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1.
J Musculoskelet Neuronal Interact ; 20(4): 610-613, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33265090

RESUMO

Spinal muscular atrophy (SMA) refers to a group of genetic neuromuscular disorders affecting lower motor neurons causative of numerous phenotypes. To date, according to the age of onset, maximum muscular activity achieved, and life expectation four types of SMA are recognized, all caused by mutations in the SMN1 gene with SMN2 copy number influencing disease severity. Herein, we describe the case of a 31-year-old young male with normal psychomotor development who has experienced fatigue, cramps, and muscle fasciculations in the lower limbs for a period of 2 months. Based on electrophysiological and clinical findings we performed SMA genetic, clinical exome and RNA expression of candidate genes which led us to suggest SMN1-SMN2 genes [(2+0) and (0+0)] combination as possibly being implicated in the phenotype.

4.
Dermatol Online J ; 26(7)2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32898404

RESUMO

We report a 6-year-old girl showing epidermolytic ichthyosis/epidermolytic hyperkeratosis (EI/EH). Targeted Next Generation Sequencing revealed a de novo, previously unidentified KRT1 mutation. The findings of this study expands the clinical and  spectrum and genotype-phenotype correlation associated with EI/EH.

5.
Neural Plast ; 2020: 8078103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32908482

RESUMO

Purpose: The advancements in the next-generation sequencing (NGS) techniques have allowed for rapid, efficient, and cost-time-effective genetic variant detection. However, in both clinical practice and research setting, sequencing is still often limited to the use of gene panels clinically targeted on the genes underlying the disease of interest. Methods: We performed a neurogenetic study through an ad hoc NGS-based custom sequencing gene panel in order to screen 16 genes in 8 patients with different types of degenerative cognitive disorders (Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, and dementia associated with Parkinson's disease). The study protocol was based on previous evidence showing a high sensitivity and specificity of the technique even when the panel is limited to some hotspot exons. Results: We found variants of the TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered "disease causing." In the remaining subjects, the pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics (ACMG). In one patient, the p.R205W variant in the CHMP2B gene was found to be likely pathogenic of the disease. A variant in the CSF1R and SERPINI1 genes found in two patients was classified as benign, whereas the other two (in the GRN and APP genes) were classified as likely pathogenic according to the ACMG. Conclusions: Notwithstanding the preliminary value of this study, some rare genetic variants with a probable disease association were detected. Although future application of NGS-based sensors and further replication of these experimental data are needed, this approach seems to offer promising translational perspectives in the diagnosis and management of a wide range of neurodegenerative disorders.

6.
Medicina (Kaunas) ; 56(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32752300

RESUMO

The DHRS9 gene is involved in several pathways including the synthesis of allopregnanolone from progesterone. Allopregnanolone is a positive modulator of gamma aminobutyric acid (GABA) action and plays a role in the control of neuronal excitability and seizures. Whole-exome sequencing performed on a girl with an early onset epilepsy revealed that she was a compound heterozygote for two novel missense mutations of the DHRS9 gene likely to disrupt protein function. No previous studies have reported the implication of this gene in epilepsy. We discuss a new potential pathogenic mechanism underlying epilepsy in a child, due to a defective progesterone pathway.

7.
J Genet ; 992020.
Artigo em Inglês | MEDLINE | ID: mdl-32482919

RESUMO

Niemann-Pick disease type C (NPC) is a progressive lysosomal storage disorder caused by mutations in the NPC1 (in 95% of cases) or NPC2 (in ~5% of cases) genes, inherited in an autosomal recessive manner. We report the case of a 38-year-old woman with learning disorder from her first year of schooling, and could notice slow progressed cognitive impairment, social withdrawal, apathy, handwriting alterations, deterioration of language skills and dysphagia. Brain magnetic resonance imaging showed severe cerebellar atrophy, hypoplasia of the corpus callosum, asymmetric lateral ventricular enlargement, and severe enlargement of frontal and parietal subarachnoid spaces. Next generation sequencing for NPC genes (NPC1 and NPC2) detected compound heterozygous mutations in NPC1 gene, including c.1553G[A (p.Arg518Gln), paternally inherited, and c.1270C[T (p.Pro424Ser) maternally inherited. The first mutation has been already described in literature and correlated to NPC, while the second mutation is still unknown. Moreover, filipin test and quantification of plasma oxysterols confirmed NPC diagnosis. We can suggest the missense mutation c.1270C[T (p.Pro424Ser) as a new causative mutation of NPC.

8.
BMC Neurol ; 20(1): 156, 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32340607

RESUMO

BACKGROUND: Genetic familiar causes of oro-facial dyskinesia are usually restricted to Huntington's disease, whereas other causes are often missed or underestimated. Here, we report the case of late-onset oro-facial dyskinesia in an elderly patient with a genetic diagnosis of Spinocerebellar Ataxia type 2 (SCA2). CASE PRESENTATION: A 75-year-old man complained of progressive balance difficulty since the age of 60 years, associated with involuntary movements of the mouth and tongue over the last 3 months. No exposure to anti-dopaminergic agents, other neuroleptics, antidepressants, or other drugs was reported. Family history was positive for SCA2 (brother and the son of the brother). At rest, involuntary movements of the mouth and tongue were noted; they appeared partially suppressible and became more evident during stress and voluntary movements. Cognitive examination revealed frontal-executive dysfunction, memory impairment, and attention deficit. Brain magnetic resonance imaging (MRI) disclosed signs of posterior periventricular chronic cerebrovascular disease and a marked ponto-cerebellar atrophy, as confirmed by volumetric MRI analysis. A dopamine transporter imaging scan demonstrated a bilaterally reduced putamen and caudate nucleus uptake. Ataxin-2 (ATXN2) gene analysis revealed a 36 cytosine-adenine-guanine (CAG) repeat expansion, confirming the diagnosis of SCA2. CONCLUSIONS: SCA2 should be considered among the possible causes of adult-onset oro-facial dyskinesia, especially when the family history suggests an inherited cerebellar disorder. Additional clinical features, including parkinsonism and motor neuron disease, may represent relevant cues for an early diagnosis and adequate management.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Ataxias Espinocerebelares/genética , Idoso , Cerebelo/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Ponte/patologia
9.
Eur J Med Genet ; 63(4): 103848, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31972370

RESUMO

An increasing number of developmental and epileptic encephalopathies have been correlated with variants of ion channel genes, and in particular of potassium channels genes, such as KCNA1, KCNA2, KCNB1, KCNQ2, KCTD7 and KCNT1. Here we report a child with an early severe developmental and epileptic encephalopathy, spastic tetraplegia, opisthotonos attacks. The whole exome sequencing showed the de novo heterozygous variant c.1411G > C (p.Val471Leu) in the KCNC2 gene. Although this is, to our knowledge, the first case of encephalopathy associated with a KCNC2 gene variant, and further confirmatory studies are needed, previous preclinical and clinical evidence seems to suggest that KCNC2 is a new candidate epilepsy gene.

13.
Nat Commun ; 10(1): 1477, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931947

RESUMO

Phenotypic and biochemical categorization of humans with detrimental variants can provide valuable information on gene function. We illustrate this with the identification of two different homozygous variants resulting in enzymatic loss-of-function in LDHD, encoding lactate dehydrogenase D, in two unrelated patients with elevated D-lactate urinary excretion and plasma concentrations. We establish the role of LDHD by demonstrating that LDHD loss-of-function in zebrafish results in increased concentrations of D-lactate. D-lactate levels are rescued by wildtype LDHD but not by patients' variant LDHD, confirming these variants' loss-of-function effect. This work provides the first in vivo evidence that LDHD is responsible for human D-lactate metabolism. This broadens the differential diagnosis of D-lactic acidosis, an increasingly recognized complication of short bowel syndrome with unpredictable onset and severity. With the expanding incidence of intestinal resection for disease or obesity, the elucidation of this metabolic pathway may have relevance for those patients with D-lactic acidosis.


Assuntos
Acidose Láctica/diagnóstico , Lactato Desidrogenases/genética , Ácido Láctico/metabolismo , Mutação com Perda de Função , Síndrome do Intestino Curto/metabolismo , Espasmos Infantis/diagnóstico , Acidose Láctica/genética , Adulto , Animais , Consanguinidade , Diagnóstico Diferencial , Homozigoto , Humanos , Lactente , Lactato Desidrogenases/deficiência , Masculino , Espasmos Infantis/genética , Peixe-Zebra
14.
Hum Genet ; 138(2): 187-198, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30656450

RESUMO

Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene-disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.


Assuntos
Actinas/genética , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Doenças Genéticas Inatas/diagnóstico por imagem , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Quadriplegia/genética , Espasmos Infantis/genética , Criança , Pré-Escolar , Cromatina/genética , Metilação de DNA/genética , Feminino , Doenças Genéticas Inatas/genética , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Linhagem , Quadriplegia/diagnóstico por imagem , Espasmos Infantis/diagnóstico por imagem
15.
J Parkinsons Dis ; 9(1): 203-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30400105

RESUMO

Technological innovation related to the advent and development of the Next-Generation Sequencing (NGS) has provided significant advances in the diagnosis of disorders with genetic and phenotypic variability, such as neurodegenerative diseases. However, the interpretation of NGS data often remains challenging, although advanced prediction tools have contributed to primarily assess the impact of some missense variants. Here, we report a patient with Parkinson's disease (PD) and a family history of disease, in which a panel of 29 disease-causing or risk genes for PD were analyzed. We identified a new missense variant in the SNCA gene. Although this variant might be associated with PD in this family, it has been currently classified as a "Variant of Unknown Significance" because of the lack of segregation with disease. Indeed, we subsequently found the same mutation in an unaffected sister. Nevertheless, this finding may help clinicians and researchers in questioning the causative role of genetic variants within the daily clinical and diagnostic settings.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , alfa-Sinucleína/genética , Predisposição Genética para Doença , Humanos , Mutação de Sentido Incorreto , Linhagem
16.
J Genet ; 97(5): 1469-1472, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30555096

RESUMO

Hereditary spastic paraplegias are clinically and genetically heterogeneous degenerative disorders, and pathological variants in the autosomal recessive ZFYVE26 gene are considered as very rare causes. We describe a novel mutation in ZFYVE26 gene found in a patient with autosomal recessive spastic paraplegias. The use of a 'target-gene' approach allowed us to expand the clinical spectrum associated with hereditary spastic paraplegias.


Assuntos
Proteínas de Transporte/genética , Predisposição Genética para Doença/genética , Mutação , Paraplegia Espástica Hereditária/genética , Adulto , Sequência de Bases , Consanguinidade , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino
18.
Eur J Med Genet ; 60(2): 93-99, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27838393

RESUMO

Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most common human autosomal dominant disorders. The patient shows different signs on the skin and other organs from early childhood. The best known are six or more café au lait spots, axillary or inguinal freckling, increased risk of developing benign nerve sheath tumours and plexiform neurofibromas. