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1.
Medicine (Baltimore) ; 99(29): e20574, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702813

RESUMO

RATIONALE: Schaaf-Yang syndrome, a rare imprinted hereditary disease caused by MAGEL2 variants, manifests as developmental delay/intellectual disability, neonatal hypotonia, feeding difficulties, contractures, and autism spectrum disorder. PATIENT CONCERNS: Patient 1 and 2 were infant girls presenting facial dysmorphisms, contractures of interphalangeal joints, neonatal hypotonia, feeding difficulties, congenital heart diseases, and respiratory complications. Besides, Patient 2 presented with delayed psychomotor development. DIAGNOSIS: Whole-exome sequencing was performed and heterozygous mutations of the MAGEL2 gene were detected in the patients. They were diagnosed as Schaaf-Yang syndrome. INTERVENTIONS: The patients received supportive treatment including mechanical ventilation, parenteral nutrition and gastric tube feeding. OUTCOMES: Whole-exome sequencing revealed de novo heterozygous c.1996dupC pathogenic mutations in the MAGEL2 gene in the 2 patients. They died due to respiratory failure at the age of 20 days and 98 days, respectively. LESSONS: Our results indicate that MAGEL2 variants can cause congenital heart disease and fatal respiratory complications, broadening the phenotypic spectrum and adding to the fatal cases of Schaaf-Yang syndrome. We highly suggest that the MAGEL2 gene should be added to gene-panels or gene-filters in next-generation sequencing-based diagnostics, which is of great significance for early diagnosis and early intervention of Schaaf-Yang syndrome patients.


Assuntos
Anormalidades Múltiplas/genética , Testes Genéticos/métodos , Proteínas/genética , Sequenciamento Completo do Exoma/métodos , Criança , Contratura/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Evolução Fatal , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Feminino , Articulações dos Dedos/fisiopatologia , Cardiopatias Congênitas/genética , Humanos , Lactente , Recém-Nascido , Masculino , Hipotonia Muscular/genética , Atrofia Muscular/genética , Cuidados Paliativos , Insuficiência Respiratória/genética , Síndrome
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.
Gene ; 742: 144542, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32184166

RESUMO

Homozygous loss-of-function variants in MYO18B have been associated with congenital myopathy, facial dysmorphism and Klippel-Feil anomaly. So far, only four patients have been reported. Comprehensive description of new cases that help to highlight recurrent features and to further delineate the phenotypic spectrum are still missing. We present the fifth case of MYO18B-associated disease in a newborn male patient. Trio exome sequencing identified the previously unreported homozygous nonsense variant c.6433C>T, p.(Arg2145*) in MYO18B (NM_032608.5). While most phenotypic features of our patient align with previously reported cases, we describe the prenatal features for the first time. Taking the phenotypic description of our patient into account, we propose that the core phenotype comprises a severe congenital myopathy with feeding difficulties in infancy and characteristic dysmorphic features.


Assuntos
Anormalidades Craniofaciais/genética , Síndrome de Klippel-Feil/genética , Hipotonia Muscular/genética , Miosinas/genética , Proteínas Supressoras de Tumor/genética , Idade de Início , Consanguinidade , Anormalidades Craniofaciais/diagnóstico , Análise Mutacional de DNA , Humanos , Lactente , Síndrome de Klippel-Feil/classificação , Síndrome de Klippel-Feil/diagnóstico , Mutação com Perda de Função , Masculino , Hipotonia Muscular/diagnóstico , Linhagem , Sequenciamento Completo do Exoma
4.
Am J Hum Genet ; 106(4): 484-495, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32220290

RESUMO

Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.


Assuntos
Aciltransferases/genética , Moléculas de Adesão Celular/genética , Doenças Cerebelares/genética , Epilepsia/genética , Variação Genética/genética , Hipotonia Muscular/genética , Transtornos do Neurodesenvolvimento/genética , Anormalidades Múltiplas/genética , Alelos , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Malformações do Sistema Nervoso/genética , Linhagem , Síndrome
5.
Am J Hum Genet ; 106(4): 438-452, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32197073

RESUMO

The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS), previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait, and abnormal brain MRI. The six variants lead to the same reading frame, adding a common proline rich C-terminal part instead of the last KH RNA binding domain. We detected 41 genes differentially spliced after NOVA2 downregulation in human neural cells. The NOVA2 variant protein shows decreased ability to bind target RNA sequences and to regulate target AS events. It also fails to complement the effect on neurite outgrowth induced by NOVA2 downregulation in vitro and to rescue alterations of retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss-of-function, although a specific contribution of the novel C-terminal extension cannot be excluded.


