Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Acta Clin Belg ; : 1-9, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31402777

RESUMO

Objective: Juvenile nephronophthisis (NPHP) is an autosomal recessive cystic disease of the kidney. It represents the most frequent genetic cause of chronic renal failure in children. Methods: we investigated clinical and molecular features in two children with Juvenile nephronophthisis using firstly Multiplex ligation-dependent probe amplification (MLPA) and secondly multiplex PCR. Results: we report a homozygous NPHP1 deletion in two children. Conclusion: NPHP1 deletion analysis using diagnostic methods (e.g. MLPA, Multiplex PCR) should always be considered in patients with nephronophthisis, especially from consanguineous families. Our results provide insights into genotype-phenotype correlations in juvenile nephronophthisis that can be utilized in genetic counseling.

2.
Mol Genet Genomic Med ; 7(9): e882, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31347275

RESUMO

BACKGROUND: Oculodentodigital dysplasia (ODDD) is a rare disorder with pleiotropic effects involving multiple body systems, caused by mutations in the gap junction protein alpha 1 (GJA1) gene. GJA1 gene encodes a polytopic connexin membrane protein, Cx43, that is a component of connexon membrane channels. METHODS: We describe two unrelated female probands referred for a genetic review in view of a dysmorphic clinical phenotype. RESULTS: Two novel missense mutations in GJA1 that substitute conserved amino acids in the first and second transmembrane domains (NM_000165.5: c.77T>C p.Leu26Pro and NM_000165.5:c.287T>G p.Val96Gly) were detected through targeted sequencing of GJA1. These variants were detected in the heterozygous state in the two Maltese probands and segregated with the disease phenotype. CONCLUSION: This report further expands the mutational spectrum of ODDD.

3.
Clin Case Rep ; 6(10): 1933-1940, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30349702

RESUMO

Germline loss-of-function GNAS mutations are associated with multiple phenotypes, depending on the parental origin of the mutant allele. Here, we describe an infantile lethal form of atypical pseudohypoparathyroidism type 1a or 1c with severe Albright's hereditary osteodystrophy phenotype, underlying the extremely variable expressivity of this syndrome.

4.
Eur J Med Genet ; 2018 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-29510240

RESUMO

Mutations in the oligophrenin 1 gene (OPHN1) have been identified in patients with X-linked intellectual disability (XLID) associated with cerebellar hypoplasia and ventriculomegaly, suggesting it could be a recognizable syndromic intellectual disability (ID). Affected individuals share additional clinical features including speech delay, seizures, strabismus, behavioral difficulties, and slight facial dysmorphism. OPHN1 is located in Xq12 and encodes a Rho-GTPase-activating protein involved in the regulation of the G-protein cycle. Rho protein members play an important role in dendritic growth and in plasticity of excitatory synapses. Here we report on 17 individuals from four unrelated families affected by mild to severe intellectual disability due to OPHN1 mutations without cerebellar anomaly on brain MRI. We describe clinical, genetic and neuroimaging data of affected patients. Among the identified OPHN1 mutations, we report for the first time a missense mutation occurring in a mosaic state. We discuss the intrafamilial clinical variability of the disease and compare our patients with those previously reported. We emphasize the power of next generation techniques (X-exome sequencing, whole-exome sequencing and targeted multi-gene panel) to expand the phenotypic and mutational spectrum of OPHN1-related ID.

5.
Kidney Int ; 93(4): 961-967, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29398133

RESUMO

The clinical diagnosis of inherited renal tubulopathies can be challenging as they are rare and characterized by significant phenotypic variability. Advances in sequencing technologies facilitate the establishment of a molecular diagnosis. Therefore, we determined the diagnostic yield of a next generation sequencing panel assessing relevant disease genes in children followed through three national networks with a clinical diagnosis of a renal tubulopathy. DNA was amplified with a kit provided by the European Consortium for High-Throughput Research in Rare Kidney Diseases with nine multiplex PCR reactions. This kit produced 571 amplicons covering 37 genes associated with tubulopathies followed by massive parallel sequencing and bioinformatic interpretation. Identified mutations were confirmed by Sanger sequencing. Overall, 384 index patients and 16 siblings were assessed. Most common clinical diagnoses were 174 patients with Bartter/Gitelman syndrome and 76 with distal renal tubular acidosis. A total of 269 different variants were identified in 27 genes, of which 95 variants were considered likely, 136 definitely pathogenic and 100 had not been described at annotation. These mutations established a genetic diagnosis in 245 of the index patients. Genetic testing changed the clinical diagnosis in 16 cases and provided insights into the phenotypic spectrum of the respective disorders. Our results demonstrate a high diagnostic yield of genetic testing in children with a clinical diagnosis of a renal tubulopathy, consistent with a predominantly genetic etiology in known disease genes. Thus, genetic testing helped establish a definitive diagnosis in almost two-thirds of patients thereby informing prognosis, management and genetic counseling.

