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1.
Am J Med Genet A ; 185(5): 1366-1378, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33522091

RESUMO

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Epilepsia/genética , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia/fisiopatologia , Facies , Feminino , Haploinsuficiência/genética , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Microcefalia/fisiopatologia , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Fatores de Transcrição/genética , Adulto Jovem
2.
Am J Med Genet A ; 185(5): 1388-1398, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33576134

RESUMO

Distal 1q21.1 microdeletions have shown highly variable clinical expressivity and incomplete penetrance, with affected individuals manifesting a broad spectrum of nonspecific features. The goals of this study were to better describe the phenotypic spectrum of patients with distal 1q21.1 microdeletions and to compare the clinical features among affected individuals. We performed a retrospective chart review of 47 individuals with distal 1q21.1 microdeletions tested at a large clinical genetic testing laboratory, with most patients being clinically evaluated in the same children's hospital. Health information such as growth charts, results of imaging studies, developmental history, and progress notes were collected. Statistical analysis was performed using Fisher's exact test to compare clinical features among study subjects. Common features in our cohort include microcephaly (51.2%), seizures (29.8%), developmental delay (74.5%), failure to thrive (FTT) (68.1%), dysmorphic features (63.8%), and a variety of congenital anomalies such as cardiac abnormalities (23.4%) and genitourinary abnormalities (19.1%). Compared to prior literature, we found that seizures, brain anomalies, and FTT were more prevalent among our study cohort. Females were more likely than males to have microcephaly (p = 0.0199) and cardiac abnormalities (p = 0.0018). Based on existing genome-wide clinical testing results, at least a quarter of the cohort had additional genetic findings that may impact the phenotype of the individual. Our study represents the largest cohort of distal 1q21.1 microdeletion carriers available in the literature thus far, and it further illustrates the wide spectrum of clinical manifestations among symptomatic individuals. These results may allow for improved genetic counseling and management of affected individuals. Future studies may help to elucidate the underlying molecular mechanisms impacting the phenotypic variability observed with this microdeletion.


Assuntos
Anormalidades Múltiplas/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Megalencefalia/genética , Microcefalia/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Insuficiência de Crescimento/complicações , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/fisiopatologia , Feminino , Aconselhamento Genético , Testes Genéticos/métodos , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/fisiopatologia , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/complicações , Megalencefalia/diagnóstico , Megalencefalia/fisiopatologia , Microcefalia/complicações , Microcefalia/diagnóstico , Microcefalia/fisiopatologia , Linhagem , Convulsões/complicações , Convulsões/genética , Convulsões/fisiopatologia , Adulto Jovem
3.
Am J Med Genet A ; 185(4): 1187-1194, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33394555

RESUMO

Congenital disorders of glycosylation (CDG) are an expanding group of metabolic disorders that result from abnormal protein glycosylation. A special subgroup of CDG type II comprises defects in the Conserved Oligomeric Golgi Complex (COG). In order to further delineate the genotypic and phenotypic spectrum of COG complex defect, we describe a novel variant of COG6 gene found in homozygosity in a Moroccan patient with severe presentation of COG6-CDG (OMIM #614576). We compared the phenotype of our patient with other previously reported COG6-CDG cases. Common features in COG6-CDG are facial dysmorphism, growth retardation, microcephaly, developmental disability, liver or gastrointestinal disease, recurrent infections, hypohidrosis/hyperthermia. In addition to these phenotypic features, our patient exhibited a disorder of sexual differentiation, which has rarely been reported in COG6-CDG. We hypothesize that the severe COG6 gene mutation interferes with glycosylation of a disintegrin and metalloprotease family members, inhibiting the correct gonadal distal tip cells migration, fundamental for the genitalia morphogenesis. This report broadens the genetic and phenotypic spectrum of COG6-CDG and provides further supportive evidence that COG6-CDG can present as a disorder of sexual differentiation.


Assuntos
Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Anormalidades Craniofaciais/genética , Transtornos do Desenvolvimento Sexual/genética , Atrofia Muscular/genética , Desenvolvimento Sexual/genética , Anormalidades Múltiplas/fisiopatologia , Códon sem Sentido/genética , Defeitos Congênitos da Glicosilação/complicações , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/fisiopatologia , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/fisiopatologia , Transtornos do Desenvolvimento Sexual/complicações , Transtornos do Desenvolvimento Sexual/fisiopatologia , Predisposição Genética para Doença , Complexo de Golgi/genética , Homozigoto , Humanos , Lactente , Recém-Nascido , Cariótipo , Masculino , Microcefalia/complicações , Microcefalia/genética , Microcefalia/fisiopatologia , Atrofia Muscular/complicações , Atrofia Muscular/fisiopatologia , Fenótipo
4.
Epilepsia ; 62(2): e35-e41, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33410539

RESUMO

The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI-APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine-responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS-related disorder. Further delineation of the molecular spectrum of PIGS-related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy.


