RESUMO
CDKL5 deficiency disorder (CDD) is an X-linked dominant epileptic encephalopathy, characterized by early-onset and drug-resistant seizures, psychomotor delay, and slight facial features. Genomic variants inactivating CDKL5 or impairing its protein product kinase activity have been reported, making next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) the standard diagnostic tests. We report a suspicious case of CDD in a female child who tested negative upon NGS and CMA and harbored an X chromosome de novo pericentric inversion. The use of recently developed genomic techniques (optical genome mapping and whole-genome sequencing) allowed us to finely characterize the breakpoints, with one of them interrupting CDKL5 at intron 1. This is the fifth case of CDD reported in the scientific literature harboring a structural rearrangement on the X chromosome, providing evidence for the hypothesis that this type of anomaly can represent a recurrent pathogenic mechanism, whose frequency is likely underestimated, with it being overlooked by standard techniques. The identification of the molecular etiology of the disorder is extremely important in evaluating the pathological outcome and to better investigate the mechanisms associated with drug resistance, paving the way for the development of specific therapies. Karyotype and genomic techniques should be considered in all cases presenting with CDD without molecular confirmation.
Assuntos
Cromossomos Humanos X , Proteínas Serina-Treonina Quinases , Humanos , Feminino , Cromossomos Humanos X/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/deficiência , Inversão Cromossômica , Síndromes Epilépticas/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Espasmos InfantisRESUMO
CTNNB1 [OMIM *116806] encodes ß-catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previously reported NEDSDV patients. While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management.
Assuntos
Cardiopatias Congênitas , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Criança , beta Catenina/genética , Cardiopatias Congênitas/diagnóstico , Síndrome , Deficiência Intelectual/genéticaRESUMO
CSNK2B encodes a regulatory subunit of casein kinase II, which is highly expressed in the brain. Heterozygous pathogenic variants in CSNK2B are associated with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) (OMIM #618732), characterized by facial dysmorphisms, seizures, intellectual disability, and behavioral disturbances. We report ten new patients with CSNK2B-related Neurodevelopmental Syndrome associated with heterozygous variants of CSNK2B. In three patients, a pathogenic variant was inherited from an affected parent. We describe both molecular and clinical features, focusing on epileptic and neurodevelopmental phenotypes. The median age at follow-up was 8.5 years (range 21 months-42 years). All patients had epilepsy, with onset at a median age of 10.5 months range 6 days-10 years). Seizures were both focal and generalized and were resistant to anti-seizure medications in two out of ten patients. Six patients had mild to moderate cognitive delays, whereas four patients had no cognitive disability. Although all previously reported patients had a de novo CSNK2B pathogenic variant, here we report, for the first time, two familial cases of CSNK2B-related Neurodevelopmental Syndrome. We confirmed the highly variable expressivity of the disease among both interfamilial and intrafamilial cases. Furthermore, this study provides information about the long-term outcome in adult patients and underlines the importance of detailed family history collection before performing genetic testing in patients with epilepsy and neurodevelopmental disorders.
Assuntos
Epilepsia , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Adulto , Humanos , Lactente , Recém-Nascido , Epilepsia/genética , Epilepsia/patologia , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Deficiência Intelectual/genética , Síndrome , FenótipoRESUMO
The search for aetiology of Mendelian disorders is traditionally based on the observation of clinical phenotypes and molecular screening of associated genes. However, a disease-specific diagnosis can be challenging. In this study we detail how the combinatorial genomic and epigenomic assessment allowed to find the underlying molecular event of a clinical case that remained misdiagnosed for years. The individual was referred as affected by an atypical form of Kabuki syndrome with a variant of uncertain significance in the KMT2D gene. However, significant inconsistencies with this diagnosis emerged upon familial segregation of the variant and after the clinical re-evaluation. Therefore, we applied an epigenomic strategy by studying the DNA methylation profile which resulted not consistent with the Kabuki syndrome episignature or with any other disorder-specific episignature described so far, providing strong evidence that the Kabuki syndrome diagnosis does not apply. This result led us to further investigate for epigenetic machinery diseases by using a multigene panel for chromatinopathies. Since this analysis yielded negative results, we applied a whole exome sequencing and identified a de novo pathogenic variant in the CTNNB1 gene associated to NEDSDV syndrome, a neurodevelopmental disorder characterized by intellectual disability and craniofacial anomalies. Based on molecular results and the updated clinical features, we confirmed the NEDSDV diagnosis. Our findings show that the combination of genomic and epigenomics strategies, along with a deeper analysis of clinical phenotype, may provide a significant improvement in the diagnostic protocols for rare genetic disorders and help resolve long-time misdiagnosed and unsolved case.