6.
Eur J Hum Genet ; 26(1): 64-74, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29180823

RESUMO

Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech, short stature with small hands and feet and facial dysmorphism consisting of a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures, and a short philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G > A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and craniosynostosis, as reported previously in a single patient. In these females, the X inactivation pattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.

7.
Int J Pediatr Otorhinolaryngol ; 103: 14-19, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29224756

RESUMO

Waardenburg syndrome (WS) is an auditory-pigmentary disease characterized by a clinical and genetic variability. WS is classified into four types depending on the presence or absence of additional symptoms: WS1, WS2, WS3 and WS4. Type 1 and 3 are mostly caused by PAX3 mutations, while type 2 and type 4 are genetically heterogeneous. The aims of this study are to confirm the diagnostic of WS1 by the sequencing of PAX3 gene and to evaluate the genotype phenotype correlation. A clinical classification was established for 14 patients WS, as proposed by the Waardenburg Consortium, and noted a predominance of type 1 and type 2 with 6 patients WS1, 7 patients WS2 and 1 patient WS3. A significant inter and intra-familial clinical heterogeneity was also observed. A sequencing of PAX3 gene in the 6 patients WS1 confirmed the diagnosis in 4 of them by revealing three novel mutations that modify two functional domains of the protein: the c.942delC; the c.933_936dupTTAC and the c.164delTCCGCCACA. These three variations are most likely responsible for the phenotype, however their pathogenic effects need to be confirmed by functional studies. The MLPA analysis of the 2 patients who were sequence negative for PAX3 gene revealed, in one of them, a heterozygous deletion of exons 5 to 9 confirming the WS1 diagnosis. Both clinical and molecular approaches led to the conclusion that there is a lack of genotype-phenotype correlation in WS1, an element that must be taken into account in genetic counseling. The absence of PAX3 mutation in one patient WS1 highlights the fact that the clinical classification is sometimes insufficient to distinguish WS1 from other types WS hence the interest of sequencing the other WS genes in this patient.


Assuntos
Fator de Transcrição PAX3/genética , Síndrome de Waardenburg/genética , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação , Linhagem , Fenótipo , Análise de Sequência de DNA/métodos , Tunísia , Adulto Jovem
8.
J Med Genet ; 54(9): 613-623, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28735298

RESUMO

BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.


Assuntos
Fatores de Transcrição Forkhead/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Transtorno do Espectro Autista/genética , Face/anormalidades , Feminino , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Humanos , Transtornos da Linguagem/genética , Masculino , Transtornos das Habilidades Motoras/genética , Mutação , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Estabilidade Proteica , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Síndrome , Transcrição Genética
9.
Nephrol Dial Transplant ; 32(5): 830-837, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27387476

RESUMO

Background: Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder, secondary to mutations in the GATA-3 gene. Due to its wide range of penetrance and expressivity, the disease may not always be recognized. We herein describe clinical and genetic features of patients with HDR syndrome, highlighting diagnostic clues. Methods: Medical records of eight patients from five unrelated families exhibiting GATA-3 mutations were reviewed retrospectively, in conjunction with all previously reported cases. Results: HDR syndrome was diagnosed in eight patients between the ages of 18 and 60 years. Sensorineural deafness was consistently diagnosed, ranging from clinical hearing loss since infancy in seven patients to deafness detected only by audiometry in adulthood in one single patient. Hypoparathyroidism was present in six patients (with hypocalcaemia and inaugural seizures in two out of six). Renal abnormalities observed in six patients were diverse and of dysplastic nature. Three patients displayed nephrotic-range proteinuria and reached end-stage renal disease (ESRD) between the ages of 19 and 61 years, whilst lesions of focal and segmental glomerulosclerosis were histologically demonstrated in one of them. Interestingly, phenotype severity differed significantly between a mother and son within one family. Five new mutations of GATA-3 were identified, including three missense mutations affecting zinc finger motifs [NM_001002295.1: c.856A>G (p.N286D) and c.1017C>G (p.C339W)] or the conserved linker region [c.896G>A (p.R299G)], and two splicing mutations (c.924+4_924+19del and c.1051-2A>G). Review of 115 previously reported cases of GATA-3 mutations showed hypoparathyroidism and deafness in 95% of patients, and renal abnormalities in only 60%. Overall, 10% of patients had reached ESRD. Conclusions: We herein expand the clinical and mutational spectrum of HDR syndrome, illustrating considerable inter- and intrafamilial phenotypic variability. Diagnosis of HDR should be considered in any patient with hypoparathyroidism and deafness, whether associated with renal abnormalities or not. HDR diagnosis is established through identification of a mutation in the GATA-3 gene.


Assuntos
Surdez/diagnóstico , Fator de Transcrição GATA3/genética , Hipoparatireoidismo/diagnóstico , Rim/anormalidades , Mutação de Sentido Incorreto/genética , Anormalidades Urogenitais/diagnóstico , Adolescente , Adulto , Idoso , Surdez/genética , Feminino , Humanos , Hipoparatireoidismo/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Prognóstico , Estudos Retrospectivos , Síndrome , Anormalidades Urogenitais/genética , Adulto Jovem
10.
J Med Genet ; 53(12): 820-827, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27439707

RESUMO

BACKGROUND: Heterozygous copy number variants (CNVs) or sequence variants in the contactin-associated protein 2 gene CNTNAP2 have been discussed as risk factors for a wide spectrum of neurodevelopmental and neuropsychiatric disorders. Bi-allelic aberrations in this gene are causative for an autosomal-recessive disorder with epilepsy, severe intellectual disability (ID) and cortical dysplasia (CDFES). As the number of reported individuals is still limited, we aimed at a further characterisation of the full mutational and clinical spectrum. METHODS: Targeted sequencing, chromosomal microarray analysis or multigene panel sequencing was performed in individuals with severe ID and epilepsy. RESULTS: We identified homozygous mutations, compound heterozygous CNVs or CNVs and mutations in CNTNAP2 in eight individuals from six unrelated families. All aberrations were inherited from healthy, heterozygous parents and are predicted to be deleterious for protein function. Epilepsy occurred in all affected individuals with onset in the first 3.5 years of life. Further common aspects were ID (severe in 6/8), regression of speech development (5/8) and behavioural anomalies (7/8). Interestingly, cognitive impairment in one of two affected brothers was, in comparison, relatively mild with good speech and simple writing abilities. Cortical dysplasia that was previously reported in CDFES was not present in MRIs of six individuals and only suspected in one. CONCLUSIONS: By identifying novel homozygous or compound heterozygous, deleterious CNVs and mutations in eight individuals from six unrelated families with moderate-to-severe ID, early onset epilepsy and behavioural anomalies, we considerably broaden the mutational and clinical spectrum associated with bi-allelic aberrations in CNTNAP2.


Assuntos
Variações do Número de Cópias de DNA , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Anormalidades Craniofaciais , Análise Mutacional de DNA , Epilepsias Parciais/genética , Epilepsias Parciais/metabolismo , Epilepsia/diagnóstico , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Masculino , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/metabolismo , Pessoa de Meia-Idade , Linhagem , Fenótipo , Síndrome
11.
J Med Genet ; 53(11): 776-785, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27334370