Assuntos
Aciltransferases/genética , Deficiências do Desenvolvimento/genética , Proteínas Ligadas por GPI/deficiência , Malformações do Sistema Nervoso/genética , Espasmos Infantis/genética , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Facies , Feminino , Perda Auditiva/genética , Perda Auditiva/fisiopatologia , Humanos , Lactente , Rim/anormalidades , Masculino , Microcefalia/genética , Microcefalia/fisiopatologia , Hipotonia Muscular/genética , Hipotonia Muscular/fisiopatologia , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/fisiopatologia , Fenótipo , Espasmos Infantis/fisiopatologia , Transtornos da Visão/genética , Transtornos da Visão/fisiopatologia
5.
Invest Ophthalmol Vis Sci ; 61(13): 2, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33137195

RESUMO

Purpose: The purpose of this study was to analyze the natural history and phenotypic overlap of patients with microcephaly and a chorioretinopathy or familial exudative vitreoretinopathy (FEVR) ocular phenotype caused by mutations in KIF11, TUBGCP4, or TUBGCP6. Methods: Patients diagnosed with congenital microcephaly and chorioretinopathy or FEVR were included. Molecular investigations consisted of targeted genetic sequencing. Data from medical records, ophthalmologic examination and imaging, electroretinography, and visual fields were analyzed for systemic and ophthalmic features and evidence of posterior segment disease progression. Results: Twelve patients from 9 families were included and had a median of 8 years of follow-up. Nine patients had KIF11 variants, two had heterozygous TUBGCP6 variants, and one had heterozygous variants in TUBGCP4. All patients had reduced visual function and multiple individuals and families showed features of both chorioretinopathy and FEVR. Progression of posterior segment disease was highly variable, with some degree of increased atrophy of the macula or peripheral retina or increased vitreoretinal traction observed in 9 of 12 patients. Conclusions: Microcephaly due to mutations in KIF11, TUBGCP4, or TUBGCP6 can be associated with retinal disease on a spectrum from chorioretinal atrophy to FEVR-like posterior segment changes. Visually significant disease progression can occur and patients should be monitored closely by a team experienced in ophthalmic genetics.


Assuntos
Vitreorretinopatias Exsudativas Familiares/genética , Cinesina/genética , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Doenças Retinianas/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletrorretinografia , Vitreorretinopatias Exsudativas Familiares/diagnóstico , Vitreorretinopatias Exsudativas Familiares/fisiopatologia , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/diagnóstico , Microcefalia/fisiopatologia , Doenças Retinianas/diagnóstico , Doenças Retinianas/fisiopatologia , Transtornos da Visão/diagnóstico , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais/fisiologia
6.
Pediatr Surg Int ; 36(11): 1309-1315, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980962

RESUMO

AIM OF THE STUDY: Mowat Wilson syndrome (MWS) is a complex genetic disorder due to mutation or deletion of the ZEB2 gene (ZFHX1B), including multiple clinical features. Hirschsprung disease is associated with this syndrome with a prevalence between 43 and 57%. The aim of this study was to demonstrate the severe outcomes and the high complication rates in children with MWS, focusing on their complicated follow-up. METHODS: A retrospective comparative study was conducted on patients referred to Robert-Debré Children's Hospital for MWS from 2003 to 2018. Multidisciplinary follow-up was carried out by surgeons, geneticists, gastroenterologists, and neurologists. Data regarding patient characteristics, surgical management, postoperative complications, and functional outcomes were collected. RESULTS: Over this period of 15 years, 23 patients were diagnosed with MWS. Hirschsprung disease was associated with 10 of them (43%). Of these cases, two patients had recto-sigmoïd aganglionosis (20%), three had aganglionic segment extension to the left colic angle (30%), two to the right colic angle (20%), and three to the whole colon (30%). The median follow-up was 8.5 years (2 months-15 years). All patients had seizures and intellectual disability. Six children (60%) presented with cardiac defects. At the last follow-up, three patients still had a stoma diversion and 7 (70%) were fed orally. One patient died during the first months. Eight (80%) of these children required a second surgery due to complications. At the last follow-up, three patients reported episodes of abdominal bloating (42%), one recurrent treated constipation (14.3%), and one soiling (14.3%). Genetic analysis identified three patients with heterozygous deletions, three with codon mutations, and three with frameshift mutations. CONCLUSIONS: MWS associated with Hirschsprung disease has a high rate of immediate surgical complications but some patients may achieve bowel function comparable with non-syndromic HD patients. A multidisciplinary follow-up is required for these patients. LEVEL OF EVIDENCE: Retrospective observational single cohort study, Level 3.


