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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(2): 170-173, 2021 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-33565074

RESUMO

OBJECTIVE: To explore the genetic basis for a child with ocular anomaly, microcephaly, growth retardation and intrauterine growth restriction. METHODS: The patient underwent ophthalmologic examinations including anterior segment photography, fundus color photography, and fundus fluorescein angiography. The patient and her parents were subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: The patient was found to have bilateral persistent pupillary membrane and coloboma of inferior iris, in addition with macular dysplasia and radial pigmentation near the hemal arch of the temporal retina. She was found to have carried compound heterozygous missense variants of the PHGDH gene, namely c.196G>A and c.1177G>A, which were respectively inherited from her father and mother. Bioinformatic analysis suggested both variants to be pathogenic. CONCLUSION: The patient was diagnosed with phosphoglycerate dehydrogenase deficiency. Above finding has enriched the phenotypic spectrum of the disease with ocular manifestations.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/genética , Microcefalia/genética , Fosfoglicerato Desidrogenase/deficiência , Transtornos Psicomotores/genética , Convulsões/genética , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Criança , Coloboma , Feminino , Humanos , Microcefalia/diagnóstico , Mutação , Fenótipo , Fosfoglicerato Desidrogenase/genética , Transtornos Psicomotores/diagnóstico , Convulsões/diagnóstico , Sequenciamento Completo do Exoma
2.
Muscle Nerve ; 62(2): 266-271, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32363625

RESUMO

BACKGROUND: Biallelic mutations in TBC1-domain containing kinase (TBCK) lead to hypotonia, global developmental delay with severe cognitive and motor deficits, and variable presentation of dysmorphic facial features and brain malformations. It remains unclear whether hypotonia in these individuals is purely neurogenic, or also caused by progressive muscle disease. METHODS: Whole exome sequencing was performed on a family diagnosed with nonspecific myopathic changes by means of histological analysis and immunohistochemistry of muscle biopsy samples. RESULTS: A novel homozygous truncation in TBCK was found in two sisters diagnosed with muscle disease and severe psychomotor delay. TBCK was completely absent in these patients. CONCLUSIONS: Our findings identify a novel early truncating variant in TBCK associated with a severe presentation and add muscle disease to the variability of phenotypes associated with TBCK mutations. Inconsistent genotype/phenotype correlation could be ascribed to the multiple roles of TBCK in intracellular signaling and endolysosomal function in different tissues.


Assuntos
Encefalopatias/genética , Mutação com Perda de Função , Hipotonia Muscular/genética , Músculo Esquelético/patologia , Doenças Musculares/genética , Proteínas Serina-Treonina Quinases/genética , Transtornos Psicomotores/genética , Convulsões/genética , Adolescente , Encéfalo/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Criança , Deficiências do Desenvolvimento/genética , Feminino , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Debilidade Muscular/genética , Debilidade Muscular/patologia , Doenças Musculares/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Reflexo Anormal/genética , Índice de Gravidade de Doença , Irmãos , Síndrome , Sequenciamento Completo do Exoma
3.
BMC Med Genet ; 21(1): 51, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171285

RESUMO

INTRODUCTION: The AP4B1 gene encodes a subunit of adaptor protein complex-4 (AP4), a component of intracellular transportation of proteins which plays important roles in neurons. Bi-allelic mutations in AP4B1 cause autosomal recessive spastic paraplegia-47(SPG47). CASE PRESENTATION: Here we present a Chinese patient with spastic tetraplegia, moderate psychomotor development delay and febrile seizures plus. Brain MRIs showed dilated supratentorial ventricle, thin posterior and splenium part of corpus callosum. The patient had little progress through medical treatments and rehabilitating regimens. Whole exome sequencing identified novel compound heterozygous truncating variants c.1207C > T (p.Gln403*) and c.52_53delAC (p.Cys18Glnfs*7) in AP4B1 gene. Causal mutations in AP4B1 have been reported in 29 individuals from 22 families so far, most of which are homozygous mutations. CONCLUSIONS: Our study enriched the genetic and phenotypic spectrum of SPG47. Early discovery, diagnosis and proper treatment on the conditions generally increase chances of improvement on the quality of life for patients.