RESUMO

BACKGROUND: Progeroid syndromes are genetic disorders that recapitulate some phenotypes of physiological ageing. Classical progerias, such as Hutchinson-Gilford progeria syndrome (HGPS), are generally caused by mutations in LMNA leading to accumulation of the toxic protein progerin and consequently, to nuclear envelope alterations. In this work, we describe a novel phenotypic feature of the progeria spectrum affecting three unrelated newborns and identify its genetic cause. METHODS AND RESULTS: Patients reported herein present an extremely homogeneous phenotype that somewhat recapitulates those of patients with HGPS and mandibuloacral dysplasia. However, pathological signs appear earlier, are more aggressive and present distinctive features including episodes of severe upper airway obstruction. Exome and Sanger sequencing allowed the identification of heterozygous de novo c.163G>A, p.E55K and c.164A>G, p.E55G mutations in LMNA as the alterations responsible for this disorder. Functional analyses demonstrated that fibroblasts from these patients suffer important dysfunctions in nuclear lamina, which generate profound nuclear envelope abnormalities but without progerin accumulation. These nuclear alterations found in patients' dermal fibroblasts were also induced by ectopic expression of the corresponding site-specific LMNA mutants in control human fibroblasts. CONCLUSIONS: Our results demonstrate the causal role of p.E55K and p.E55G lamin A mutations in a disorder which manifests novel phenotypic features of the progeria spectrum characterised by neonatal presentation and aggressive clinical evolution, despite being caused by lamin A/C missense mutations with effective prelamin A processing.

12.
Am J Med Genet A ; 170(11): 2927-2933, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27333055

RESUMO

X-chromosome exome sequencing was performed to identify the genetic cause of syndromic intellectual disability in two unrelated families with suspected X-linked inheritance. In both families, affected males presented with severe intellectual disability, microcephaly, growth retardation, and epilepsy. A missense mutation (c.777T>G p.(Ile259Met)) and a frameshift mutation (c.1394_1397del p.(Ile465Serfs*4)) were identified in the EIF2S3 gene in the hemizygous state in affected patients, and in the heterozygous states female obligate carriers. A missense mutation in EIF2S3, coding for the gamma-subunit of the translation initiation factor eIF2, was reported once in a family presenting with similar clinical features. Morpholino-based knockdown of the zebrafish EIF2S3 ortholog (eif2s3) recapitulates the human microcephaly and short stature phenotype, supporting the pathogenicity of the identified variants. Our data confirm that EIF2S3 mutation is implicated in a rare, but recognizable, form of syndromic intellectual disability. © 2016 Wiley Periodicals, Inc.


Assuntos
Epilepsia/genética , Fator de Iniciação 2 em Eucariotos/genética , Estudos de Associação Genética , Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Microcefalia/genética , Mutação , Adolescente , Alelos , Sequência de Aminoácidos , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Epilepsia/diagnóstico , Exoma , Facies , Feminino , Técnicas de Silenciamento de Genes , Genes Ligados ao Cromossomo X , Genótipo , Transtornos do Crescimento/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/diagnóstico , Imagem por Ressonância Magnética , Masculino , Microcefalia/diagnóstico , Linhagem , Fenótipo , Síndrome , Peixe-Zebra
13.
Neurology ; 86(10): 954-62, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26865513

RESUMO

OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Proteínas Munc18/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Encefalopatias/diagnóstico , Encefalopatias/epidemiologia , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Adulto Jovem
14.
Am J Med Genet A ; 167A(10): 2231-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26079862

RESUMO

De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase-activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi-gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss-of-function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate-to-severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide-based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 Wiley Periodicals, Inc.


Assuntos
Heterozigoto , Deficiência Intelectual/genética , Mutação , Proteínas Ativadoras de ras GTPase/genética , Adolescente , Criança , Pré-Escolar , Constipação Intestinal/diagnóstico , Constipação Intestinal/genética , Constipação Intestinal/patologia , Análise Mutacional de DNA , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/patologia , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/genética , Transtornos Neurológicos da Marcha/patologia , Expressão Gênica , Haploinsuficiência , Luxação do Quadril/diagnóstico , Luxação do Quadril/genética , Luxação do Quadril/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Fenótipo , Estrabismo/diagnóstico , Estrabismo/genética , Estrabismo/patologia , Gêmeos Monozigóticos
15.
Am J Med Genet A ; 167(7): 1483-92, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25755104