Assuntos
Defecação/fisiologia , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Previsões , Doença de Hirschsprung/fisiopatologia , Deficiência Intelectual/fisiopatologia , Microcefalia/fisiopatologia , Análise Mutacional de DNA , Facies , Feminino , Seguimentos , Doença de Hirschsprung/genética , Doença de Hirschsprung/cirurgia , Humanos , Recém-Nascido , Deficiência Intelectual/genética , Deficiência Intelectual/cirurgia , Masculino , Microcefalia/genética , Microcefalia/cirurgia , Mutação , Estudos Retrospectivos , Resultado do Tratamento , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Dedos de Zinco
7.
Int J Infect Dis ; 98: 359-365, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619757

RESUMO

OBJECTIVES: This study aimed to describe the demographic and clinical parameters of women infected by Zika virus who had infants with stigmata of Congenital Zika Syndrome (CZS) versus those who had normal-appearing infants at birth, thereby providing further details on the clinical caveats of neonatal ZIKV infection. METHODOLOGY: This cross-sectional study was performed in the state of Mato Grosso do Sul, Central-West region of Brazil, and included 117 mother-infant pairs who were interviewed and 120 gestational outcomes. All mothers had laboratory confirmation by qRT-PCR of ZIKV infection during pregnancy. RESULTS: The prevalence of congenital abnormalities related to ZIKV was 2.69 cases per 10,000 live births during this period. Exanthem was the main clinical finding, observed in 92.5% of the mothers in this study. Regarding the timing of ZIKV infection, the first trimester was the most frequent time of infection among mothers of infants with CZS (54.55%) (p=0.0007). The case fatality rate was 5% (n=6). Among the 23 children who were classified as having CZS, 13 (56.52%) of them presented with microcephaly. Only 13 (56.52%) children with CZS were tested by qRT-PCR for ZIKV infection at birth, five (38%) were positive. CONCLUSIONS: This study highlights the congenital alterations of ZIKV infection during pregnancy in an epidemic burst, demonstrating that the alterations found in other studies are similar to the present research.


Assuntos
Microcefalia/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Adulto , Brasil/epidemiologia , Estudos Transversais , Exantema/diagnóstico , Exantema/epidemiologia , Exantema/fisiopatologia , Exantema/virologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/diagnóstico , Microcefalia/fisiopatologia , Microcefalia/virologia , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/fisiopatologia , Complicações Infecciosas na Gravidez/virologia , Resultado da Gravidez , Estudos Retrospectivos , Adulto Jovem , Zika virus/genética , Zika virus/isolamento & purificação , Zika virus/fisiologia
8.
BMC Public Health ; 20(1): 827, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32487247