Assuntos
Mutação da Fase de Leitura/genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Neurônios/fisiologia , Processamento de RNA/genética , Proteínas de Ligação a RNA/genética , Processamento Alternativo/genética , Animais , Orientação de Axônios/genética , Sequência de Bases/genética , Células Cultivadas , Pré-Escolar , Regulação para Baixo/genética , Feminino , Heterozigoto , Humanos , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Camundongos , Hipotonia Muscular/genética , Peixe-Zebra/genética
6.
Nat Commun ; 11(1): 480, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980599

RESUMO

Mutations in the actively expressed, maternal allele of the imprinted KCNK9 gene cause Birk-Barel intellectual disability syndrome (BBIDS). Using a BBIDS mouse model, we identify here a partial rescue of the BBIDS-like behavioral and neuronal phenotypes mediated via residual expression from the paternal Kcnk9 (Kcnk9pat) allele. We further demonstrate that the second-generation HDAC inhibitor CI-994 induces enhanced expression from the paternally silenced Kcnk9 allele and leads to a full rescue of the behavioral phenotype suggesting CI-994 as a promising molecule for BBIDS therapy. Thus, these findings suggest a potential approach to improve cognitive dysfunction in a mouse model of an imprinting disorder.


Assuntos
Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Histonas/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Hipotonia Muscular/genética , Hipotonia Muscular/metabolismo , Canais de Potássio/genética , Animais , Comportamento Animal , Encéfalo/metabolismo , Anormalidades Craniofaciais/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Impressão Genômica , Inibidores de Histona Desacetilases/farmacologia , Humanos , Deficiência Intelectual/tratamento farmacológico , Locus Cerúleo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hipotonia Muscular/tratamento farmacológico , Mutação , Fenótipo , Fenilenodiaminas/farmacologia , Canais de Potássio/deficiência , Canais de Potássio/metabolismo , Regulação para Cima/efeitos dos fármacos
7.
Int J Pediatr Otorhinolaryngol ; 131: 109863, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31945734

RESUMO

We present a case of two siblings born to nonconsanguineous parents that presented with hypotonia, respiratory insufficiency, and auditory neuropathy spectrum disorder (ANSD) correlated with NFASC (MIM: 609145) and the homozygous loss of function variant p.P924RfsX35. This appears to be the first two reported cases of NFASC correlated with ANSD. NFASC encodes for neurofascin which plays an important role in the formation, function and maintenance of axon initial segments and nodes of Ranvier. Due to the rarity of this gene variation, reports are sparse in the literature leading to delays in diagnosis which can impact patient's language acquisition and spoken language skills.


Assuntos
Moléculas de Adesão Celular/genética , Perda Auditiva Central/genética , Mutação com Perda de Função , Fatores de Crescimento Neural/genética , Feminino , Homozigoto , Humanos , Lactente , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Hipotonia Muscular/genética , Irmãos
8.
J Hum Genet ; 65(4): 387-396, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31965062