Assuntos
Complexo 4 de Proteínas Adaptadoras/genética , Subunidades beta do Complexo de Proteínas Adaptadoras/genética , Proteínas de Ligação a DNA/genética , Transtornos Psicomotores/genética , Quadriplegia/genética , Proteínas de Ligação a RNA/genética , Convulsões Febris/genética , Grupo com Ancestrais do Continente Asiático , Criança , China , Códon sem Sentido , Heterozigoto , Humanos , Masculino , Fenótipo , Subunidades Proteicas/genética , Transtornos Psicomotores/complicações , Quadriplegia/complicações , Convulsões Febris/complicações , Sequenciamento Completo do Exoma
4.
Clin Dysmorphol ; 29(2): 97-100, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31929334

RESUMO

Deletion of the 1q43q44 chromosomal region has been related to a clinical syndrome characterized by neurodevelopmental delay, intellectual disability, microcephaly, congenital abnormality of the corpus callosum, and epilepsy and dysmorphic features. A wide variability of the clinical features have been linked to the contiguous deleted genes and incomplete penetrance has been observed too. Here, we report a 4-years-old boy with microcephaly, neurodevelopmental delay, and cardiac atrial septal defect, who had a de-novo 117 Kb 1q43-q44 microdeletion. The deleted chromosomal region encompassed the two genes SDCCAG8 and AKT3. The characteristics of the deletion and the clinical condition of the patient suggest a pathogenic role of the 1q43-q44 deletion, supporting a pivotal role of AKT3 gene in the expression of the clinical phenotype.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1 , Haploinsuficiência/genética , Microcefalia/diagnóstico , Microcefalia/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transtornos Psicomotores/diagnóstico , Transtornos Psicomotores/genética , Pré-Escolar , Hibridização Genômica Comparativa , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino
5.
Am J Perinatol ; 37(3): 281-290, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30731481

RESUMO

OBJECTIVE: To evaluate sex-specific genetic susceptibility to adverse neurodevelopmental outcome (ANO, defined as cerebral palsy [CP], mental, or psychomotor delay) at risk for early preterm birth (EPTB, < 32 weeks). STUDY DESIGN: Secondary case-control analysis of a trial of magnesium sulfate (MgSO4) before anticipated EPTB for CP prevention. Cases are infants who died by the age of 1 year or developed ANO. Controls, matched by maternal race and infant sex, were neurodevelopmentally normal survivors. Neonatal DNA was evaluated for 80 polymorphisms in inflammation, coagulation, vasoregulation, excitotoxicity, and oxidative stress pathways using Taqman assays. The primary outcome for this analysis was sex-specific ANO susceptibility. Conditional logistic regression estimated each polymorphism's odds ratio (OR) by sex stratum, adjusting for gestational age, maternal education, and MgSO4-corticosteroid exposures. Holm-Bonferroni corrections, adjusting for multiple comparisons (p < 7.3 × 10-4), accounted for linkage disequilibrium between markers. RESULTS: Analysis included 211 cases (134 males; 77 females) and 213 controls (130 males; 83 females). An interleukin-6 (IL6) polymorphism (rs2069840) was associated with ANO in females (OR: 2.6, 95% confidence interval [CI]: 1.5-4.7; p = 0.001), but not in males (OR: 0.8, 95% CI: 0.5-1.2; p = 0.33). The sex-specific effect difference was significant (p = 7.0 × 10-4) and was unaffected by MgSO4 exposure. No other gene-sex associations were significant. CONCLUSION: An IL6 gene locus may confer susceptibility to ANO in females, but not males, after EPTB.


Assuntos
Paralisia Cerebral/genética , Predisposição Genética para Doença , Interleucina-6/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos Psicomotores/genética , Estudos de Casos e Controles , Feminino , Humanos , Lactente , Modelos Logísticos , Sulfato de Magnésio/uso terapêutico , Masculino , Polimorfismo de Nucleotídeo Único , Gravidez , Nascimento Prematuro/prevenção & controle , Fatores Sexuais , Tocolíticos/uso terapêutico
6.
J Med Case Rep ; 13(1): 386, 2019 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-31883531

RESUMO

BACKGROUND: It is not uncommon that an infant with a disease of unknown etiology is presented to a physician. Facial dysmorphic features lead to a different diagnosis. It is a challenge to link the presentation to the newfound diagnosis. CASE PRESENTATION: A 37-day-old Yemenite Jewish girl was presented to our institution with a clinical picture of pseudohypoaldosteronism due to abnormal facial features and a psychomotor developmental delay. Further investigation led to the diagnosis of CDK13-related disorder. According to the literature, CDK13 has a key role in the cell cycle, but no interference with the aldosterone signaling pathway or electrolyte balance was described. No mutations in the previously described gene NR3C2 (cytogenetic location 4q31.23), encoding the mineralocorticoid receptor, were found. Although the clinical presentation corresponded to pseudohypoaldosteronism type 1, we could not genetically confirm this. CONCLUSIONS: Probably pseudohypoaldosteronism was a coincidental finding in this girl with a CDK13 mutation, but because only limited information is known about CDK13-related disorders, further investigation could be more informative to clarify this presentation.


Assuntos
Proteína Quinase CDC2/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Pseudo-Hipoaldosteronismo/diagnóstico , Transtornos Psicomotores/genética , Quelantes/uso terapêutico , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Metilfenidato/uso terapêutico , Poliestirenos/uso terapêutico , Pseudo-Hipoaldosteronismo/genética , Pseudo-Hipoaldosteronismo/fisiopatologia , Transtornos Psicomotores/diagnóstico , Receptores de Mineralocorticoides/genética , Risperidona/uso terapêutico , Antagonistas da Serotonina/uso terapêutico
7.
Indian Pediatr ; 56(9): 792-794, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31638014

RESUMO

BACKGROUND: Bainbridge-Ropers syndrome is a rare autosomal dominant genetic disorder. CASE CHARACTERISTICS: A 26-day-old neonate presented with feeding difficulties, excessive sleeping, and hirsutism over forehead and lumbosacral skin. OUTCOME: Whole-exome sequencing identified a novel nonsense mutation. MESSAGE: We report a novel mutation in a Chinese neonate with Bainbridge-Ropers syndrome.


Assuntos
Códon sem Sentido , Anormalidades Craniofaciais/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Hipotonia Muscular/diagnóstico , Transtornos Psicomotores/diagnóstico , Fatores de Transcrição/genética , Anormalidades Craniofaciais/genética , Distúrbios do Sono por Sonolência Excessiva/genética , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/genética , Feminino , Marcadores Genéticos , Hirsutismo/diagnóstico , Hirsutismo/genética , Humanos , Recém-Nascido , Hipotonia Muscular/genética , Transtornos Psicomotores/genética , Síndrome
8.
Ups J Med Sci ; 124(4): 273-277, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31623496

RESUMO

Background: Mitochondrial disorders are heterogeneous clinical syndromes caused by defective activity in the mitochondrial respiratory chain, resulting in a faulty oxidative phosphorylation system. These inherited disorders are individually rare, and furthermore they are phenotypic variables. The genetically characterized mitochondrial disorders are rarely associated with epileptic encephalopathies.Case presentation: We present the clinical phenotype, biochemical analysis, and electrographic and neuro-radiological features of a 5-month-old girl with epileptic encephalopathy, microcephaly, severe psychomotor delay, hypertrophic cardiomyopathy, and abnormal MRI scan. Using whole-genome sequencing technique, compound heterozygous mutations of the VARS2 gene were revealed, with one previously unreported frameshift mutation.Conclusion: Our report extends the phenotypic spectrum of VARS2-related disorders with an initial presentation of epileptic encephalopathy and early death due to malignant arrhythmia.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Antígenos HLA/genética , Doenças Mitocondriais/genética , Valina-tRNA Ligase/genética , Anormalidades Múltiplas , Cardiomiopatia Hipertrófica/genética , Evolução Fatal , Feminino , Mutação da Fase de Leitura , Heterozigoto , Humanos , Lactente , Imagem por Ressonância Magnética , Microcefalia/genética , Fenótipo , Transtornos Psicomotores/genética , Sequenciamento Completo do Genoma
9.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370244

RESUMO

Aneurysmal subarachnoid hemorrhage (aSAH), characterized by the extravasation of blood into the subarachnoid space caused by an intracranial aneurysm rupture, may lead to neurocognitive impairments and permanent disability and usually carries poor outcome. Dental or gingiva-derived stem cells have been shown to contribute to immune modulation and neuroregeneration, but the underlying mechanisms are unclear. In the present study, we sought to investigate whether dental pulp stem cells (DPSCs) secrete certain factor(s) that can ameliorate the neural damage and other manifestations in a rat aSAH model. Twenty-four hours after the induction of aSAH, microthrombosis, cortical vasoconstriction, and the decrease in microcirculation and tissue oxygen pressure were detected. Intrathecal administration of DPSC-derived conditioned media (DPSC-CM) ameliorated aSAH-induced vasoconstriction, neuroinflammation, and improved the oxygenation in the injured brain. Rotarod test revealed that the aSAH-induced cognitive and motor impairments were significantly improved by this DPSC-CM administration. Cytokine array indicated the major constituent of DPSC-CM was predominantly insulin growth factor-1 (IGF-1). Immunohistochemistry staining of injured brain tissue revealed the robust increase in Iba1-positive cells that were also ameliorated by DPSC-CM administration. Antibody-mediated neutralization of IGF-1 moderately deteriorated the rescuing effect of DPSC-CM on microcirculation, Iba1-positive cells in the injured brain area, and the cognitive/motor impairments. Taken together, the DPSC-derived secretory factors showed prominent therapeutic potential for aSAH. This therapeutic efficacy may include improvement of microcirculation, alleviation of neuroinflammation, and microglial activation; partially through IGF-1-dependent mechanisms.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Meios de Cultivo Condicionados/farmacologia , Transtornos Neurocognitivos/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Transtornos Psicomotores/tratamento farmacológico , Hemorragia Subaracnóidea/tratamento farmacológico , Trombose/tratamento farmacológico , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Meios de Cultivo Condicionados/química , Polpa Dentária/citologia , Polpa Dentária/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Injeções Espinhais , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Microcirculação/efeitos dos fármacos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Transtornos Neurocognitivos/genética , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/fisiopatologia , Fármacos Neuroprotetores/química , Consumo de Oxigênio/efeitos dos fármacos , Transtornos Psicomotores/genética , Transtornos Psicomotores/metabolismo , Transtornos Psicomotores/fisiopatologia , Ratos , Ratos Wistar , Teste de Desempenho do Rota-Rod , Células-Tronco/química , Células-Tronco/citologia , Células-Tronco/metabolismo , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/fisiopatologia , Trombose/genética , Trombose/metabolismo , Trombose/fisiopatologia , Vasoconstrição/efeitos dos fármacos
10.
Sci Rep ; 9(1): 11791, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409833

RESUMO

The excitability of neurons is tightly dependent on their ion channel repertoire. Among these channels, the leak sodium channel NALCN plays a crucial role in the maintenance of the resting membrane potential. Importantly, NALCN mutations lead to complex neurodevelopmental syndromes, including infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) and congenital contractures of limbs and face, hypotonia and developmental delay (CLIFAHDD), which are recessively and dominantly inherited, respectively. Unfortunately, the biophysical properties of NALCN are still largely unknown to date, as well as the functional consequences of both IHPRF and CLIFAHDD mutations on NALCN current. Here we have set-up the heterologous expression of NALCN in the neuronal cell line NG108-15 to investigate the electrophysiological properties of NALCN carrying representative IHPRF and CLIFAHDD mutations. Several original properties of the wild-type (wt) NALCN current were retrieved: mainly carried by external Na+, blocked by Gd3+, insensitive to TTX and potentiated by low external Ca2+ concentration. However, we found that this current displays a time-dependent inactivation in the -80/-40 mV range of membrane potential, and a non linear current-voltage relationship indicative of voltage sensitivity. Importantly, no detectable current was recorded with the IHPRF missense mutation p.Trp1287Leu (W1287L), while the CLIFAHDD mutants, p.Leu509Ser (L509S) and p.Tyr578Ser (Y578S), showed higher current densities and slower inactivation, compared to wt NALCN current. This study reveals that heterologous expression of NALCN channel can be achieved in the neuronal cell line NG108-15 to study the electrophysiological properties of wt and mutants. From our results, we conclude that IHPRF and CLIFAHDD missense mutations are loss- and gain-of-function variants, respectively.