RESUMO

BACKGROUND: Although it is known that Zika virus (ZIKV) infection during pregnancy may lead to microcephaly in the fetus, the prognostic factors associated with this tragic disorder remain unclear. We conducted a systematic review and meta-analysis to assess the prognostic factors associated with the incidence of microcephaly in congenital ZIKV infection. METHODS: We conducted a comprehensive search in Ovid MEDLINE, Ovid MEDLINE (R) Epub ahead of print, Embase, Embase Classic, Web of Science, CINAHL, Cochrane CENTRAL, LILACS, and various thesis databases to identify human studies reporting microcephaly associated with congenital ZIKV infection. We requested primary data from the authors of the included studies to calculate summary estimates and conduct the meta-analysis of the most prevalent factors. RESULTS: We screened 4106 titles and abstracts, and identified 12 studies for inclusion in the systematic review. The assessment of ZIKV infection and the definition of microcephaly varied among studies. A total of 6154 newborns/fetuses were enrolled; of those, 1120 (18.20%) had a diagnostic of ZIKV infection, of which 509 (45.45%) were diagnosed with microcephaly. Nine studies addressed the link between congenital ZIKV infection and neurological findings in newborns/fetuses. Half of the studies provided primary data. Three out of 11 factors of interest seem to be prognostic factors of microcephaly: infant's sex - males compared to females: Relative Risk (RR) 1.30, 95% Confidence Interval (95% CI) 1.14 to 1.49; the stage of pregnancy when infection occurred - infection in the first trimester of pregnancy compared to infection at other stages of pregnancy: RR 1.41, 95% CI 1.09 to 1.82; and asymptomatic infection compared to symptomatic infection during pregnancy: RR 0.68; 95% CI 0.60 to 0.77. CONCLUSION: Our findings support the female-biased resistance hypothesis and reinforce the risk associated with the stage of pregnancy when ZIKV infection occurs. Continued surveillance of ZIKV infection during pregnancy is needed to identify additional factors that could contribute to developing microcephaly in affected fetuses. PROTOCOL REGISTRATION: This systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO), registration no. CRD 42018088075.


Assuntos
Feto/virologia , Microcefalia/fisiopatologia , Complicações Infecciosas na Gravidez/fisiopatologia , Infecção por Zika virus/fisiopatologia , Zika virus/patogenicidade , Adulto , Idade de Início , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/epidemiologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/virologia , Trimestres da Gravidez , Prevalência , Fatores Sexuais , Infecção por Zika virus/epidemiologia
9.
Mol Brain ; 13(1): 69, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375900

RESUMO

Significant clinical symptoms of Cohen syndrome (CS), a rare autosomal recessive disorder, include intellectual disability, facial dysmorphism, postnatal microcephaly, retinal dystrophy, and intermittent neutropenia. CS has been associated with mutations in the VPS13B (vacuolar protein sorting 13 homolog B) gene, which regulates vesicle-mediated protein sorting and transport; however, the cellular mechanism underlying CS pathogenesis in patient-derived neurons remains uncertain. This report states that autophagic vacuoles accumulate in CS fibroblasts and the axonal terminals of CS patient-specific induced pluripotent stem cells (CS iPSC)-derived neurons; additionally, autophagic flux was significantly increased in CS-derived neurons compared to control neurons. VPS13B knockout HeLa cell lines generated using the CRISPR/Cas9 genome editing system showed significant upregulation of autophagic flux, indicating that VSP13B may be associated with autophagy in CS. Transcriptomic analysis focusing on the autophagy pathway revealed that genes associated with autophagosome organization were dysregulated in CS-derived neurons. ATG4C is a mammalian ATG4 paralog and a crucial regulatory component of the autophagosome biogenesis/recycling pathway. ATG4C was significantly upregulated in CS-derived neurons, indicating that autophagy is upregulated in CS neurons. The autophagy pathway in CS neurons may be associated with the pathophysiology exhibited in the neural network of CS patients.


Assuntos
Autofagossomos/metabolismo , Autofagia/genética , Fibroblastos/metabolismo , Dedos/anormalidades , Células-Tronco Pluripotentes Induzidas/metabolismo , Deficiência Intelectual/metabolismo , Microcefalia/metabolismo , Hipotonia Muscular/metabolismo , Miopia/metabolismo , Neurônios/metabolismo , Obesidade/metabolismo , Degeneração Retiniana/metabolismo , Proteínas de Transporte Vesicular/genética , Autofagossomos/genética , Autofagossomos/ultraestrutura , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Axônios/metabolismo , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/fisiopatologia , Fibroblastos/patologia , Fibroblastos/ultraestrutura , Dedos/fisiopatologia , Técnicas de Inativação de Genes , Células HeLa , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Deficiência Intelectual/fisiopatologia , Microcefalia/fisiopatologia , Microscopia Eletrônica , Hipotonia Muscular/fisiopatologia , Mutação de Sentido Incorreto , Miopia/fisiopatologia , Rede Nervosa/fisiologia , Neurônios/patologia , Obesidade/fisiopatologia , Degeneração Retiniana/fisiopatologia , Regulação para Cima , Vacúolos/metabolismo
10.
Am J Med Genet A ; 182(7): 1785-1790, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32324310