RESUMO

NGLY1 deficiency is the first and only autosomal recessive congenital disorder of N-linked deglycosylation (NGLY1-CDDG). To date, no patients with NGLY1 deficiency has been reported from mainland China or East Asia in English literature. Here, we present six patients with a diagnosis of NGLY1-CDDG on the basis of clinical phenotype, genetic testing, and functional studies. We retrospectively analyzed clinical phenotypes and NGLY1 genotypes of six cases from four families. Informed consent was obtained for diagnosis and treatment. In-silico tools and in vitro enzyme activity assays were used to determine pathogenicity of NGLY1 varaints. All patients had typical features of NGLY1-CDDG, including global developmental delay, microcephaly, hypotonia, hypertransaminasemia, alacrimia, and feeding difficulty. Dysmorphic features found in our patients include flat nasal bridge, loose and hollow cheeks, short stature, malnutrition, and ptosis. Pachylosis could be a novel cutaneous feature that may be explained by lack of sweat. We found three novel variants, including one missense (c.982C > G/p.Arg328Gly), one splice site (c.1003+3A > G), and one frame-shift (c.1637-1652delCATCTTTTGCTTATAT/p.Ser546PhefsTer) variant. All mutations were predicted to be disease causing with in-silico prediction tools, and affected at least one feature of gene splicing. Protein modeling showed missense variants may affect covalent bonding within the protein structure, or interrupt active/binding amino-acid residues. In vitro studies indicated that proteins carrying missense variants (p.Arg328Gly and p.Tyr342Cys) lost the enzyme activity. We expanded clinical phenotype and genetic mutation spectrum of NGLY1-CDDG by reporting six cases, three novel variants, and novel clinical features from mainland China.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Deficiências do Desenvolvimento/genética , Oftalmopatias Hereditárias/genética , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Doenças do Aparelho Lacrimal/genética , Microcefalia/genética , Hipotonia Muscular/genética , Mutação , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/deficiência , Defeitos Congênitos da Glicosilação/patologia , Deficiências do Desenvolvimento/patologia , Oftalmopatias Hereditárias/patologia , Transtornos da Alimentação e da Ingestão de Alimentos/patologia , Feminino , Humanos , Lactente , Doenças do Aparelho Lacrimal/patologia , Masculino , Microcefalia/patologia , Hipotonia Muscular/patologia , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/genética
9.
BMC Med Genet ; 20(1): 187, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752730

RESUMO

BACKGROUND: Cohen syndrome (CS) is an uncommon developmental disease with evident clinical heterogeneity. VPS13B is the only gene responsible for CS. Only few sporadic cases of CS have been reported in China. CASE PRESENTATION: A Chinese family with two offspring-patients affected by developmental delay and intellectual disability was investigated in this study. Exome sequencing was performed, and compound heterozygous mutations in VPS13B were segregated for family members with autosomal recessive disorder. Splicing mutation c.3666 + 1G > T (exon 24) and nonsense mutation c. 9844 A > T:p.K3282X (exon 54) were novel. We revisited the family and learned that both patients are affected by microcephaly, developmental delay, neutropenia, and myopia and have a friendly disposition, all of which are consistent with CS phenotypes. We also found that both patients have hyperlinear palms, which their parents do not have. VPS13B mutations reported among the Chinese population were reviewed accordingly. CONCLUSIONS: This study presents two novel VPS13B mutations in CS. The identification of hyperlinear palms in a family affected by CS expands the phenotype spectrum of CS.


Assuntos
Dedos/anormalidades , Mãos/patologia , Deficiência Intelectual/genética , Microcefalia/genética , Hipotonia Muscular/genética , Mutação , Miopia/genética , Obesidade/genética , Degeneração Retiniana/genética , Proteínas de Transporte Vesicular/genética , Criança , Pré-Escolar , China , Deficiências do Desenvolvimento/genética , Feminino , Testes Genéticos , Humanos , Masculino , Linhagem , Fenótipo
10.
Genes (Basel) ; 10(10)2019 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614862

RESUMO

Variations in genes encoding for the enzymes responsible for synthesizing the linker region of proteoglycans may result in recessive conditions known as "linkeropathies". The two phenotypes related to mutations in genes B4GALT7 and B3GALT6 (encoding for galactosyltransferase I and II respectively) are similar, characterized by short stature, hypotonia, joint hypermobility, skeletal features and a suggestive face with prominent forehead, thin soft tissue and prominent eyes. The most outstanding feature of these disorders is the combination of severe connective tissue involvement, often manifesting in newborns and infants, and skeletal dysplasia that becomes apparent during childhood. Here, we intend to more accurately define some of the clinical features of B4GALT7 and B3GALT6-related conditions and underline the extreme hypermobility of distal joints and the soft, doughy skin on the hands and feet as features that may be useful as the first clues for a correct diagnosis.