Assuntos
Metilação de DNA , Deficiência Intelectual , Anormalidades Múltiplas , Metilação de DNA/genética , Erros de Diagnóstico , Exoma/genética , Face/anormalidades , Doenças Hematológicas , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Fenótipo , Doenças Vestibulares , Sequenciamento do ExomaRESUMO
Congenital heart defects (CHDs) are known to occur in 9%-25% of patients with KBG syndrome. In this study we analyzed the prevalence and anatomic types of CHDs in 46 personal patients with KBG syndrome, carrying pathogenetic variants in ANKRD11 or 16q24.3 deletion, and reviewed CHDs in patients with molecular diagnosis of KBG syndrome from the literature. CHD was diagnosed in 15/40 (38%) patients with ANKRD11 variant, and in one patient with 16q24.3 deletion. Left ventricular outflow tract obstructions have been diagnosed in 9/15 (60%), subaortic or muscular ventricular septal defect in 5/15 (33%), dextrocardia in 1/15 (8%). The single patient with 16q24.3 deletion and CHD had complete atrioventricular septal defect (AVSD) with aortic coarctation. Review of KBG patients from the literature and present series showed that septal defects have been diagnosed in 44% (27/61) of the cases, left ventricular tract obstructions in 31% (19/61), AVSD in 18% (11/61). Septal defects have been diagnosed in 78% of total patients with 16q24.3 deletion. Valvar anomalies are frequently diagnosed, prevalently involving the left side of the heart. A distinctive association with AVSD is identifiable and could represent a marker to suggest the diagnosis in younger patients. In conclusion, after precise molecular diagnosis and systematic cardiological screening the prevalence of CHD in KBG syndrome seems to be higher than previously reported in clinical articles. In addition to septal defects, left-sided anomalies and AVSD should be considered. Clinical management of KBG syndrome should include accurate and detailed echocardiogram at time of diagnosis.
Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Cardiopatias Congênitas , Deficiência Intelectual , Anormalidades Dentárias , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Deleção Cromossômica , Fácies , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Defeitos dos Septos Cardíacos , Humanos , Deficiência Intelectual/genética , Anormalidades Dentárias/genética , Fatores de TranscriçãoRESUMO
Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.
Assuntos
Apolipoproteína C-III/sangue , Deficiências do Desenvolvimento/genética , N-Acetilgalactosaminiltransferases/genética , Adolescente , Animais , Apolipoproteína C-III/genética , Criança , Pré-Escolar , Feminino , Glicosilação , Humanos , Mutação com Perda de Função , Masculino , Camundongos , Linhagem , Ratos , Adulto Jovem , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
Blue cone monochromatism (BCM) is an X-linked recessive cone dysfunction disorder caused by mutations in the OPN1LW/OPN1MW gene cluster, encoding long (L)- and middle (M)-wavelength-sensitive cone opsins. Here, we report on the unusual clinical presentation of BCM caused by a novel mutation in the OPN1LW gene in a young man. We describe in detail the phenotype of the proband, and the subclinical morpho-functional anomalies shown by his carrier mother. At a clinical level, the extensive functional evaluation demonstrated in the proband the M/L cone affection and the sparing of S-cone function, distinctive findings of BCM. Interestingly, spectral-domain optical coherence tomography showed the presence of foveal hypoplasia with focal irregularities of the ellipsoid layer in the foveal area, reported to be associated with some cases of cone-rod dystrophy and achromatopsia. At a molecular level, we identified the novel mutation c.427T > C p.(Ser143Pro) in the OPN1LW gene and the common missense mutation c.607T > C (p.Cys203Arg) in the OPN1MW gene. In addition, we discovered the c.768-2_769delAGTT splicing variant in the GPR143 gene. To our knowledge, this is the first case of foveal hypoplasia in a BCM patient and of mild clinical affection in a female carrier caused by the concomitant effect of variants in OPN1LW/OPN1MW and GPR143 genes, thus as the result of the simultaneous action of two independent genetic defects.
Assuntos
Defeitos da Visão Cromática/genética , Proteínas do Olho/genética , Fóvea Central/anormalidades , Glicoproteínas de Membrana/genética , Opsinas de Bastonetes/genética , Adulto , Defeitos da Visão Cromática/patologia , Humanos , Masculino , Mutação , LinhagemRESUMO
Craniosynostosis-microphthalmia linked to BCOR haploinsufficiency.
Assuntos
Craniossinostoses/genética , Anormalidades do Olho/genética , Microftalmia/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Adolescente , Criança , Cromossomos Humanos X/genética , Craniossinostoses/complicações , Craniossinostoses/patologia , Anormalidades do Olho/complicações , Anormalidades do Olho/patologia , Feminino , Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Haploinsuficiência/genética , Humanos , Microftalmia/complicações , Microftalmia/patologiaRESUMO
The tubulinopathies refer to a wide range of brain malformations caused by mutations in one of the seven genes encoding different tubulin's isotypes. The ß-tubulin isotype III (TUBB3) gene has a primary function in nervous system development and axon generation and maintenance, due to its neuron-specific expression pattern. A recurrent heterozygous mutation, c.1228G > A; p.E410K, in TUBB3 gene is responsible of a rare disorder clinically characterized by congenital fibrosis of the extraocular muscle type 3 (CFEOM3), intellectual disability and a wide range of neurological and endocrine abnormalities. Other mutations have been described spanning the entire gene and genotype-phenotype correlations have been proposed. We report on a 3-year-old boy in whom clinical exome sequencing allowed to identify a de novo TUBB3 E410K mutation as the molecular cause underlying a complex phenotype characterized by a severe bilateral palpebral ptosis refractory to eye surgery, psychomotor delay, absent speech, hypogonadism, celiac disease, and cyclic vomiting. Brain MRI revealed thinning of the corpus callosum with no evidence of malformation cortical dysplasia. We reviewed available records of patients with TUBB3 E410K mutation and compared their phenotype with the clinical outcome of patients with other mutations in TUBB3 gene. The present study confirms that TUBB3 E410K results in a clinically recognizable phenotype, unassociated to the distinct cortical dysplasia caused by other mutations in the same gene. Early molecular characterization of TUBB3 E410K syndrome is critical for targeted genetic counseling and prompt prospective care in term of neurological, ophthalmological, endocrine, and gastrointestinal follow-up.
Assuntos
Fibrose/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Malformações do Desenvolvimento Cortical/genética , Oftalmoplegia/genética , Tubulina (Proteína)/genética , Encéfalo/anormalidades , Pré-Escolar , Fibrose/complicações , Fibrose/diagnóstico , Fibrose/patologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Estudos de Associação Genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/diagnóstico , Malformações do Desenvolvimento Cortical/patologia , Neurônios/metabolismo , Neurônios/patologia , Oftalmoplegia/complicações , Oftalmoplegia/diagnóstico , Oftalmoplegia/patologia , Sequenciamento do ExomaRESUMO
KBG syndrome (MIM #148050) is an autosomal dominant disorder characterized by developmental delay, intellectual disability, distinct craniofacial anomalies, macrodontia of permanent upper central incisors, skeletal abnormalities, and short stature. This study describes clinical features of 28 patients, confirmed by molecular testing of ANKRD11 gene, and three patients with 16q24 deletion encompassing ANKRD11 gene, diagnosed in a single center. Common clinical features are reported, together with uncommon findings, clinical expression in the first years of age, distinctive associations, and familial recurrences. Unusual manifestations emerging from present series include juvenile idiopathic arthritis, dysfunctional dysphonia, multiple dental agenesis, idiopathic precocious telarche, oral frenula, motor tics, and lipoma of corpus callosum, pilomatrixoma, and endothelial corneal polymorphic dystrophy. Facial clinical markers suggesting KBG syndrome before 6 years of age include ocular and mouth conformation, wide eyebrows, synophrys, long black eyelashes, long philtrum, thin upper lip. General clinical symptoms leading to early genetic evaluation include developmental delay, congenital malformations, hearing anomalies, and feeding difficulties. It is likely that atypical clinical presentation and overlapping features in patients with multiple variants are responsible for underdiagnosis in KBG syndrome. Improved knowledge of common and atypical features of this disorder improves clinical management.
Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Nanismo/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/patologia , Doenças do Desenvolvimento Ósseo/patologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Nanismo/patologia , Fácies , Feminino , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/patologia , Masculino , Fenótipo , Anormalidades Dentárias/patologiaRESUMO
Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features. The duplications overlapped for 108 kb including FLNA, RPL10 and GDI1 genes, highly expressed in brain and candidates for the neurologic phenotype.