RESUMO

Basel-Vanagaite-Smirin-Yosef syndrome is a recently described autosomal recessive intellectual disability syndrome caused by variants in the MED25 gene. While it was originally identified in Brazil, it was further described in Israel by authors who are now the namesake of the condition. A 2018 publication further contributed to its delineation, but the patient's phenotype was complicated by a dual diagnosis. More recently, an article describing a set of affected siblings was published. We describe three, previously unreported, patients showing clinical variability for this newly defined syndrome. The major features determined by "reverse phenotyping" include significant to profound developmental delays/intellectual disability with absent or delayed speech, epilepsy, ocular abnormalities, cleft lip and/or palate, congenital heart disease, urogenital anomalies, skeletal abnormalities, brain malformations and/or microcephaly, failure to thrive, and dysmorphic features. The authors suggest the delineation of an acronym using the gene name and common features seen across the majority of patients reported so far. This new nomination, MED-DOCS, may help clinicians to recognize, suspect, and remember this novel syndrome.


Assuntos
Anormalidades Múltiplas/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Complexo Mediador/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Brasil/epidemiologia , Pré-Escolar , Fenda Labial/genética , Fenda Labial/fisiopatologia , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/fisiopatologia , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Israel/epidemiologia , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Microcefalia/fisiopatologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
11.
Ann Clin Transl Neurol ; 7(5): 610-627, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32286009

RESUMO

OBJECTIVE: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. METHODS: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. RESULTS: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood. CONCLUSION: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.


Assuntos
Epilepsia/genética , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Receptores de Glutamato Metabotrópico/genética , Adolescente , Alelos , Atrofia/genética , Atrofia/patologia , Criança , Pré-Escolar , Estudos de Coortes , Consanguinidade , Epilepsia/patologia , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Microcefalia/patologia , Microcefalia/fisiopatologia , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
12.
Cell Rep ; 31(2): 107506, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32294449

RESUMO

A distinctive feature of neocortical development is the highly coordinated production of different progenitor cell subtypes, which are critical for ensuring adequate neurogenic outcome and the development of normal neocortical size. To further understand the mechanisms that underlie neocortical growth, we focused our studies on the microcephaly gene Mcph1, and we report here that Mcph1 (1) exerts its functions in rapidly dividing apical radial glial cells (aRGCs) during mouse neocortical development stages that precede indirect neurogenesis; (2) is expressed at mitochondria; and (3) controls the proper proliferation and survival of RGCs, potentially through crosstalk with cellular metabolic pathways involving the stimulation of mitochondrial activity via VDAC1/GRP75 and AKT/HK2/VDAC1 and glutaminolysis via ATF4/PCK2. We currently report the description of a MCPH-gene implication in the interplay between bioenergetic pathways and neocortical growth, thus pointing to alterations of cellular metabolic pathways, in particular glutaminolysis, as a possible cause of microcephalic pathogenesis.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Microcefalia/genética , Microcefalia/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Proteínas do Citoesqueleto/metabolismo , Feminino , Células HEK293 , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcefalia/fisiopatologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mutação , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/genética , Neuroglia/metabolismo , Neurônios/metabolismo , Canal de Ânion 1 Dependente de Voltagem/genética , Canal de Ânion 1 Dependente de Voltagem/metabolismo
13.
Lancet Child Adolesc Health ; 4(5): 378-387, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32199080

