoplasia in one case. Further complications observed in two affected individuals included liver dysfunction and microcytic anemia, while one had fatal cardiomyopathy with lactic acidosis following a febrile illness. We postulate that deficiency of TKFC causes disruption of endogenous fructose metabolism leading to generation of by-products that can cause cataract. In line with this, an affected individual had mildly elevated urinary galactitol, which has been linked to cataract development in the galactosemias. Further, in light of a previously reported role of TKFC in regulating innate antiviral immunity through suppression of MDA5, we speculate that deficiency of TKFC leads to impaired innate immunity in response to viral illness, which may explain the fatal illness observed in the most severely affected individual.


Assuntos
Catarata/etiologia , Cerebelo/anormalidades , Deficiências do Desenvolvimento/etiologia , Mutação , Malformações do Sistema Nervoso/etiologia , Fósforo-Oxigênio Liases/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Alelos , Sequência de Aminoácidos , Catarata/patologia , Cerebelo/patologia , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Homozigoto , Humanos , Lactente , Masculino , Malformações do Sistema Nervoso/patologia , Linhagem , Fenótipo , Fosforilação , Homologia de Sequência , Sequenciamento Completo do Exoma
11.
BMC Med Genet ; 21(1): 18, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000717

RESUMO

BACKGROUND: Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance. CASE PRESENTATION: We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03. CONCLUSION: This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Predisposição Genética para Doença , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adulto , Cerebelo/fisiopatologia , Criança , Éxons/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/fisiopatologia , Feminino , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mutação/genética , Linhagem , Isoformas de Proteínas/genética , Retina/metabolismo , Retina/patologia , Retina/fisiopatologia , Vietnã , Sequenciamento Completo do Exoma
12.
Neurology ; 94(8): e797-e801, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-31969461

RESUMO

OBJECTIVE: To estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descriptive epidemiology and to provide a molecular characterization of the described patient cohort. METHODS: We enrolled all patients with a neuroradiologically confirmed diagnosis of JS who resided in Italy in 2018 and calculated age and sex prevalence, assuming a Poisson distribution. We also investigated the correlation between proband chronological age and age at diagnosis and performed next-generation sequencing (NGS) analysis on probands' DNA when available. RESULTS: We identified 284 patients with JS: the overall, female- and male-specific population-based prevalence rates were 0.47 (95% confidence interval [CI] 0.41-0.53), 0.41 (95% CI 0.32-0.49), and 0.53 (95% CI 0.45-0.61) per 100,000 population, respectively. When we considered only patients in the age range from 0 to 19 years, the corresponding population-based prevalence rates rose to 1.7 (95% CI 1.49-1.97), 1.62 (95% CI 1.31-1.99), and 1.80 (95% CI 1.49-2.18) per 100,000 population. NGS analysis allowed identifying the genetic cause in 131 of 219 screened probands. Age at diagnosis was available for 223 probands, with a mean of 6.67 ± 8.10 years, and showed a statistically significant linear relationship with chronological age (r 2 = 0.79; p < 0.001). CONCLUSIONS: We estimated for the first time the age and sex prevalence of JS in Italy and investigated the patients' genetic profile. The obtained population-based prevalence rate was ≈10 times higher than that available in literature for children population.


Assuntos
Anormalidades Múltiplas/epidemiologia , Cerebelo/anormalidades , Anormalidades do Olho/epidemiologia , Doenças Renais Císticas/epidemiologia , Retina/anormalidades , Anormalidades Múltiplas/genética , Adolescente , Adulto , Fatores Etários , Idade de Início , Criança , Pré-Escolar , Bases de Dados Genéticas , Anormalidades do Olho/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Itália/epidemiologia , Doenças Renais Císticas/genética , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores Sexuais , Adulto Jovem
13.
Clin Imaging ; 60(1): 33-37, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31864197

RESUMO

We present a case of acute and chronic ischemia in the bilateral cerebellar border zones in a patient with migraine with aura. To our knowledge, this imaging presentation has not been published. The patient presented with 20 years of migraines that had worsened with developing aura prior to MRI, which showed restricted diffusion in the bilateral cerebellar border zones, consistent with acute ischemia. Additional ADC hyperintensities were demonstrated in the border zones, consistent with chronic infarcts. Follow-up CT angiogram showed no occlusion, stenosis, vasospasm, or significant atherosclerosis in the posterior circulation. Additionally, follow-up MRI performed 56 days after initial MRI showed that post-migraine ischemia can be associated with signs of microscopic damage on DWI/ADC map that are not visible with T2 weighted or FLAIR sequences. Cerebellar border zone hypoperfusion from cortical spreading depression and/or transient vasospasm is the most likely etiology due to poor collateral circulation and thus a lower ischemic threshold. Changes in physiologic response to 5-HT during migraine with aura may be responsible for these perfusional abnormalities. Some patients may be more prone due to anatomic variability of the superior cerebellar arteries (SCA) and posterior inferior cerebellar arteries (PICA). Radiologist should be aware of subtle small cerebellar zone infarcts with migraine patients when scrutinizing the posterior fossa.