Assuntos
Duplicação Cromossômica , Cromossomos Humanos X , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Proteínas rab de Ligação ao GTP/genética , Adolescente , Adulto , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Criança , Fácies , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Adulto JovemRESUMO
Psychological distress is a known feature of generalized joint hypermobility (gJHM), as well as of its most common syndromic presentation, namely Ehlers-Danlos syndrome, hypermobility type (a.k.a. joint hypermobility syndrome - JHS/EDS-HT), and significantly contributes to the quality of life of affected individuals. Most published articles dealt with the link between gJHM (or JHS/EDS-HT) and anxiety-related conditions, and a novel generation of studies is emerging aimed at investigating the psychopathologic background of such an association. In this paper, literature review was carried out with a semi-systematic approach spanning the entire spectrum of psychopathological findings in gJHM and JHS/EDS-HT. Interestingly, in addition to the confirmation of a tight link between anxiety and gJHM, preliminary connections with depression, attention deficit (and hyperactivity) disorder, autism spectrum disorders, and obsessive-compulsive personality disorder were also found. Few papers investigated the relationship with schizophrenia with contrasting results. The mind-body connections hypothesized on the basis of available data were discussed with focus on somatotype, presumed psychopathology, and involvement of the extracellular matrix in the central nervous system. The hypothesis of positive Beighton score and alteration of interoceptive/proprioceptive/body awareness as possible endophenotypes in families with symptomatic gJHM or JHS/EDS-HT is also suggested. Concluding remarks addressed the implications of the psychopathological features of gJHM and JHS/EDS-HT in clinical practice.
Assuntos
Tecido Conjuntivo/fisiopatologia , Síndrome de Ehlers-Danlos/fisiopatologia , Instabilidade Articular/congênito , Estresse Psicológico , Ansiedade/genética , Ansiedade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Depressão/genética , Depressão/fisiopatologia , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/psicologia , Humanos , Instabilidade Articular/genética , Instabilidade Articular/fisiopatologia , Instabilidade Articular/psicologia , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
Oculo auriculo vertebral spectrum (OAVS; OMIM 164210) is a clinically and genetically heterogeneous disorder originating from an abnormal development of the first and second branchial arches. Main clinical characteristics include defects of the aural, oral, mandibular, and vertebral development. Anomalies of the cardiac, pulmonary, renal, skeletal, and central nervous systems have also been described. We report on a 25-year-old male showing a spectrum of clinical manifestations fitting the OAVS diagnosis: hemifacial microsomia, asymmetric mandibular hypoplasia, preauricular pits and tags, unilateral absence of the auditory meatus, dysgenesis of the inner ear and unilateral microphthalmia. A SNP-array analysis identified a de novo previously unreported microduplication spanning 723 Kb on chromosome 3q29. This rearrangement was proximal to the 3q29 microdeletion/microduplication syndrome region, and encompassed nine genes including ATP13A3 and XXYLT1, which are involved in the organogenesis and regulation of the Notch pathway, respectively. The present observation further expands the spectrum of genomic rearrangements associated to OAVS, underlying the value of array-based studies in patients manifesting OAVS features.
Assuntos
Transtornos Cromossômicos/diagnóstico por imagem , Síndrome de Goldenhar/diagnóstico por imagem , Adulto , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Síndrome de Goldenhar/genética , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Polimorfismo de Nucleotídeo Único , RadiografiaRESUMO
PURPOSE: The aim of our study was to evaluate bone quality by quantitative ultrasound (QUS) at the phalanges in 129 monozygotic twin couples, outlining the differences between growing subjects and adults. MATERIALS AND METHODS: A total of 129 healthy monozygotic twin couples (42 of children under 18 years of age and 87 of adults) were studied by phalangeal QUS, measuring amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT). Anthropometric data were also recorded. RESULTS: In children AD-SoS and BTT were positively correlated with age (r = 0.91, r = 0.91), height (r = 0.88, r = 0.90) and weight (r = 0.81, r = 0.87); in adults AD-SoS was negatively related to age (r = -0.36), AD-SoS and BTT were positively related to height (r = 0.37, r = 0.58). Absolute value differences between twins for AD-SoS and BTT were significantly higher in adult twins (25.9 ± 21.9 for AD-SoS and 0.08 ± 0.08 for BTT) than in children (14.5 ± 12.4 for AD-SoS and 0.05 ± 0.04 for BTT). CONCLUSION: Differentiation in bone tissue quality in twins increases with age, probably reflecting lifestyle, personal habits, likely acting through epigenetic mechanisms.
