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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 841-844, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487526

RESUMO

OBJECTIVE: To analyze the phenotype and genetic variant of a fetus with dysplasia of cerebellar vermis. METHODS: Gestational status and family history of the gravida was taken in combination with the imaging results of the fetus. Following elected abortion, fetal tissue and peripheral blood samples of the couple were collected for the extraction of genome DNA. Whole exome sequencing was carried out to screen potential variant associated with the phenotype of the proband. Specific PCR primers were designed to verify the results by Sanger sequencing. RESULTS: Prenatal ultrasound revealed that the fetal vermis cerebellum was poorly developed, which was similar to the previous pregnancy. Whole exome sequencing revealed that the fetus has carried compound heterozygous variants of the CPLANE1 gene, namely c.7978C>T and c.7169delT, which were respectively inherited from the husband and wife. CONCLUSION: The c.7978C>T and c.7169delT compound heterozygous variants of the CPLANE1 gene probably underlay the dysplasia of cerebellar vermis in the fetus, which has provided a basis for genetic counseling and prenatal diagnosis.


Assuntos
Anormalidades Múltiplas , Anormalidades do Olho , Doenças Renais Císticas , Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Anormalidades do Olho/genética , Feminino , Feto , Humanos , Mutação , Fenótipo , Gravidez , Retina/anormalidades
2.
N Engl J Med ; 384(25): 2406-2417, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34161705

RESUMO

BACKGROUND: Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare. METHODS: We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle-biopsy specimens, mouse embryonic fibroblasts, and yeast. RESULTS: We found deleterious, recessive variants in human ATG7, a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7. CONCLUSIONS: We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.).


Assuntos
Anormalidades Múltiplas/genética , Ataxia/genética , Proteína 7 Relacionada à Autofagia/genética , Autofagia/genética , Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/fisiologia , Células Cultivadas , Cerebelo/anormalidades , Simulação por Computador , Face/anormalidades , Feminino , Fibroblastos , Genes Recessivos , Humanos , Lactente , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Malformações do Sistema Nervoso/genética , Linhagem , Fenótipo
3.
Stem Cell Res ; 54: 102430, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34182252

RESUMO

We have developed Joubert syndrome (JS)-derived induced pluripotent stem cell (iPSC) lines from dermal fibroblasts biopsied from a female patient harbouring novel compound heterozygous mutations in CC2D2A gene. The newly established iPSC lines provide tremendous promises for development of JS-derived neuronal cell lines to uncover the molecular and cellular mechanisms underlying the pathogenesis of JS and to develop therapeutic interventions for treatment of JS.


Assuntos
Anormalidades Múltiplas , Anormalidades do Olho , Células-Tronco Pluripotentes Induzidas , Doenças Renais Císticas , Diferenciação Celular , Cerebelo/anormalidades , Anormalidades do Olho/genética , Feminino , Fibroblastos , Humanos , Mutação , Retina/anormalidades
4.
Am J Hum Genet ; 108(5): 951-961, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33894126

RESUMO

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and ßIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and ßIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.


Assuntos
Agenesia do Corpo Caloso/genética , Cerebelo/anormalidades , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/genética , Adulto , Agenesia do Corpo Caloso/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Hidrolases/química , Hidrolases/genética , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Masculino , Proteínas Associadas aos Microtúbulos/química , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Modelos Moleculares , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Tubulina (Proteína)/metabolismo , Adulto Jovem
5.
Eur J Med Genet ; 64(6): 104212, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33794348