Assuntos
Transtornos de Enxaqueca/diagnóstico por imagem , Cerebelo/anormalidades , Constrição Patológica , Deficiências do Desenvolvimento , Imagem de Difusão por Ressonância Magnética , Humanos , Infarto , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Malformações do Sistema Nervoso , Perfusão , Artéria Vertebral
14.
Clin Dysmorphol ; 29(1): 10-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31577543

RESUMO

With the increasing availability and clinical use of exome and whole-genome sequencing, reverse phenotyping is now becoming common practice in clinical genetics. Here, we report a patient identified through the Wellcome Trust Deciphering Developmental Disorders study who has homozygous pathogenic variants in CC2D2A and a de-novo heterozygous pathogenic variant in KIDINS220. He presents with developmental delay, intellectual disability, and oculomotor apraxia. Reverse phenotyping has demonstrated that he likely has a composite phenotype with contributions from both variants. The patient is much more mildly affected than those with Joubert Syndrome or Spastic paraplegia, intellectual disability, nystagmus, and obesity, the conditions associated with CC2D2A and KIDINS220 respectively, and therefore, contributes to the phenotypic variability associated with the two conditions.


Assuntos
Anormalidades Múltiplas , Cerebelo/anormalidades , Proteínas do Citoesqueleto/genética , Deficiências do Desenvolvimento , Anormalidades do Olho , Deficiência Intelectual , Doenças Renais Císticas , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Cerebelo/patologia , Cerebelo/fisiopatologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/fisiopatologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/fisiopatologia , Homozigoto , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Doenças Renais Císticas/fisiopatologia , Masculino , Retina/patologia , Retina/fisiopatologia
15.
Proc Natl Acad Sci U S A ; 117(2): 1113-1118, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31879347

RESUMO

Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd (alias Barttin) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290-deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Anormalidades do Olho/genética , Genes Modificadores , Doenças Renais Císticas/genética , Retina/anormalidades , Animais , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Predisposição Genética para Doença/genética , Nefropatias , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença
16.
Dev Cell ; 51(6): 759-774.e5, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31846650

RESUMO

Appropriate axonal growth and connectivity are essential for functional wiring of the brain. Joubert syndrome-related disorders (JSRD), a group of ciliopathies in which mutations disrupt primary cilia function, are characterized by axonal tract malformations. However, little is known about how cilia-driven signaling regulates axonal growth and connectivity. We demonstrate that the deletion of related JSRD genes, Arl13b and Inpp5e, in projection neurons leads to de-fasciculated and misoriented axonal tracts. Arl13b deletion disrupts the function of its downstream effector, Inpp5e, and deregulates ciliary-PI3K/AKT signaling. Chemogenetic activation of ciliary GPCR signaling and cilia-specific optogenetic modulation of downstream second messenger cascades (PI3K, AKT, and AC3) commonly regulated by ciliary signaling receptors induce rapid changes in axonal dynamics. Further, Arl13b deletion leads to changes in transcriptional landscape associated with dysregulated PI3K/AKT signaling. These data suggest that ciliary signaling acts to modulate axonal connectivity and that impaired primary cilia signaling underlies axonal tract defects in JSRD.


Assuntos
Anormalidades Múltiplas/metabolismo , Axônios/metabolismo , Cerebelo/anormalidades , Cílios/metabolismo , Anormalidades do Olho/genética , Doenças Renais Císticas/metabolismo , Retina/anormalidades , Anormalidades Múltiplas/genética , Animais , Cerebelo/metabolismo , Modelos Animais de Doenças , Anormalidades do Olho/metabolismo , Doenças Renais Císticas/genética , Camundongos , Mutação/genética , Neurogênese/fisiologia , Retina/metabolismo
17.
Am J Hum Genet ; 105(3): 606-615, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474318

RESUMO

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.


Assuntos
Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Masculino , Gravidez
18.
BMC Neurol ; 19(1): 218, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481008

RESUMO

BACKGROUND: There are no established theories regarding the role of the cerebellum in dystonia. We report a case of focal limb dystonia secondary to a vasogenic edema of the dentate nucleus caused by a symptomatic developmental venous anomaly. CASE PRESENTATION: A 44-year-old woman presented with sudden onset dystonia in her left arm for 1 week. Brain imaging revealed vasogenic edema in the deep white matter of the left cerebellar hemisphere, including the left dentate nucleus, secondary to a developmental venous anomaly. 18F-fluorodeoxyglucose positron emission tomography images showed hypometabolism in the corresponding cerebellar deep nuclei without the involvement of other brain regions. She was treated with a steroid. At the one-month follow-up, computed tomography scan demonstrated remission of the cerebellar edema, which was thought to be the cause of dystonia. CONCLUSIONS: This case demonstrates that the cerebellum has an important role in the development of dystonia. Further studies are needed to elucidate the relationship between dystonia and cerebellar dysfunction.


Assuntos
Doenças Cerebelares/etiologia , Distonia/etiologia , Distúrbios Distônicos/etiologia , Adulto , Encéfalo/diagnóstico por imagem , Cerebelo/anormalidades , Feminino , Humanos , Tomografia por Emissão de Pósitrons/efeitos adversos , Tomografia Computadorizada por Raios X , Veias/anormalidades
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