Assuntos
Canalopatias/genética , Deficiência Intelectual/genética , Canais Iônicos/genética , Proteínas de Membrana/genética , Hipotonia Muscular/genética , Canalopatias/patologia , Facies , Humanos , Deficiência Intelectual/patologia , Mutação com Perda de Função/genética , Potenciais da Membrana/genética , Hipotonia Muscular/patologia , Mutação de Sentido Incorreto/genética , Neurônios/metabolismo , Neurônios/patologia , Transtornos Psicomotores/genética , Transtornos Psicomotores/patologia , Sódio/metabolismo , Canais de Sódio/genética
11.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340538

RESUMO

WW domain-containing oxidoreductase (Wwox) is a putative tumor suppressor. Several germline mutations of Wwox have been associated with infant neurological disorders characterized by epilepsy, growth retardation, and early death. Less is known, however, about the pathological link between Wwox mutations and these disorders or the physiological role of Wwox in brain development. In this study, we examined age-related expression and histological localization of Wwox in forebrains as well as the effects of loss of function mutations in the Wwox gene in the immature cortex of a rat model of lethal dwarfism with epilepsy (lde/lde). Immunostaining revealed that Wwox is expressed in neurons, astrocytes, and oligodendrocytes. lde/lde cortices were characterized by a reduction in neurite growth without a reduced number of neurons, severe reduction in myelination with a reduced number of mature oligodendrocytes, and a reduction in cell populations of astrocytes and microglia. These results indicate that Wwox is essential for normal development of neurons and glial cells in the cerebral cortex.


Assuntos
Sistemas de Transporte de Aminoácidos Acídicos/deficiência , Antiporters/deficiência , Córtex Cerebral/metabolismo , Nanismo/genética , Epilepsia/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Mitocondriais/genética , Neurogênese/genética , Transtornos Psicomotores/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Sistemas de Transporte de Aminoácidos Acídicos/genética , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animais , Antiporters/genética , Antiporters/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Contagem de Células , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Modelos Animais de Doenças , Nanismo/metabolismo , Nanismo/patologia , Epilepsia/metabolismo , Epilepsia/patologia , Regulação da Expressão Gênica no Desenvolvimento , Mutação em Linhagem Germinativa , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Masculino , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Prosencéfalo/crescimento & desenvolvimento , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Transtornos Psicomotores/metabolismo , Transtornos Psicomotores/patologia , Ratos , Ratos Transgênicos , Transdução de Sinais , Proteínas Supressoras de Tumor/deficiência , Oxidorredutase com Domínios WW/deficiência
12.
J Neurochem ; 151(1): 103-115, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31318984

RESUMO

The Fizzy-related protein 1 (Fzr1) gene encodes Cdh1 protein, a coactivator of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C). Previously, we found that genetic ablation of Fzr1 promotes the death of neural progenitor cells leading to neurogenesis impairment and microcephaly in mouse. To ascertain the possible translation of these findings in humans, we searched for mutations in the Fzr1 gene in 390 whole exomes sequenced in trio in individuals showing neurodevelopmental disorders compatible with a genetic origin. We found a novel missense (p.Asp187Gly) Fzr1 gene mutation (c.560A>G) in a heterozygous state in a 4-year-old boy, born from non-consanguineous Spanish parents, who presents with severe antenatal microcephaly, psychomotor retardation, and refractory epilepsy. Cdh1 protein levels in leucocytes isolated from the patient were significantly lower than those found in his parents. Expression of the Asp187Gly mutant form of Cdh1 in human embryonic kidney 293T cells produced less Cdh1 protein and APC/C activity, resulting in altered cell cycle distribution when compared with cells expressing wild-type Cdh1. Furthermore, ectopic expression of the Asp187Gly mutant form of Cdh1 in cortical progenitor cells in primary culture failed to abolish the enlargement of the replicative phase caused by knockout of endogenous Cdh1. These results indicate that the loss of function of APC/C-Cdh1 caused by Cdh1 Asp187Gly mutation is a new cause of prenatal microcephaly, psychomotor retardation, and severe epilepsy. Read the Editorial Highlight for this article on page 8. Cover Image for this issue: doi: 10.1111/jnc.14524.


Assuntos
Ciclossomo-Complexo Promotor de Anáfase/genética , Antígenos CD/genética , Caderinas/genética , Epilepsia/genética , Microcefalia/genética , Transtornos Psicomotores/genética , Pré-Escolar , Humanos , Masculino , Mutação de Sentido Incorreto
13.
Geroscience ; 41(2): 185-208, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31076997