RESUMO

BACKGROUND: Congenital Zika syndrome causes a spectrum of neurological symptoms with varying effects on function that require different therapeutic strategies. To date, this spectrum of effects and its clinical implications have not been completely described. We describe the neurological examination findings in toddlers and preschoolers, including predominant symptom complexes and comorbidities. METHODS: This study is a case-series neurological evaluation of 75 children with congenital Zika syndrome in Campina Grande, Brazil. The study is part of a cohort of children with congenital Zika syndrome that started in 2015 and is still ongoing. Children with Zika virus infection detected during pregnancy (mothers exhibited rash and were followed and diagnosed by fetal ultrasound abnormalities or RT-PCR) or through microcephaly screening after birth, using Intergrowth 21 guidelines, were selected by laboratory and radiological criteria. Children were examined during a 10-day period in September, 2018, and underwent neurological interview, examination, and assessment of functional outcomes and comorbidities. Children were divided in groups of predominant corticospinal or neuromuscular clinical signs and the associations between these groups and clinical comorbidities were assessed. FINDINGS: All of the children recruited to the study from Nov 29, 2015 to Nov 30, 2017 had imaging correlates of congenital Zika syndrome. Children were assigned to groups depending on the signs exhibited, either corticospinal or neuromuscular, with or without dyskinetic signs. 75 children completed the evaluation, 38 (51%) girls and 37 (49%) boys. Median age was 33 months (range 26-40 months; IQR 29-34). Microcephaly was present at birth in 56 (75%) children, and 19 (25%) children were born with normal head circumference, 15 of whom later developed microcephaly. Neurological examination grouped four children as having isolated dyskinetic signs, 48 children were assigned to the corticospinal group and 23 into the neuromuscular group. Dyskinetic findings were present in 30 (40%) children, either alone (four [5%]) or combined with corticospinal (19 [40%] of 48) or neuromuscular (seven [30%] of 23) findings. Comorbidities were highly prevalent, and the neuromuscular group had worse functional outcomes, evaluated by gross motor function (p=0·026), manual abilities (p=0·0013), and communication function (p<0·0005) classification scales, than the corticospinal group, whereas pneumonia (p<0·0005) and urinary tract infections (p<0·0005) were more frequent in the corticospinal group. Cortical hyperexcitability was supported by several clinical correlates, such as early onset epilepsy, persistence of primitive reflexes, and dystonia. INTERPRETATION: We describe distinct neurological profiles in the congenital Zika syndrome spectrum, with functional outcomes tending to correlate with these groups. The clinical division of children based on the disease signs proposed here is supported by the literature on central and peripheral nervous system pathology in congenital Zika syndrome. The high prevalence of dyskinetic symptoms merits special attention. FUNDING: Brazilian National Council for Scientific and Technological Development and by the Coordination for the Improvement of Higher Education Personnel.


Assuntos
Discinesias/fisiopatologia , Doenças Neuromusculares/fisiopatologia , Infecção por Zika virus/fisiopatologia , Encéfalo/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Encefalopatias/epidemiologia , Brasil/epidemiologia , Calcinose/diagnóstico por imagem , Calcinose/epidemiologia , Pré-Escolar , Comorbidade , Transtornos de Deglutição/epidemiologia , Discinesias/epidemiologia , Epilepsia/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/epidemiologia , Malformações do Desenvolvimento Cortical/fisiopatologia , Microcefalia/epidemiologia , Microcefalia/fisiopatologia , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/fisiopatologia , Exame Neurológico , Doenças Neuromusculares/epidemiologia , Pneumonia/epidemiologia , Tratos Piramidais/fisiopatologia , Transtornos do Sono-Vigília/epidemiologia , Tomografia Computadorizada por Raios X , Infecções Urinárias/epidemiologia , Infecção por Zika virus/congênito , Infecção por Zika virus/diagnóstico por imagem , Infecção por Zika virus/epidemiologia
14.
Am J Med Genet A ; 182(5): 953-956, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32128942

RESUMO

Wiedemann-Steiner syndrome (WWS) is a rare disorder characterized by hypotonia, postnatal growth restriction, striking facial dysmorphism, and hirsutism. It is caused by heterozygous pathogenic variants in KMT2A. This gene has an established role in histone methylation, which explains the overlap of WWS with syndromes caused by genes involved in chromatin remodeling. We describe an infant with a novel single base pair deletion in KMT2A with features consistent with WWS, as well as additional features of stenosis of aqueduct of Sylvius and broad toes. The usefulness of Face2Gene as a tool for identification of dysmorphology syndromes is discussed, as in this patient, it suggested WWS as the top candidate disorder. To the best of our knowledge, this is the first patient of WWS reported from India, with a novel genotype and expanded phenotype.


Assuntos
Anormalidades Múltiplas/genética , Contratura/genética , Transtornos do Crescimento/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Microcefalia/genética , Anormalidades Musculoesqueléticas/genética , Proteína de Leucina Linfoide-Mieloide/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/fisiopatologia , Contratura/diagnóstico , Contratura/epidemiologia , Contratura/fisiopatologia , Facies , Feminino , Genótipo , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/fisiopatologia , Heterozigoto , Humanos , Índia/epidemiologia , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/fisiopatologia , Masculino , Microcefalia/diagnóstico , Microcefalia/epidemiologia , Microcefalia/fisiopatologia , Anormalidades Musculoesqueléticas/diagnóstico , Anormalidades Musculoesqueléticas/epidemiologia , Anormalidades Musculoesqueléticas/fisiopatologia , Mutação/genética , Fenótipo
15.
Epileptic Disord ; 22(1): 111-115, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32031527