Assuntos
Densidade Óssea , Falanges dos Dedos da Mão/diagnóstico por imagem , Gêmeos Monozigóticos , Adolescente , Adulto , Idoso , Estatura , Índice de Massa Corporal , Peso Corporal , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Valores de Referência , Reprodutibilidade dos Testes , UltrassonografiaRESUMO
The D2/AKT1/GSK-3ß signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3ß proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3ß, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.
Assuntos
Antipsicóticos/farmacologia , Atenção/fisiologia , Benzodiazepinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Transdução de Sinais/fisiologia , Antipsicóticos/uso terapêutico , Atenção/efeitos dos fármacos , Benzodiazepinas/uso terapêutico , AMP Cíclico/metabolismo , Epistasia Genética , Genótipo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Imageamento por Ressonância Magnética , Olanzapina , Fosforilação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Receptores de Dopamina D2/genética , Esquizofrenia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes ERCC6 (CS type B) and ERCC8 (CS type A). We assessed this, presenting a series of patients with genetically confirmed CSB. (2) Materials and Methods: We retrospectively collected demographic, clinical, genetic, neuroimaging, and serum neurofilament light-chain (sNFL) data about CSB patients; diagnostic and severity scores were also determined. (3) Results: Data of eight ERCC6/CSB patients are presented. Four patients had CS I, three patients CS II, and one patient CS III. Various degrees of ataxia and spasticity were cardinal neurologic features, with variably combined systemic characteristics. Mean age at diagnosis was lower in the type II form, in which classic CS signs were more evident. Interestingly, sNFL determination appeared to reflect clinical classification. Two novel premature stop codon and one novel missense variants were identified. All CS I subjects harbored the p.Arg735Ter variant; the milder CS III subject carried the p.Leu764Ser missense change. (4) Conclusion: Our work confirms clinical variability also in the ERCC6/CSB type, where manifestations may range from severe involvement with prenatal or neonatal onset to normal psychomotor development followed by progressive ataxia. We propose, for the first time in CS, sNFL as a useful peripheral biomarker, with increased levels compared to currently available reference values and with the potential ability to reflect disease severity.
Assuntos
Síndrome de Cockayne , DNA Helicases , Enzimas Reparadoras do DNA , Proteínas de Ligação a Poli-ADP-Ribose , Fatores de Transcrição , Humanos , Síndrome de Cockayne/genética , Síndrome de Cockayne/patologia , Síndrome de Cockayne/diagnóstico , Proteínas de Ligação a Poli-ADP-Ribose/genética , Enzimas Reparadoras do DNA/genética , Feminino , Masculino , DNA Helicases/genética , Criança , Pré-Escolar , Adolescente , Estudos Retrospectivos , Adulto , Lactente , Estudos de Associação Genética , Adulto JovemRESUMO
INTRODUCTION: CTNNB1 gene loss-of-function variants cause Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV, OMIM 615075). Although motor impairment represents a core feature of this condition, the motor phenotype remains poorly described. We systematically assessed a cohort of 14 patients with disease-causing CTNNB1 variants to better characterize the movement disorder phenotype. METHODS: patients were enrolled at Bambino Gesù Children's Hospital in Rome, Italy, between January 2019 and February 2024. 14 participants were included and underwent extensive genetic and neurologic examination. Clinical features, neuroimaging and neurophysiological investigations were retrospectively analyzed from medical charts and video recordings. RESULTS: 13 out of 14 patients showed motor disorders (one only showing mild coordination difficulties). 12 presented abnormal gait (11 patients with broad-based gait, one with narrow-based in-toeing gait, one with broad-based gait with unilateral intoeing). One did not achieve walking ability. 13 patients presented progressive lower limbs hypertonia without overt pyramidal signs. Five patients reported exaggerated startle, three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13). Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients. CONCLUSIONS: CTNNB1-syndrome is associated with a peculiar, but recognizable movement disorder phenotype, encompassing complex gait disorders with progressive lower limb hypertonia, exaggerated startle, and possible occurrence in the second decade of life of upper body dystonia with or without bradykinesia.