RESUMO

Disruptions in growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling have been linked to improved longevity in mice and humans. Nevertheless, while IGF-1 levels are associated with increased cancer risk, they have been paradoxically implicated with protection from other age-related conditions, particularly in the brain, suggesting that strategies aimed at selectively increasing central IGF-1 action may have favorable effects on aging. To test this hypothesis, we generated inducible, brain-specific (TRE-IGF-1 × Camk2a-tTA) IGF-1 (bIGF-1) overexpression mice and studied effects on healthspan. Doxycycline was removed from the diet at 12 weeks old to permit post-development brain IGF-1 overexpression, and animals were monitored up to 24 months. Brain IGF-1 levels were increased approximately twofold in bIGF-1 mice, along with greater brain weights, volume, and myelin density (P < 0.05). Age-related changes in rotarod performance, exercise capacity, depressive-like behavior, and hippocampal gliosis were all attenuated specifically in bIGF-1 male mice (P < 0.05). However, chronic brain IGF-1 failed to prevent declines in cognitive function or neurovascular coupling. Therefore, we performed a short-term intranasal (IN) treatment of either IGF-1 or saline in 24-month-old male C57BL/6 mice and found that IN IGF-1 treatment tended to reduce depressive (P = 0.09) and anxiety-like behavior (P = 0.08) and improve motor coordination (P = 0.07) and unlike transgenic mice improved motor learning (P < 0.05) and visuospatial and working memory (P < 0.05). These data highlight important sex differences in how brain IGF-1 action impacts healthspan and suggest that translational approaches that target IGF-1 centrally can restore cognitive function, a possibility that should be explored as a strategy to combat age-related cognitive decline.


Assuntos
Envelhecimento/genética , Disfunção Cognitiva/genética , Regulação da Expressão Gênica , Fator de Crescimento Insulin-Like I/genética , Transtornos Psicomotores/genética , Animais , Modelos Animais de Doenças , Feminino , Longevidade/genética , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Distribuição Aleatória , Córtex Sensório-Motor , Transdução de Sinais
14.
Cytogenet Genome Res ; 158(1): 25-31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31055587

RESUMO

Diagnosing a complex genetic syndrome and correctly assigning the concomitant phenotypic traits to a well-defined clinical form is often a medical challenge. In this work, we report the analysis of a family with complex phenotypes, including microcephaly, intellectual disability, dysmorphic features, and polydactyly in the proband, with the aim of adding new aspects for obtaining a clear diagnosis. We performed array-comparative genomic hybridization and quantitative reverse transcriptase PCR (qRT-PCR) analyses. We identified a deletion of chromosome 20p12.1 involving the macrodomain containing 2/mono-ADP ribosylhydrolase 2 gene (MACROD2) in several members of the family. This gene is actually not associated with a specific syndrome but with congenital anomalies of multiple organs. qRT-PCR showed higher levels of a MACROD2 mRNA isoform in the individuals carrying the deletion. Our results, together with other data reported in the literature, support the hypothesis that the deletion in MACROD2 can affect correct embryonic development and that the presence of another associated event, such as epigenetic modifications at the MACROD2 locus, can influence the level of severity of the pathology.


Assuntos
Anormalidades Múltiplas/genética , Enzimas Reparadoras do DNA/genética , Hidrolases/genética , Deficiência Intelectual/genética , Rim/anormalidades , Microcefalia/genética , Pâncreas/anormalidades , Polidactilia/genética , Deleção de Sequência , Adulto , Cromossomos Humanos Par 20/genética , Cromossomos Humanos Par 20/ultraestrutura , Hibridização Genômica Comparativa , Enzimas Reparadoras do DNA/deficiência , Enzimas Reparadoras do DNA/fisiologia , Desenvolvimento Embrionário/genética , Feminino , Humanos , Hidrolases/deficiência , Hidrolases/fisiologia , Masculino , Linhagem , Fenótipo , Transtornos Psicomotores/genética
16.
Hum Mol Genet ; 28(11): 1755-1767, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30615115

RESUMO

Acute intermittent porphyria (AIP) is an inborn error of heme biosynthesis due to the deficiency of hydroxymethylbilane synthase (HMBS) activity. Human AIP heterozygotes have episodic acute neurovisceral attacks that typically start after puberty, whereas patients with homozygous dominant AIP (HD-AIP) have early-onset chronic neurological impairment, including ataxia and psychomotor retardation. To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype. Homozygous R173Q mice were embryonic lethal, while R167Q homozygous mice (R167Q+/+) had ~5% of normal HMBS activity, constitutively elevated plasma and urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), profound early-onset ataxia, delayed motor development and markedly impaired rotarod performance. Central nervous system (CNS) histology was grossly intact, but CNS myelination was delayed and overall myelin volume was decreased. Heme concentrations in liver and brain were similar to those of T1/T2 mice. Notably, ALA and PBG concentrations in the cerebral spinal fluid and CNS regions were markedly elevated in R167Q+/+ mice compared with T1/T2 mice. When the T1/T2 mice were administered phenobarbital, ALA and PBG markedly accumulated in their liver and plasma, but not in the CNS, indicating that ALA and PBG do not readily cross the blood-brain barrier. Taken together, these studies suggest that the severe HD-AIP neurological phenotype results from decreased myelination and the accumulation of locally produced neurotoxic porphyrin precursors within the CNS.


Assuntos
Hidroximetilbilano Sintase/genética , Doenças do Sistema Nervoso/genética , Porfiria Aguda Intermitente/genética , Transtornos Psicomotores/genética , Ácido Aminolevulínico/sangue , Ácido Aminolevulínico/urina , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Técnicas de Introdução de Genes , Genes Dominantes , Homozigoto , Humanos , Hidroximetilbilano Sintase/metabolismo , Fígado/metabolismo , Camundongos , Mutação de Sentido Incorreto/genética , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/urina , Fenobarbital/farmacologia , Porfobilinogênio/sangue , Porfobilinogênio/urina , Porfiria Aguda Intermitente/sangue , Porfiria Aguda Intermitente/patologia , Porfiria Aguda Intermitente/urina , Transtornos Psicomotores/sangue , Transtornos Psicomotores/patologia , Transtornos Psicomotores/urina
17.
Am J Med Genet A ; 179(2): 290-294, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30569622

RESUMO

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are very rare conditions caused by KAT6B truncating variants. Because of both syndromes often share common features the associated phenotypes are usually grouped under the term "KAT6B-related disorders." However, particular signs of each syndrome have been reported and their appearance seems to be dependent on where the KAT6B variant is located. Thus, whereas truncating variants associated with SBBYSS have their highest density in the distal part of exon 18, those resulting in GTPTS are distributed between the end of exon 17 and beginning of exon 18. Here, we reported two de novo heterozygous KAT6B truncating variants. The first variant (c.5802delA; p.A1935Pfs*16), identified in a boy with SSBYSS phenotype, resulting in the most distal KAT6B truncating variant reported up-to-date in the scientific literature. The second variant (c.3152delG; p.S1051Tfs*63), located in a region hitherto defined as specific of SBBYSS, seems to cause an overlapping SBBYSS/GTPTS phenotype. The clinical and genetic characterization of these patients could contribute to the understanding of the KAT6B-related disorders.


Assuntos
Anormalidades Múltiplas/genética , Blefarofimose/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Histona Acetiltransferases/genética , Deficiência Intelectual/genética , Instabilidade Articular/genética , Rim/anormalidades , Patela/anormalidades , Transtornos Psicomotores/genética , Escroto/anormalidades , Anormalidades Urogenitais/genética , Anormalidades Múltiplas/fisiopatologia , Blefarofimose/fisiopatologia , Criança , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/fisiopatologia , Éxons/genética , Facies , Cardiopatias Congênitas/fisiopatologia , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Instabilidade Articular/fisiopatologia , Rim/fisiopatologia , Masculino , Mutação , Patela/fisiopatologia , Fenótipo , Transtornos Psicomotores/fisiopatologia , Escroto/fisiopatologia , Anormalidades Urogenitais/fisiopatologia
18.
J Pediatr Hematol Oncol ; 41(1): e54-e56, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29620684

RESUMO

BACKGROUND: Disorders of intracellular cobalamin (Cbl) metabolism are classified from A to J according to biochemical phenotype, and genetic and complementation analyses. CblD-deficient patients present with developmental, hematologic, neurologic, and metabolic findings. CLINICAL OBSERVATION: An 11-year-old boy presented with neutropenia, increased mean corpuscular volume, psychomotor retardation, and seizures. His plasma total homocysteine and urinary methylmalonic acid levels were elevated, and a homozygous nonsense mutation [p. R250X (c.748C>T] leading to premature termination of translation was identified in the MMADHC gene, which was compatible with CblD defect. CONCLUSION: In the presence of increased mean corpuscular volume and other hematologic manifestations, such as leukopenia, thrombocytopenia, and megaloblastic anemia, with severe nonspecific or mild neurologic symptoms, Cbl synthesis defects should be considered.