RESUMO

BACKGROUD: Joubert syndrome is a rare neurodevelopmental disorder characterized by clinical and genetic heterogeneity. The characteristic molar tooth sign, which resulted from cerebellar vermis hypoplasia and midbrain anomalies, is expected to be the key diagnostic feature for this disease. However, it is not easy to make a definite diagnosis in prenatal only based on the imageology due to its clinical heterogeneity. CASE REPORT: We report on a fetus who was detected cerebellum dysplasia and encephalocele by ultrasound at 19 and 23 gestational weeks and confirmed by MRI examination. The pregnancy was terminated at 23 weeks of gestation. Postaxial polydactyly and deficiency in occipital bone and skin were identified in the induced fetus. RESULTS: The whole exome sequencing identified a novel compound heterozygous variation in the CPLANE1 gene related with Joubert syndrome, including a 2-bp insertion, NM_023073.3:c.1383_1384dup; p.(Gly462Glufs*3) and a non-classic splicing variation, NC_000005.10(NM_023073.3):c.7691-5_7691-4del. The pathogenicity of the non-classic splicing variation was further confirmed by cDNA level sequencing, which showed a exon 39 skipping that would introduce a premature termination. The novel compound heterozygous variation caused a complete function loss of the CPLANE1 gene. CONCLUSION: The cerebellum dysplasia fetus without obvious molar tooth sign was finally diagnosed as Joubert syndrome, combined with genetic detecting and the postnatal clinical symptoms. We also highlight the clinical heterogeneity of encephalodysplasia in Joubert syndrome, which increases the clinical diagnosis difficulty, especially for prenatal diagnosis. Our findings provided a new perspective for the prenatal diagnosis of Joubert syndrome with severe craniocerebral dysplasia and expanded the variation spectrum of the CPLANE1 gene.


Assuntos
Anormalidades Múltiplas/genética , Feto Abortado/anormalidades , Cerebelo/anormalidades , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Mutação , Retina/anormalidades , Anormalidades Múltiplas/patologia , Adulto , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Anormalidades do Olho/patologia , Feminino , Humanos , Doenças Renais Císticas/patologia , Splicing de RNA , Retina/patologia , Ultrassonografia Pré-Natal
6.
Am J Med Genet A ; 185(5): 1561-1568, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33645901

RESUMO

Cerebellofaciodental syndrome is characterized by facial dysmorphisms, intellectual disability, cerebellar hypoplasia, and dental anomalies. It is an autosomal-recessive condition described in 2015 caused by pathogenic variants in BRF1. Here, we report a Brazilian patient who faced a diagnostic challenge beginning at 11 months of age. Fortunately, whole-exome sequencing (WES) was performed, detecting the BRF1 variants NM_001519.3:c.1649delG:p.(Gly550Alafs*36) and c.421C>T:p.(Arg141Cys) in compound heterozygosity, thus finally achieving a diagnosis of cerebellofaciodental syndrome. The patient is currently 25 years old and is the oldest patient yet reported. The clinical report and a review of published cases are presented. Atlanto-occipital fusion, a reduced foramen magnum and basilar invagination leading to compression of the medulla-spinal cord transition are skeletal findings not reported in previous cases. The description of syndromes with dental findings shows that such anomalies can be an important clue to relevant differential diagnoses. The cooperation of groups from different international centers made possible the resolution of this and other cases and is one of the strategies to bring medical advances to developing countries, where many patients with rare diseases are difficult to diagnose definitively.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades Craniofaciais/genética , Deficiência Intelectual/genética , Atrofia Muscular/genética , Malformações do Sistema Nervoso/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Adulto , Brasil/epidemiologia , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Atrofia Muscular/diagnóstico por imagem , Atrofia Muscular/fisiopatologia , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/fisiopatologia , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/fisiopatologia , Sequenciamento Completo do Exoma
7.
Am J Med Genet A ; 185(5): 1589-1597, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33682303