Assuntos
Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Galactosiltransferases/genética , Células Cultivadas , Criança , Pré-Escolar , Síndrome de Ehlers-Danlos/patologia , Humanos , Instabilidade Articular/genética , Masculino , Hipotonia Muscular/genética , Mutação , Osteocondrodisplasias/genética , Fenótipo
11.
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
12.
Turk J Pediatr ; 61(1): 92-96, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31559727

RESUMO

Aydin HI, Sönmez FM. A novel mutation in two cousins with guanidinoacetate methyltransferase (GAMT) deficiency presented with autism. Turk J Pediatr 2019; 61: 92-96. Guanidinoacetate methyltransferase (GAMT) deficiency is a rare autosomal recessive disorder of creatine biosynthesis. Here, we report 9 and 10-year-old cousins with GAMT deficiency caused by a novel mutation who both exhibited neurodevelopmental retardation, seizures, behavioral problems, and autism that began during early infancy. The patients were diagnosed as having only autism and followed for years without a specific diagnosis although they had very low levels of serum creatinine for several times. A novel nonsense mutation in the GAMT gene that caused cessation of synthesis of the protein encoded by this gene was identified in these patients. GAMT deficiency is a treatable inborn error of metabolism and should be considered for all patients with hypotonia, developmental delay, seizures and autism, particularly if low serum creatinine levels are observed.


Assuntos
Transtorno Autístico/genética , Códon sem Sentido , Guanidinoacetato N-Metiltransferase/deficiência , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos dos Movimentos/congênito , Criança , Creatinina/sangue , Deficiências do Desenvolvimento/genética , Feminino , Guanidinoacetato N-Metiltransferase/genética , Humanos , Masculino , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/genética , Hipotonia Muscular/genética , Convulsões/genética
13.
Dev Med Child Neurol ; 61(12): 1439-1447, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31410843

RESUMO

The aim of the study was to redefine the phenotype of Allan-Herndon-Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty-four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro-orthopaedic, pulmonary, and epileptic complications. WHAT THIS PAPER ADDS: Mild intellectual disability is associated with SLC16A2 mutations. A thyroid hormone profile with a free T3 /T4 ratio higher than 0.75 can help diagnose patients. Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders. Axial hypotonia is a consistent feature of Allan-Herndon-Dudley syndrome and leads to specific complications.


Assuntos
Deficiência Intelectual , Retardo Mental Ligado ao Cromossomo X , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular , Atrofia Muscular , Simportadores/genética , Hormônios Tireóideos/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/sangue , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Humanos , Lactente , Deficiência Intelectual/sangue , Deficiência Intelectual/etiologia , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem , Imagem por Ressonância Magnética , Masculino , Retardo Mental Ligado ao Cromossomo X/sangue , Retardo Mental Ligado ao Cromossomo X/complicações , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/fisiopatologia , Hipotonia Muscular/sangue , Hipotonia Muscular/complicações , Hipotonia Muscular/etiologia , Hipotonia Muscular/genética , Hipotonia Muscular/fisiopatologia , Atrofia Muscular/sangue , Atrofia Muscular/complicações , Atrofia Muscular/genética , Atrofia Muscular/fisiopatologia , Fenótipo , Adulto Jovem
14.
Metab Brain Dis ; 34(6): 1565-1575, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31332729

RESUMO

Mutations in the thyroid hormone transporter MCT8 cause severe intellectual and motor disability and abnormal serum thyroid function tests, a syndrome known as MCT8 deficiency (or: Allan-Herndon-Dudley syndrome, AHDS). Although the majority of patients are unable to sit or walk independently and do not develop any speech, some are able to walk and talk in simple sentences. Here, we report on two cases with such a less severe clinical phenotype and consequent gross delay in diagnosis. Genetic analyses revealed two novel hemizygous mutations in the SLC16A2 gene resulting in a p.Thr239Pro and a p.Leu543Pro substitution in the MCT8 protein. In vitro studies in transiently transfected COS-1 and JEG-3 cells, and ex vivo studies in patient-derived fibroblasts revealed substantial residual uptake capacity of both mutant proteins (Leu543Pro > Thr239Pro), providing an explanation for the less severe clinical phenotype. Both mutations impair MCT8 protein stability and interfere with proper subcellular trafficking. In one of the patients calcifications were observed in the basal ganglia at the age of 29 years; an abnormal neuroradiological feature at this age that has been linked to untreated (congenital) hypothyroidism and neural cretinism. Our studies extend on previous work by identifying two novel pathogenic mutations in SLC16A2 gene resulting in a mild clinical phenotype.