Assuntos
Transtornos dos Movimentos , Fenótipo , beta Catenina , Humanos , Masculino , Feminino , Criança , Adolescente , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/fisiopatologia , beta Catenina/genética , Estudos Retrospectivos , Pré-Escolar , Adulto , Adulto Jovem , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/genética , SíndromeRESUMO
Sotos syndrome is an autosomal dominant condition characterized by overgrowth with advanced bone age, macrodolicocephaly, motor developmental delays and learning difficulties, and characteristic facial features caused by heterozygous pathogenetic variants in the NSD1 gene located on chromosome 5q35. The prevalence of heart defects (HDs) in individuals with Sotos syndrome is estimated to be around 15-40%. Septal defects and patent ductus arteriosus are the most commonly diagnosed malformations, but complex defects have also been reported. The aim of our study was to analyze the prevalence of HD, the anatomic types, and the genetic characteristics of 45 patients with Sotos syndrome carrying pathogenetic variants of NSD1 or a 5q35 deletion encompassing NSD1, who were followed at Bambino Gesù Children's Hospital in Rome. Thirty-nine of the forty-five patients (86.7%) had a mutation in NSD1, while six of the forty-five (13.3%) had a deletion. Most of the patients (62.2%, 28/45) were male, with a mean age of 14 ± 7 years (range 0.2-37 years). A total of 27/45 (60.0%) of the patients had heart defects, isolated or combined with other defects, including septal defects (12 patients), aortic anomalies (9 patients), mitral valve and/or tricuspid valve dysplasia/insufficiency (1 patient), patent ductus arteriosus (3 patients), left ventricular non-compaction/hypertrabeculated left ventricle (LV) (4 patients), aortic coarctation (1 patient), aortopulmonary window (1 patient), and pulmonary valve anomalies (3 patients). The prevalences of HD in the two subgroups (deletion versus intragenic mutation) were similar (66.7% (4/6) in the deletion group versus 58.91% (23/39) in the intragenic variant group). Our results showed a higher prevalence of HD in patients with Sotos syndrome in comparison to that described in the literature, with similar distributions of patients with mutated and deleted genes. An accurate and detailed echocardiogram should be performed in patients with Sotos syndrome at diagnosis, and a specific cardiological follow-up program is needed.
RESUMO
Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have been associated with syndromic craniosynostosis involving various cranial sutures and Chitayat syndrome, an ultrarare condition with respiratory distress, skeletal anomalies, and facial dysmorphism. Recently, a single patient with craniosynostosis and a phenotype resembling Noonan syndrome (NS), the most common disorder among the RASopathies, was reported to carry a de novo loss-of-function variant in ERF. Here, we clinically profile 26 individuals from 15 unrelated families carrying different germline heterozygous variants in ERF and showing a phenotype reminiscent of NS. The majority of subjects presented with a variable degree of global developmental and/or language delay. Their shared facial features included absolute/relative macrocephaly, high forehead, hypertelorism, palpebral ptosis, wide nasal bridge, and low-set/posteriorly angulated ears. Stature was below the 3rd centile in two-third of the individuals, while no subject showed typical NS cardiac involvement. Notably, craniosynostosis was documented only in three unrelated individuals, while a dolichocephalic aspect of the skull in absence of any other evidence supporting a premature closing of sutures was observed in other 10 subjects. Unilateral Wilms tumor was diagnosed in one individual. Most cases were familial, indicating an overall low impact on fitness. Variants were nonsense and frameshift changes, supporting ERF haploinsufficiency. These findings provide evidence that heterozygous loss-of-function variants in ERF cause a "RASopathy" resembling NS with or without craniosynostosis, and allow a first dissection of the molecular circuits contributing to MAPK signaling pleiotropy.
Assuntos
Craniossinostoses , Síndrome de Noonan , Fenótipo , Humanos , Craniossinostoses/genética , Craniossinostoses/patologia , Feminino , Masculino , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Criança , Pré-Escolar , Lactente , Mutação com Perda de Função , Adolescente , Proteínas Repressoras/genética , AdultoRESUMO
CTNNB1 syndrome is an autosomal-dominant neurodevelopmental disorder featuring developmental delay; intellectual disability; behavioral disturbances; movement disorders; visual defects; and subtle facial features caused by de novo loss-of-function variants in the CTNNB1 gene. Due to paucity of data, this study intends to describe feeding issues and oral-motor dyspraxia in an unselected cohort of 10 patients with a confirmed molecular diagnosis. Pathogenic variants along with key information regarding oral-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children's Hospital Feeding Scale (I-MCH-FS). Mild-to-severe coordination difficulties in single or in a sequence of movements involving the endo-oral and peri-oral muscles were noticed across the entire cohort. Mild-to-profuse drooling was a commonly complained-about issue by 30% of parents. The mean total I-MCH-FS t-score equivalent was 43.1 ± 7.5. These findings contribute to the understanding of the CTNNB1 syndrome highlighting the oral motor phenotype, and correlating specific gene variants with clinical characteristics.