RESUMO

THG1L-associated autosomal recessive ataxia belongs to a group of disorders that occur due to abnormal mitochondrial tRNA modification. The product of THG1L is the tRNA-histidine guanylyltransferase 1-like enzyme that catalyzes the 3'-5"addition of guanine to the 5"-end of tRNA-histidine in the mitochondrion. To date, five individuals with homozygosity for p.(Val55Ala) in THG1L have been reported and presented with mild delays or normal development and cerebellar dysfunction. We present seven individuals with biallelic variants in THG1L. Three individuals were compound heterozygous for the p.(Cys51Trp) and p.(Val55Ala) variants and presented with profound developmental delays, microcephaly, intractable epilepsy, and cerebellar hypoplasia. Four siblings were homozygous for the p.(Val55Ala) variant and presented with cerebellar ataxia with cerebellar vermis hypoplasia, dysarthria, mild developmental delays, and normal/near-normal cognition. All seven patients were of Ashkenazi Jewish descent. Carrier rates for the two variants were calculated in a cohort of 26,731 Ashkenazi Jewish individuals tested by the Dor Yeshorim screening program. The p.(Cys51Trp) variant is novel and was found in 40 of the Ashkenazi Jewish individuals tested, with a carrier rate of 1 in 668 (0.15%). The p.(Val55Ala) variant was found in 229 of the Ashkenazi Jewish individuals tested, with a carrier rate of 1 in 117 (0.85%). The individuals with compound heterozygosity of the p.(Val55Ala) and p.(Cys51Trp) variants expand the phenotypic spectrum of THG1L-related disorders to include severe epileptic encephalopathy. The individuals with homozygosity of the p.(V55A) variant further establish the associated mild and slowly progressive or nonprogressive neurodevelopmental phenotype.


Assuntos
Encefalopatias/genética , Ataxia Cerebelar/genética , Epilepsia/genética , Proteínas/genética , Adolescente , Alelos , Encefalopatias/complicações , Encefalopatias/patologia , Ataxia Cerebelar/complicações , Ataxia Cerebelar/patologia , Doenças Cerebelares/complicações , Doenças Cerebelares/genética , Doenças Cerebelares/patologia , Cerebelo/anormalidades , Cerebelo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Epilepsia/complicações , Epilepsia/patologia , Feminino , Heterozigoto , Homozigoto , Humanos , Lactente , Judeus/genética , Masculino , Microcefalia/complicações , Microcefalia/genética , Microcefalia/patologia , Mutação/genética , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Fenótipo , Irmãos
8.
Genet Med ; 23(6): 1041-1049, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33531668

RESUMO

PURPOSE: Ciliopathies are a group of disorders caused by defects of the cilia. Joubert syndrome (JBTS) is a recessive and pleiotropic ciliopathy that causes cerebellar vermis hypoplasia and psychomotor delay. Although the intraflagellar transport (IFT) complex serves as a key module to maintain the ciliary structure and regulate ciliary signaling, the function of IFT in JBTS remains largely unknown. We aimed to explore the impact of IFT dysfunction in JBTS. METHODS: Exome sequencing was performed to screen for pathogenic variants in IFT genes in a JBTS cohort. Animal model and patient-derived fibroblasts were used to evaluate the pathogenic effects of the variants. RESULTS: We identified IFT74 as a JBTS-associated gene in three unrelated families. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants. CONCLUSION: IFT74 is identified as a JBTS-related gene. Cellular and biochemical mechanisms are also provided.


Assuntos
Anormalidades Múltiplas , Anormalidades do Olho , Doenças Renais Císticas , Anormalidades Múltiplas/genética , Animais , Cerebelo/anormalidades , Proteínas do Citoesqueleto , Anormalidades do Olho/genética , Proteínas Hedgehog , Humanos , Doenças Renais Císticas/genética , Monoéster Fosfórico Hidrolases/genética , Retina/anormalidades , Peixe-Zebra/genética
10.
J Biol Chem ; 296: 100389, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33561442