RESUMO

Mowat-Wilson syndrome is a genetic disorder associated with a variable phenotype including peculiar facial features associated with intellectual disability, epilepsy, language impairment, and multiple congenital anomalies caused by heterozygous mutation of the ZEB2 gene. The ZEB2 protein is a complex transcription factor that encompasses multiple functional domains that interact with the regulatory regions of target genes including those involved in brain development. Recently, it has been documented that ZEB2 regulates the differentiation of interneuron progenitors migrating from the medial ganglionic eminence to cortical layers by repression of the Nkx2-1 homeobox transcription factor. It has therefore been suggested that the deficit in ZEB2 may induce an imbalance of neuronal inhibition/excitation leading to epileptic seizures. Given the phenotypic variability of Mowat-Wilson syndrome, to date, a distinctive genotype-phenotype correlation has not been delineated. Here, we report a patient with a severe phenotype of Mowat-Wilson syndrome, associated with a novel heterozygous de novo frame-shift variant in the ZEB2 gene, as well as an additional novel heterozygous missense variant in the SCN1A gene, the mutation of which is known to affect NaV1.1-mediated sodium current in GABAergic interneurons. We hypothesize that the severe neurological phenotype of our patient may be influenced by the coexistence of both genetic mutations. [Published with video sequence].


Assuntos
Epilepsia , Facies , Doença de Hirschsprung , Deficiência Intelectual , Microcefalia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Criança , Eletroencefalografia , Epilepsia/etiologia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Estudos de Associação Genética , Doença de Hirschsprung/complicações , Doença de Hirschsprung/genética , Doença de Hirschsprung/fisiopatologia , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Microcefalia/complicações , Microcefalia/genética , Microcefalia/fisiopatologia
16.
Am J Med Genet A ; 182(5): 1021-1031, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32065501

RESUMO

Both point mutations and deletions of the MYT1L gene as well as microdeletions of chromosome band 2p25.3 including MYT1L are associated with intellectual disability, obesity, and behavioral problems. Thus, MYT1L is assumed to be the-at least mainly-causative gene in the 2p25.3 deletion syndrome. Here, we present comprehensive descriptions of nine novel individuals bearing MYT1L mutations; most of them single nucleotide variants (SNVs). This increases the number of known individuals with causative deletions or SNVs of MYT1L to 51. Since eight of the nine novel patients bear mutations affecting MYT1L only, the total number of such individuals now nearly equals the number of individuals with larger microdeletions affecting additional genes, allowing for a comprehensive phenotypic comparison of these two patient groups. For example, 55% of the individuals with mutations affecting MYT1L only were overweight or obese as compared to 86% of the individuals with larger microdeletions. A similar trend was observed regarding short stature with 5 versus 35%, respectively. However, these differences were nominally significant only after correction for multiple testing, further supporting the hypothesis that MYT1L haploinsufficiency is central to the 2p25.3 deletion phenotype. Most importantly, the large number of individuals with MYT1L mutations presented and reviewed here allowed for the delineation of a more comprehensive clinical picture. Seizures, postnatal short stature, macrocephaly, and microcephaly could be shown to be over-represented among individuals with MYT1L mutations.


Assuntos
Predisposição Genética para Doença , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Obesidade/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Feminino , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Análise em Microsséries , Microcefalia/genética , Microcefalia/fisiopatologia , Obesidade/fisiopatologia , Fenótipo , Mutação Puntual , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Exoma , Adulto Jovem
17.
Epilepsia ; 61(3): 509-518, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32065676

RESUMO

OBJECTIVE: To estimate the incidence of epilepsy in children with Zika-related microcephaly in the first 24 months of life; to characterize the associated clinical and electrographic findings; and to summarize the treatment responses. METHODS: We followed a cohort of children, born during the 2015-2016 Zika virus (ZIKV) epidemic in Brazil, with congenital microcephaly and evidence of congenital ZIKV infection on neuroimaging and/or laboratory testing. Neurological assessments were performed at ≤3, 6, 12, 15, 18, 21, and 24 months of life. Serial electroencephalograms were performed over the first 24 months. RESULTS: We evaluated 91 children, of whom 48 were female. In this study sample, the cumulative incidence of epilepsy was 71.4% in the first 24 months, and the main type of seizure was infantile spasms (83.1%). The highest incidence of seizures occurred between 3 and 9 months of age, and the risk remained high until 15 months of age. The incidence of infantile spasms peaked between 4 and 7 months and was followed by an increased incidence of focal epilepsy cases after 12 months of age. Neuroimaging results were available for all children, and 100% were abnormal. Cortical abnormalities were identified in 78.4% of the 74 children evaluated by computed tomography and 100% of the 53 children evaluated by magnetic resonance imaging. Overall, only 46.1% of the 65 children with epilepsy responded to treatment. The most commonly used medication was sodium valproate with or without benzodiazepines, levetiracetam, phenobarbital, and vigabatrin. SIGNIFICANCE: Zika-related microcephaly was associated with high risk of early epilepsy. Seizures typically began after the third month of life, usually as infantile spasms, with atypical electroencephalographic abnormalities. The seizure control rate was low. The onset of seizures in the second year was less frequent and, when it occurred, presented as focal epilepsy.