Assuntos
Índices de Eritrócitos , Proteínas de Transporte da Membrana Mitocondrial/genética , Neutropenia , Transtornos Psicomotores , Deficiência de Vitamina B 12 , Criança , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Transporte da Membrana Mitocondrial/sangue , Neutropenia/sangue , Neutropenia/genética , Transtornos Psicomotores/sangue , Transtornos Psicomotores/genética , Deficiência de Vitamina B 12/sangue , Deficiência de Vitamina B 12/genética
19.
Taiwan J Obstet Gynecol ; 57(4): 583-587, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30122583

RESUMO

OBJECTIVE: We report a 13-year-old girl with 18p deletion syndrome presenting Turner syndrome-like clinical features. CASE REPORT: A 13-year-old girl was referred for genetic counseling of Turner syndrome-like clinical features of short stature, short webbed neck, low posterior hair line, puffy eyelids and increased carrying angle of the elbows. The girl also had mild intellectual disability, psychomotor developmental delay, speech disorder, high-arched palate, hypertelorism and mid-face hypoplasia. Cytogenetic analysis of the girl revealed a karyotype of 46,XX,del(18) (p11.2). The parental karyotypes were normal. Array comparative genomic hybridization analysis on the DNA extracted from the peripheral blood revealed a 13.93-Mb deletion of 18p11.32-p11.21 or arr 18p11.32p11.21 (148,993-14,081,858) × 1.0 [GRCh37 (hg19)] encompassing 52 Online Mendelian Inheritance in Man (OMIM) genes including USP14, TYMS, SMCHD1, TGIF1, LAMA1, TWSG1, GNAL and PTPN2. Polymorphic DNA marker analysis revealed a maternal origin of the deletion. CONCLUSION: Females with Turner syndrome-like clinical features in association with intellectual disability, facial dysmorphism and psychomotor developmental delay should be suspected of having chromosome deletion syndromes.


Assuntos
Transtornos Cromossômicos/genética , Fenótipo , Síndrome de Turner , Adolescente , Deleção Cromossômica , Cromossomos Humanos Par 18/genética , Hibridização Genômica Comparativa , Anormalidades Craniofaciais/genética , DNA/sangue , Feminino , Marcadores Genéticos/genética , Genótipo , Humanos , Deficiência Intelectual/genética , Cariótipo , Polimorfismo Genético/genética , Transtornos Psicomotores/genética
20.
BMC Med Genomics ; 11(1): 69, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30126420

RESUMO

BACKGROUND: Balanced reciprocal chromosomal translocations (RCTs) are the ones of the most common structural aberrations in the population, with an incidence of 1:625. RCT carriers usually do not demonstrate changes in phenotype, except when the translocation results in gene interruption. However, these people are at risk of production of unbalanced gametes during meiosis, as a result of various forms of chromosome segregation. This may cause infertility, non-implantation of the embryo, shorter embryo or foetus survival, as well as congenital defects and developmental disorders in children after birth. The increasing popularity of cytogenetic molecular techniques, such as microarray-based CGH (aCGH), contributed to the improved detection of chromosomal abnormalities in patients with intellectual disability, however, these modern techniques do not allow the identification of the balanced in potential carriers. Therefore, classical chromosome analysis with GTG technique still plays an important role in the identification of balanced rearrangements in every case of procreation failure. CASE PRESENTATION: In this article, a family with multiple occurrences of 17p13.3 duplication syndrome in the offspring and multiple miscarriages resulting from carrying of the balanced reciprocal translocation t(7;17)(p22;p13.2) by proband father is presented. The aCGH diagnostics allowed the identification of an unbalanced fragment responsible for the occurrence of clinical signs in the female patient, while karyotyping and FISH using specific probes allowed the localization of the additional material in the patient chromosomes, and identified the type of this translocation in the carriers. CONCLUSIONS: Identification of a balanced structural aberration in one of the partners allows direct diagnostics for the exclusion or confirmation of genetic imbalance in the foetus via traditional invasive prenatal diagnostics. It is also possible to use an alternative method, Preimplantation Genetic Diagnosis (PGD) after in vitro fertilization, which prevents initiating pregnancy if genetic imbalance is detected in the embryo.


Assuntos
Aborto Habitual/genética , Linhagem , Transtornos Psicomotores/genética , Translocação Genética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino
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