RESUMO

The c-RET proto-oncogene encodes a receptor-tyrosine kinase. Loss-of-function mutations of RET have been shown to be associated with Hirschsprung disease and Down's syndrome (HSCR-DS) in humans. DS is known to involve cerebellar hypoplasia, which is characterized by reduced cerebellar size. Despite the fact that c-Ret has been shown to be associated with HSCR-DS in humans and to be expressed in Purkinje cells (PCs) in experimental animals, there is limited information about the role of activity of c-Ret/c-RET kinase in cerebellar hypoplasia. We found that a loss-of-function mutation of c-Ret Y1062 in PCs causes cerebellar hypoplasia in c-Ret mutant mice. Wild-type mice had increased phosphorylation of c-Ret in PCs during postnatal development, while c-Ret mutant mice had postnatal hypoplasia of the cerebellum with immature neurite outgrowth in PCs and granule cells (GCs). c-Ret mutant mice also showed decreased numbers of glial fibers and mitogenic sonic hedgehog (Shh)-positive vesicles in the external germinal layer of PCs. c-Ret-mediated cerebellar hypoplasia was rescued by subcutaneous injection of a smoothened agonist (SAG) as well as by reduced expression of Patched1, a negative regulator for Shh. Our results suggest that the loss-of-function mutation of c-Ret Y1062 results in the development of cerebellar hypoplasia via impairment of the Shh-mediated development of GCs and glial fibers in mice with HSCR-DS.


Assuntos
Cerebelo/anormalidades , Síndrome de Down/genética , Doença de Hirschsprung/genética , Mutação com Perda de Função , Malformações do Sistema Nervoso/genética , Proteínas Proto-Oncogênicas c-ret/genética , Animais , Cerebelo/metabolismo , Cerebelo/patologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Síndrome de Down/complicações , Síndrome de Down/metabolismo , Síndrome de Down/patologia , Técnicas de Introdução de Genes/métodos , Proteínas Hedgehog/metabolismo , Doença de Hirschsprung/complicações , Doença de Hirschsprung/metabolismo , Doença de Hirschsprung/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-ret/metabolismo , Células de Purkinje/metabolismo , Células de Purkinje/patologia
11.
Am J Med Genet A ; 185(5): 1575-1581, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33638601

RESUMO

Mutations in the OPHN1 gene cause a rare X-linked recessive neurodevelopmental disorder characterized by intellectual disability, variably associated with cerebellar hypoplasia and distinctive facial appearance. In most of cases so far reported, the identified genomic variants involve the region encoding the central RhoGAP domain of the oligophrenin-1 protein, and are predicted to result in a complete loss of function. By using a NGS-based diagnostic approach, we identified three male and a female patients from two unrelated families carrying novel non-disruptive OPHN1 variants (the in-frame c.116_127 deletion and the missense c.2129C>T change, respectively), affecting either the BAR domain or the C-terminus proline-rich domain of the protein. Clinical and neuroimaging findings in the patients recapitulated the main features of OPHN1-related syndrome, including developmental delay, intellectual disability, behavioral disorder, dysmorphic features, seizures, cerebellar hypoplasia, and ventriculomegaly. Yet, we observed a wide variability even among affected siblings, confirming the lack of clear genotype-phenotype correlation. Our results expand the allelic spectrum of OPHN1 and illustrate the challenges for clinical interpretation of non-disruptive variants affecting X-linked genes.


Assuntos
Cerebelo/anormalidades , Proteínas do Citoesqueleto/genética , Proteínas Ativadoras de GTPase/genética , Deficiência Intelectual/genética , Malformações do Sistema Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Adolescente , Cerebelo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Feminino , Genes Recessivos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Malformações do Sistema Nervoso/patologia , Transtornos do Neurodesenvolvimento/patologia , Linhagem
12.
Am J Med Genet A ; 185(4): 1266-1269, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33547761

RESUMO

TTC21B encodes the protein IFT139, a critical component of the retrograde transport system within the primary cilium. Biallelic, pathogenic TTC21B variants are associated with classic ciliopathy syndromes, including nephronophthisis, Jeune asphyxiating thoracic dystrophy, and Joubert Syndrome, with ciliopathy-spectrum traits such as biliary dysgenesis, primary ciliary dyskinesia, and situs inversus, and also with focal segmental glomerulosclerosis. We report a 9-year-old male with focal segmental glomerulosclerosis requiring kidney transplant, primary ciliary dyskinesia, and biliary dysgenesis, found by research-based exome sequencing to have biallelic pathogenic TTC21B variants. A sibling with isolated heterotaxy was found to harbor the same variants. This case highlights the phenotypic spectrum and unpredictable manifestations of TTC21B-related disease, and also reports the first association between TTC21B and heterotaxy, nominating TTC21B as an important new heterotaxy gene.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Transtornos da Motilidade Ciliar/genética , Anormalidades do Olho/genética , Síndrome de Heterotaxia/genética , Doenças Renais Císticas/congênito , Proteínas Associadas aos Microtúbulos/genética , Retina/anormalidades , Anormalidades Múltiplas/patologia , Cerebelo/patologia , Criança , Transtornos da Motilidade Ciliar/complicações , Transtornos da Motilidade Ciliar/patologia , Anormalidades do Olho/complicações , Anormalidades do Olho/patologia , Predisposição Genética para Doença , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Síndrome de Heterotaxia/complicações , Síndrome de Heterotaxia/patologia , Humanos , Rim/metabolismo , Rim/patologia , Doenças Renais Císticas/complicações , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Transplante de Rim , Masculino , Retina/patologia , Sequenciamento Completo do Exoma
13.
Spec Care Dentist ; 41(3): 411-416, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33544393

RESUMO

BACKGROUND: Joubert syndrome (JS) is a rare autosomal recessive inherited ciliopathy caused by gene mutation. Manifestations can include intermittent dyspnea, apnea, ataxia, and other nervous system abnormalities. CASE PRESENTATION: The patient was a 21-year-old female with JS, severe intellectual disability, cerebral palsy, and epilepsy. Dental caries in both mandibular lower first molars was diagnosed by a local dentist, and the patient was referred to us for further treatment. Although her oral hygiene was good, the dental caries had reached the vicinity of the dental pulp. The caries had developed symmetrically on both first molars and was completely covered with the gingiva. As she was hesitant to receive treatment without anxiolysis, we considered using general anesthesia or intravenous sedation. However, we were recommended against it by the patient's family doctor because of the risk of apneic episodes in JS. Accordingly, dental treatment was performed over multiple days through physical behavior adjustment, while providing oxygenation (3 L/min) in preparation for an apneic episode. The dental treatment was successfully completed with a good postoperative outcome. CONCLUSIONS: Dental treatment can be safely performed in patients with JS through physical behavior adjustment, thereby minimizing the risk of an apnea attack.


Assuntos
Anormalidades Múltiplas , Cárie Dentária , Anormalidades do Olho , Doenças Renais Císticas , Adulto , Cerebelo/anormalidades , Feminino , Humanos , Hipnóticos e Sedativos , Retina/anormalidades , Adulto Jovem
14.
Sci Rep ; 11(1): 462, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33432080

RESUMO

Joubert syndrome (JS) is an inherited ciliopathy characterized by a distinctive cerebellar and brain stem malformation which is known as the "molar tooth sign" on axial brain images, hypotonia, and developmental delay. Approximately 25-30% of patients with JS have kidney disease and many of them progress to end-stage kidney disease (ESKD). However, there are few reports on the outcomes of renal replacement therapy (RRT) in patients with JS and ESKD. In this study, we clarified the clinical features, treatment, and outcomes of patients with JS who underwent RRT. We retrospectively analyzed the medical records and clinical characteristics of 11 patients with JS who underwent RRT between June 1994 and July 2019. Data are shown as the median (range). Gene analysis was performed in 8 of the 11 cases, and CEP290 mutations were found in four patients, two had TMEM67 mutations, one had a RPGRIP1L mutation, and one patient showed no mutation with the panel exome analysis. Complications in other organs included hydrocephalus in two cases, retinal degeneration in eight cases, coloboma in one case, liver diseases in four cases, and polydactyly in one case. Peritoneal dialysis (PD) was introduced in seven cases, with a median treatment duration of 5.4 (3.4-10.7) years. Hemodialysis was performed using arteriovenous fistula in two cases, and kidney transplantation was performed 9 times in eight cases. Only one of the grafts failed during the observation period of 25.6 (8.2-134.2) months. The glomerular filtration rate at the final observation was 78.1 (41.4-107.7) mL/min/1.73 m2. The median age at the final observation was 13.4 (5.6-25.1) years, and all patients were alive except one who died of hepatic failure while on PD. Any type of RRT modality can be a treatment option for patients with JS and ESKD.


Assuntos
Cerebelo/anormalidades , Anormalidades do Olho/complicações , Doenças Renais Císticas/complicações , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Terapia de Substituição Renal/métodos , Retina/anormalidades , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , Proteínas do Citoesqueleto/genética , Progressão da Doença , Anormalidades do Olho/genética , Feminino , Humanos , Doenças Renais Císticas/genética , Falência Renal Crônica/genética , Transplante de Rim , Masculino , Proteínas de Membrana/genética , Mutação , Diálise Renal , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
15.
Ann Neurol ; 89(4): 828-833, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33443317

RESUMO

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828-833.


Assuntos
Cerebelo/anormalidades , Deficiências do Desenvolvimento/genética , Distonia/genética , Complexo Mediador/genética , Malformações do Sistema Nervoso/genética , Adolescente , Adulto , Sequência de Aminoácidos , Catarata/genética , Criança , Pré-Escolar , Epilepsia/genética , Variação Genética , Humanos , Lactente , Fenótipo , Sequenciamento Completo do Exoma
17.
Adv Ther ; 38(1): 278-289, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33098555

RESUMO

INTRODUCTION: Joubert syndrome (JS) is a recessive disorder characterized by a congenital malformation of the mid-hindbrain and a large spectrum of clinical features including optic nerve morphologic abnormalities. The function of the visual pathways, including the optic nerve, can be objectively evaluated by visual evoked potential (VEP) recordings. Our work aims to employ VEP to evaluate the neural conduction along the visual pathways in JS patients with or without optic nerve morphologic abnormalities (ONMA). METHODS: In this observational and prospective study, 18 children with genetic diagnosis of JS (mean age 8.78 ± 5.87 years) and 17 healthy age-similar control subjects (control group, 9.05 ± 6.02 years) were enrolled. Based on presence/absence of ONMA at fundus examination, JS patients were divided into two groups: the JS-A group (eight patients with ONMA) and JS-N group (ten patients without ONMA). Following the ISCEV standards, pattern VEPs were recorded in patients and controls in response to 60' and 15' checks to obtain a prevalent activation of large or small axons, respectively. RESULTS: Compared to controls, both the JS-A and JS-N groups showed significant abnormalities in 60' and 15' VEP implicit time and amplitude. Only in the JS-N group were values of 15' VEP implicit significantly correlated with the corresponding values of visual acuity. CONCLUSIONS: Our results suggest that a visual pathways dysfunction (of both large and small axons) detectable by VEP may occur in JS patients regardless of the presence of ONMA. Since clinical trials are envisaged in the near future to address JS-related ocular problems, our results might provide information about the potential usefulness of VEP recordings to assess the efficacy of treatments targeted to improve the visual pathways' function.


Assuntos
Anormalidades Múltiplas , Anormalidades do Olho , Doenças Renais Císticas , Adolescente , Cerebelo/anormalidades , Criança , Pré-Escolar , Eletrorretinografia , Potenciais Evocados Visuais , Anormalidades do Olho/diagnóstico , Humanos , Doenças Renais Císticas/diagnóstico , Estudos Prospectivos , Retina/anormalidades , Vias Visuais
18.
Am J Kidney Dis ; 77(3): 410-419, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33039432

RESUMO

Primary cilia are specialized sensory organelles that protrude from the apical surface of most cell types. During the past 2 decades, they have been found to play important roles in tissue development and signal transduction, with mutations in ciliary-associated proteins resulting in a group of diseases collectively known as ciliopathies. Many of these mutations manifest as renal ciliopathies, characterized by kidney dysfunction resulting from aberrant cilia or ciliary functions. This group of overlapping and genetically heterogeneous diseases includes polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome as the main focus of this review. Renal ciliopathies are characterized by the presence of kidney cysts that develop due to uncontrolled epithelial cell proliferation, growth, and polarity, downstream of dysregulated ciliary-dependent signaling. Due to cystic-associated kidney injury and systemic inflammation, cases result in kidney failure requiring dialysis and transplantation. Of the handful of pharmacologic treatments available, none are curative. It is important to determine the molecular mechanisms that underlie the involvement of the primary cilium in cyst initiation, expansion, and progression for the development of novel and efficacious treatments. This review updates research progress in defining key genes and molecules central to ciliogenesis and renal ciliopathies.


Assuntos
Síndrome de Bardet-Biedl/genética , Cílios/metabolismo , Ciliopatias/genética , Doenças Renais Policísticas/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Síndrome de Bardet-Biedl/metabolismo , Síndrome de Bardet-Biedl/fisiopatologia , Cerebelo/anormalidades , Cerebelo/metabolismo , Cerebelo/fisiopatologia , Chaperoninas/genética , Cílios/fisiologia , Transtornos da Motilidade Ciliar/genética , Transtornos da Motilidade Ciliar/metabolismo , Transtornos da Motilidade Ciliar/fisiopatologia , Ciliopatias/metabolismo , Ciliopatias/fisiopatologia , Proteínas do Citoesqueleto/genética , Encefalocele/genética , Encefalocele/metabolismo , Encefalocele/fisiopatologia , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Anormalidades do Olho/fisiopatologia , Humanos , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/fisiopatologia , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/metabolismo , Amaurose Congênita de Leber/fisiopatologia , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Atrofias Ópticas Hereditárias/genética , Atrofias Ópticas Hereditárias/metabolismo , Atrofias Ópticas Hereditárias/fisiopatologia , Doenças Renais Policísticas/metabolismo , Doenças Renais Policísticas/fisiopatologia , Proteínas/genética , Retina/anormalidades , Retina/metabolismo , Retina/fisiopatologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/fisiopatologia , Canais de Cátion TRPP/genética
19.
Mol Genet Genomics ; 296(1): 33-40, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32944789

RESUMO

Joubert syndrome (JBTS), a rare genetic disorder resulted from primary cilium defects or basal-body dysfunction, is characterized by agenesis of cerebellar vermis and abnormal brain stem. Both genotypes and phenotypes of JBTS are highly heterogeneous. The identification of pathogenic gene variation is essential for making a definite diagnosis on JBTS. Here, we found that hypoplasia of cerebellar vermis occurred in three male members in a Chinese family. Then, we performed whole exome sequencing to identify a novel missense mutation c.599T > C (p. L200P) in the OFD1 gene which is the candidate gene of X-linked JBTS (JBST10). The following analysis showed that the variant was absent in the 1000 Genomes, ExAC and the 200 female controls; the position 200 Leucine residue was highly conserved across species; the missense variant was predicted to be deleterious using PolyPhen-2, PROVEAN, SIFT and Mutation Taster. The OFD1 expression was heavily lower in the proband and an induced male fetus compared with a healthy male with a wild-type OFD1 gene. The in vitro expression analysis of transiently transfecting c.599T or c.599C plasmids into HEK-293T cells confirmed that the missense mutation caused OFD1 reduction at the protein level. And further the mutated OFD1 decreased the level of Gli1 protein, a read-out of Sonic hedgehog (SHH) signaling essential for development of central neural system. A known pathogenic variant c.515T > C (p. L172P) showed the similar results. All of these observations suggested that the missense mutation causes the loss function of OFD1, resulting in SHH signaling impairs and brain development abnormality. In addition, the three patients have Dandy-Walker malformation, macrogyria and tetralogy of Fallot, respectively, the latter two of which are firstly found in JBTS10 patients. In conclusion, our findings expand the context of genotype and phenotype in the JBTS10 patients.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Síndrome de Dandy-Walker/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Lisencefalia/genética , Mutação de Sentido Incorreto , Proteínas/genética , Retina/anormalidades , Tetralogia de Fallot/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Sequência de Aminoácidos , Tronco Encefálico/anormalidades , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/metabolismo , Vermis Cerebelar/anormalidades , Vermis Cerebelar/diagnóstico por imagem , Vermis Cerebelar/metabolismo , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Cerebelo/patologia , Pré-Escolar , Síndrome de Dandy-Walker/diagnóstico por imagem , Síndrome de Dandy-Walker/metabolismo , Síndrome de Dandy-Walker/patologia , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Família , Feminino , Expressão Gênica , Genótipo , Células HEK293 , Proteínas Hedgehog/deficiência , Proteínas Hedgehog/genética , Humanos , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/patologia , Lisencefalia/diagnóstico por imagem , Lisencefalia/metabolismo , Lisencefalia/patologia , Masculino , Linhagem , Fenótipo , Proteínas/metabolismo , Retina/diagnóstico por imagem , Retina/metabolismo , Retina/patologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Fatores Sexuais , Transdução de Sinais , Tetralogia de Fallot/diagnóstico por imagem , Tetralogia de Fallot/metabolismo , Tetralogia de Fallot/patologia , Proteína GLI1 em Dedos de Zinco/deficiência , Proteína GLI1 em Dedos de Zinco/genética
20.
Am J Med Genet A ; 185(3): 884-888, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33369122

RESUMO

We report a male adult with early infantile-onset epilepsy, facial dysmorphism, and iridal and choroidal coloboma who had a de novo heterozygous mutation in PACS2, that is, c.625G > A p.(Glu209Lys). This specific mutation was previously reported in a patient with PACS2-related disorder (early infantile epileptic encephalopathy 66). De novo heterozygous mutations in WDR37 have been shown to cause a novel human disorder, neurooculocardiogenitourinary syndrome (NOCGUS syndrome) (OMIM #618652), characterized by intellectual disability, facial dysmorphism, and coloboma. According to large-scale interactome data, WDR37 interacts most strongly, by far, with PACS1 and PACS2. Clinically, coloboma has been described as a feature in a WDR37-related disorder and a PACS1-related disorder (Schuurs-Hoeijmakers syndrome), but not in a PACS2-related disorder. Our review of the phenotypes of three human disorders caused by WDR37, PACS1, and PACS2 mutations showed a significant overlap of epilepsy, intellectual disability, cerebellar atrophy, and facial features. The present observation of coloboma as a shared feature among these three disorders suggests that this group of genes may be involved in ocular development. We propose that dysregulation of the WDR37-PACS1-PACS2 axis results in a spectrum that is recognizable by intellectual disability, distinctive facial features, and coloboma.


Assuntos
Anormalidades Múltiplas/genética , Corioide/anormalidades , Coloboma/genética , Iris/anormalidades , Proteínas Nucleares/genética , Proteínas de Transporte Vesicular/genética , Substituição de Aminoácidos , Cerebelo/anormalidades , Anormalidades Craniofaciais/genética , Criptorquidismo/genética , Face/anormalidades , Estudos de Associação Genética , Perda Auditiva Neurossensorial/genética , Cardiopatias Congênitas/genética , Heterozigoto , Humanos , Deficiência Intelectual/genética , Masculino , Mutação de Sentido Incorreto , Proteínas Nucleares/deficiência , Mutação Puntual , Convulsões/genética , Síndrome , Proteínas de Transporte Vesicular/deficiência , Adulto Jovem
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