Assuntos
Epilepsias Parciais/fisiopatologia , Malformações do Desenvolvimento Cortical/fisiopatologia , Microcefalia/fisiopatologia , Espasmos Infantis/fisiopatologia , Infecção por Zika virus/fisiopatologia , Anticonvulsivantes/uso terapêutico , Brasil , Córtex Cerebral/diagnóstico por imagem , Pré-Escolar , Eletroencefalografia , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/epidemiologia , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Microcefalia/diagnóstico por imagem , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/epidemiologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Infecção por Zika virus/congênito , Infecção por Zika virus/diagnóstico por imagem
19.
J Med Genet ; 57(3): 160-168, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31586944

RESUMO

BACKGROUND: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro. METHODS: DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients. RESULTS: We detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation. CONCLUSION: We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.


Assuntos
Anormalidades Múltiplas/genética , Desenvolvimento Fetal/genética , Retardo do Crescimento Fetal/genética , Transtornos do Crescimento/genética , Receptor IGF Tipo 1/genética , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Nanismo/genética , Nanismo/fisiopatologia , Feminino , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/fisiopatologia , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like II/genética , Masculino , Microcefalia/genética , Microcefalia/fisiopatologia , Mutação de Sentido Incorreto/genética , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Receptores de Somatomedina/genética
20.
Acta Ophthalmol ; 98(3): e316-e321, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31580008

RESUMO

PURPOSE: The aim of this study is to report on the phenotype and genotype of five patients diagnosed with Cohen syndrome, an extremely rare autosomal recessive disorder manifesting with mental and physiological defects. METHODS: Five patients from three German families and one Syrian family underwent a comprehensive ophthalmological examination. The scheduled visual acuity measurements, fundus ophthalmoscopy, spectral domain optical coherence tomography (OCT), full-field electrophysiological recordings of scotopic and photopic electroretinograms (ERGs) and colour vision testing could not be carried out in all subjects, because of the mental and physical retardation. The genetic diagnosis was achieved by next-generation sequencing. RESULTS: The ophthalmic and systemic phenotype of the patients is typical for Cohen syndrome including myopia, night blindness, photophobia, fundus pigmentary changes and bull's eye maculopathy. Electroretinograms (ERGs) were extinguished in the four patients, whose recording was possible. Genetic testing revealed homozygous or two heterozygous bi-allelic mutations in the VPS13B (COH1) gene in all five patients, with five different allelic variants observed. The homozygous mutation c.6055_6056delGA; p.Asp2019Glnfs*15 in two sibling patients as well as the homozygous nonsense mutation c.8112C>G;p.Tyr2704* have not previously been reported. CONCLUSIONS: The phenotype of the five patients reported here is typical for Cohen syndrome; however, their genotype is heterogeneous. Two new allelic variants were found to be the causative mutation.


Assuntos
Dedos/anormalidades , Deficiência Intelectual/genética , Microcefalia/genética , Hipotonia Muscular/genética , Miopia/genética , Obesidade/genética , Degeneração Retiniana/genética , Retinite Pigmentosa/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Criança , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Dedos/fisiopatologia , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Masculino , Microcefalia/complicações , Microcefalia/fisiopatologia , Hipotonia Muscular/complicações , Hipotonia Muscular/fisiopatologia , Mutação , Miopia/complicações , Miopia/fisiopatologia , Obesidade/complicações , Obesidade/fisiopatologia , Fenótipo , Degeneração Retiniana/complicações , Degeneração Retiniana/fisiopatologia , Retinite Pigmentosa/etiologia , Retinite Pigmentosa/fisiopatologia , Adulto Jovem
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