Assuntos
Retardo Mental Ligado ao Cromossomo X/genética , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/genética , Atrofia Muscular/genética , Mutação , Fenótipo , Simportadores/genética , Encéfalo/diagnóstico por imagem , Criança , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico por imagem , Hipotonia Muscular/diagnóstico por imagem , Atrofia Muscular/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto Jovem
15.
Am J Hum Genet ; 105(2): 283-301, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31353023

RESUMO

The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.


Assuntos
RNA Polimerases Dirigidas por DNA/genética , Hipotonia Muscular/patologia , Mutação , Transtornos do Neurodesenvolvimento/patologia , Saccharomyces cerevisiae/crescimento & desenvolvimento , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Células HeLa , Heterozigoto , Humanos , Masculino , Hipotonia Muscular/enzimologia , Hipotonia Muscular/genética , Transtornos do Neurodesenvolvimento/enzimologia , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
16.
Handb Clin Neurol ; 162: 435-448, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31324324

RESUMO

The differential diagnosis of neonatal hypotonia is a complex task, as in newborns hypotonia can be the presenting sign of different underlying causes, including peripheral and central nervous system involvement and genetic and metabolic diseases. This chapter describes how a combined approach, based on the combination of clinical signs and new genetic techniques, can help not only to establish when the hypotonia is related to peripheral involvement but also to achieve an accurate and early diagnosis of the specific neuromuscular diseases with neonatal onset. The early identification of such disorders is important, as this allows early intervention with disease-specific standards of care and, more importantly, because of the possibility to treat some of them, such as spinal muscular atrophy, with therapeutic approaches that have recently become available.


Assuntos
Doenças do Recém-Nascido/terapia , Hipotonia Muscular/congênito , Hipotonia Muscular/terapia , Doenças Musculares/congênito , Doenças Musculares/terapia , Adulto , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/fisiopatologia , Técnicas de Diagnóstico Molecular , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Gravidez
17.
Mol Med Rep ; 20(1): 505-512, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180560

RESUMO

De novo sequence variants, including truncating and splicing variants, in the additional sex­combs like 3 gene (ASXL3) have been described as the cause of Bainbridge­Ropers syndrome (BRS). This pathology is characterized by delayed psychomotor development, severe intellectual disability, growth delay, hypotonia and facial dimorphism. The present study reports a case of a girl (born in 2013) with severe global developmental delay, central hypotonia, microcephaly and poor speech. The proband was examined using a multi­step molecular diagnostics algorithm, including karyotype and array­comparative genomic hybridization analysis, with negative results. Therefore, the proband and her unaffected parents were enrolled for a pilot study using targeted next­generation sequencing technology (NGS) with gene panel ClearSeq Inherited DiseaseXT and subsequent validation by Sanger sequencing. A novel de novo heterozygous frameshift variant in the ASXL3 gene (c.3006delT, p.R1004Efs*21), predicted to result in a premature termination codon, was identified. In conclusion, the present study demonstrated that targeted NGS using a suitable, gene­rich panel may provide a conclusive molecular genetics diagnosis in children with severe global developmental delays.


Assuntos
Deficiências do Desenvolvimento/genética , Microcefalia/genética , Hipotonia Muscular/genética , Fatores de Transcrição/genética , Criança , Feminino , Mutação da Fase de Leitura , Humanos , Masculino , Linhagem , Projetos Piloto , Distúrbios da Fala/genética
18.
Brain Dev ; 41(9): 783-789, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31122804

RESUMO

BACKGROUND: Cyclin-dependent kinase-like 5 (CDKL5), which maps to chromosome Xp22.13 and contains 20 coding exons, has been recognized as the gene responsible for early-onset epileptic encephalopathy (EoEE). A retrospective study is carried out to analyze potential genotypic and phenotypic differences between male and female patients with CDKL5 mutations. MATERIALS AND METHODS: Targeted next-generation DNA sequencing was employed to search for mutations in patients with cryptogenic EE. A total of 44 patients with EoEE/infantile spasms (ISs)/West syndrome were enrolled for pathogenic mutation screening. The clinical phenotypes of patients with CDKL5 mutations were analyzed and compared with those of 166 published cases. RESULTS: One novel and three recurrent mutations were found in four enrolled patients (two boys and two girls). One female patient had partial seizures during the early infantile period and epileptic spasms and tonic seizures several weeks thereafter. The other female patient had IS with hypsarrhythmia. The two male patients had IS without typical hypsarrhythmia and were bedridden. Brain MRIs of the male patients revealed brain atrophy and white matter hyperintensity. The female patients exhibited autistic features with hand stereotypies. CONCLUSION: Our study highlights that both girls and boys with IS harbor CDKL5 mutations. Male children with CDKL5 mutations demonstrate a higher frequency of infantile spasms and brain atrophy, whereas female children often exhibit atypical Rett syndrome with EoEE. In addition, male children have a more severe phenotype than female children.


Assuntos
Mutação , Proteínas Serina-Treonina Quinases/genética , Criança , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Hipotonia Muscular/genética , Fenótipo , Síndrome de Rett/genética , Fatores Sexuais
19.
Endocrinology ; 160(6): 1536-1546, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31127274

RESUMO

Allan-Herndon-Dudley syndrome (AHDS) is a severe genetic disease caused by mutations in the monocarboxylate transporter 8 (MCT8) gene. MCT8 mediates transport of thyroid hormones in and out of cells, which is thought to play a pivotal role for embryonic and postnatal development of the human brain. Disconcertingly, MCT8R271H leads to a severe form of AHDS but shows residual transport activity when expressed in several types of cultured cells. Here we try to determine the mechanism behind the transport function of MCT8R271H found in overexpressing cell systems. Mutations of Arg271 were introduced into human MCT8 and stably transfected into Madin-Darby canine kidney cells and the human-derived cell line JEG1. Radioactive thyroid hormone-uptake experiments were performed to analyze the pH-dependent effect of the mutation on transport activity. Arg271His transports thyroid hormones in and out of cells in a pH-dependent manner. Its transport activity increases below pH 7.3 and is clearly diminished at physiological pH. The Michaelis constant of the mutant is unaltered, whereas the maximum velocity is reduced. The expression of Arg271His in JEG1 cells leads to an almost nonfunctional transporter at physiological pH replicating the human phenotype for this mutant in vitro and demonstrates, again, that mutant MCT8 activity depends on cellular background. The protonation of His271 at acidic pH restores activity of the mutant protein, which is not active in its deprotonated form at physiological pH. Thus, experimental parameters must be controlled carefully when modeling MCT8 deficiency in cells.


Assuntos
Transportadores de Ácidos Monocarboxílicos/genética , Mutação , Fenótipo , Hormônios Tireóideos/metabolismo , Animais , Linhagem Celular , Cães , Humanos , Células Madin Darby de Rim Canino , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Hipotonia Muscular/genética , Hipotonia Muscular/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Transporte Proteico
20.
Am J Hum Genet ; 104(4): 721-730, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929742

RESUMO

VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.


Assuntos
Deficiência Intelectual/genética , Hipotonia Muscular/genética , Transtornos do Neurodesenvolvimento/genética , Neurônios/metabolismo , Sinapses/metabolismo , Proteína 2 Associada à Membrana da Vesícula/genética , Adolescente , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Epilepsia/metabolismo , Exocitose , Feminino , Heterozigoto , Humanos , Lipídeos/química , Imagem por Ressonância Magnética , Masculino , Fusão de Membrana , Transtornos dos Movimentos/genética , Mutação , Transtornos do Neurodesenvolvimento/metabolismo , Neurotransmissores/metabolismo , Fenótipo , Domínios Proteicos , Proteínas R-SNARE/metabolismo , Proteína 2 Associada à Membrana da Vesícula/fisiologia
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