RESUMO

Speech and language deficits are commonly associated with Kabuki syndrome. Yet little is known regarding the specific symptomatology of these disorders, preventing use of targeted treatment programs. Here we detail speech and language in 16 individuals with Kabuki syndrome (thirteen with KMT2D mutations, one with a KDM6A mutation, and two mutation-negative cases), aged 4-21 years. The most striking speech deficit was dysarthria, characterised by imprecise consonants, harsh vocal quality, hypernasality, reduced rate and stress, and distorted pitch. Oromotor functioning was also impaired. Delayed, rather than disordered, articulation and phonology was common. Both receptive and expressive language abilities were reduced in the majority and deficits were noted across all language sub-domains (i.e., semantics, syntax, morphology, and pragmatics) with no clear differentiation or specific language profile. Individuals with Kabuki syndrome present with a heterogenous pattern of oromotor, speech, and language deficits. This variability fits with the multisystem nature of the disorder, which may encompass neurological, orofacial structural, hearing, and cognitive deficits, any or all of which may contribute to speech or language impairment. Our results suggest that all individuals with Kabuki syndrome have some level of communication deficit, warranting speech pathology involvement in all cases.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Face/anormalidades , Doenças Hematológicas/genética , Doenças Hematológicas/patologia , Transtornos da Linguagem/patologia , Distúrbios da Fala/patologia , Doenças Vestibulares/genética , Doenças Vestibulares/patologia , Adolescente , Criança , Pré-Escolar , Face/patologia , Feminino , Genótipo , Humanos , Masculino , Vitória , Adulto Jovem
16.
Eur J Med Genet ; 58(3): 168-74, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25641759

RESUMO

The Dual-specify tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene has been extensively studied for its role in the pathophysiology of intellectual disability (ID) in Down syndrome. The rise of next generation sequencing (NGS) and array-CGH (aCGH) in diagnostic settings for the evaluation of patients with ID allowed the identification of 17 patients carrying heterozygous genetic aberrations involving DYRK1A to date. The rate of DYRK1A mutations in this population reaches >1% in published NGS studies. The current report aims at further defining the phenotype of this encephalopathy with the detailed report of two unrelated patients. Both patients were boys with developmental delay, febrile seizures, facial dysmorphism and brain atrophy on MRI. Patient #1 had autistic behaviors and micropenis and Patient #2 had stereotypies and microcephaly. NGS analyses identified heterozygous de novo variants in DYRK1A: the c.613C >T (p.Arg205*) nonsense mutation in Patient #1 and the c.932C >T (p.Ser311Phe) missense mutation in Patient #2. Together with previously reported cases, patients with DYRK1A mutations share many clinical features and may have a recognizable phenotype that includes, by decreasing order of frequency: developmental delay or ID with behaviors suggesting autism spectrum disorder, microcephaly, epileptic seizures, facial dysmorphism including ear anomalies (large ears, hypoplastic lobes), thin lips, short philtrum and frontal bossing. Delineation of the phenotype/genotype correlation is not feasible at the moment and will be a challenge for the coming years.


Assuntos
Síndrome de Down/genética , Deficiência Intelectual/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Síndrome de Down/diagnóstico , Epilepsia/diagnóstico , Epilepsia/genética , Proteína do X Frágil de Retardo Mental/genética , Proteína do X Frágil de Retardo Mental/metabolismo , Loci Gênicos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Mutação de Sentido Incorreto , Fenótipo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco , Proteínas Centrais de snRNP/genética , Proteínas Centrais de snRNP/metabolismo
17.
Eur J Med Genet ; 57(5): 212-5, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24613578

RESUMO

Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder characterized by profuse sweating at cold environmental temperatures, facial dysmorphism and skeletal features. The infantile presentation of CISS, referred to as Crisponi syndrome (CS), is characterized by facial muscular contractures in response to slight tactile stimuli or during crying, by life-threatening feeding difficulties caused by suck and swallow inabilities, and by intermittent hyperthermia. High febrile crises can lead to death within the first months of life. In preadolescence, surviving patients develop kyphoscoliosis and abnormal sweating. CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 in more than 90 percent of patients (CISS1) and by mutations in CLCF1 in the remaining patients (CISS2). It is now well demonstrated that all patients with an infantile-onset CS will develop CISS, confirming that CS and CISS are not "allelic disorders" but the same clinical entity described at different ages of affected patients. Here we report on a Turkish patient with a phenotype consistent with CS/CISS1 and a nonsense homozygous mutation (c.829C>T, p.R277X) in the CRLF1 gene. This mutation has already been reported in another Turkish patient with CS/CISS1.


Assuntos
Febre/diagnóstico , Deformidades Congênitas da Mão/diagnóstico , Receptores de Citocinas/genética , Trismo/congênito , Sequência de Bases , Consanguinidade , Análise Mutacional de DNA , Morte Súbita , Facies , Febre/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deformidades Congênitas da Mão/genética , Homozigoto , Humanos , Hiperidrose , Lactente , Masculino , Técnicas de Diagnóstico Molecular , Contração Muscular/genética , Mutação de Sentido Incorreto , Trismo/diagnóstico , Trismo/genética
18.
Am J Med Genet A ; 164A(5): 1289-92, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24664873

RESUMO

Kabuki syndrome is a rare malformation syndrome characterized by a typical facial appearance, skeletal anomalies, cardiac malformation, and mild to moderate intellectual disability. In 55-80% of patients with Kabuki syndrome, a mutation in MLL2 is identified. Recently, eight patients with Kabuki syndrome and a mutation in KDM6A were described. In this report, we describe two brothers with a mutation in KDM6A inherited from their mother and maternal grandmother. The two boys have Kabuki-like phenotypes whereas the mother and grandmother present with attenuated phenotypes. This family represents the first instance of hereditary X-linked Kabuki syndrome. We present a short literature review of the patients described with a mutation in KDM6A.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Face/anormalidades , Mutação da Fase de Leitura , Genes Ligados ao Cromossomo X , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Histona Desmetilases/genética , Proteínas Nucleares/genética , Fenótipo , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/genética , Adulto , Facies , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Linhagem , Gravidez , Diagnóstico Pré-Natal
19.
Bone ; 59: 7-13, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24495359

RESUMO

Adequate protein intake during development is critical to ensure optimal bone gain and to attain a higher peak bone mass later on. We hypothesized that the quality of the dietary protein is of prime importance for bone physiology during moderate protein restriction. The target population was growing Balb/C mice. We compared two protein restricted diets (6% of total energy as protein), one based on soy (LP-SOY) and one based on casein (LP-CAS). For comparison, a normal protein soy-based control group (NP-SOY) and a low protein group receiving an anabolic daily parathyroid hormone (PTH) 1-34 injection (LP-SOY+PTH) were included in the protocol. After 8weeks, LP-SOY mice had reduced body weights related to a lower lean mass whereas LP-CAS mice were not different from the NP-SOY group. LP-SOY mice were characterized by lower femoral cortical thickness, bone volume, trabecular number and thickness and increased medullar adiposity when compared to both the LP-CAS and NP-SOY groups. However, the dietary intervention had no effect on the vertebral parameters. The negative effect of the LP-SOY diet was correlated to an impaired bone formation as shown by the reduced P1NP serum level as well as the reduced osteoid surfaces and bone formation rate in the femur. PTH injection in LP-SOY mice had no effect on total weight or lean mass, but improved all bone parameters at both femoral and vertebral sites, suggesting that amino acid deficiency was not the primary reason for degraded bone status in mice consuming soy protein. In conclusion, our study showed that under the same protein restriction (6% of energy), a soy diet leads to impaired bone health whereas a casein diet has little effect when compared to a normal protein control.


Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Caseínas/farmacologia , Dieta com Restrição de Proteínas , Proteínas de Soja/farmacologia , Animais , Biomarcadores/metabolismo , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/anatomia & histologia , Camundongos , Camundongos Endogâmicos BALB C , Tamanho do Órgão/efeitos dos fármacos , Osteogênese/efeitos dos fármacos
20.
J Child Neurol ; 29(8): NP18-23, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23864591

RESUMO

Leber hereditary optic neuropathy is a well-known mitochondrial disorder that leads to bilateral subacute visual failure. Although visual impairment is often the sole clinical feature, additional and severe neurologic abnormalities also have been documented for this disease. We report on a 13-year-old boy who has presented with severe visual failure since early childhood in a context of prematurity. In the first years of his life, clinical features included delayed psychomotor development and ataxia. The clinical presentation, which was initially attributed to prematurity, worsened thereafter, and the child developed acute neurologic degradation with the typical radiological findings of Leigh syndrome. The mitochondrial DNA point mutation 11778G>A was identified in the ND4 gene. The probable influence of environmental background on clinical expression of Leber optic neuropathy, particularly those of prematurity and oxygen therapy, is discussed in our manuscript.


Assuntos
Senilidade Prematura/genética , DNA Mitocondrial/genética , Amaurose Congênita de Leber/genética , Mutação/genética , Adolescente , Senilidade Prematura/complicações , Encéfalo/patologia , Humanos , Amaurose Congênita de Leber/complicações , Imagem por Ressonância Magnética , Masculino
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA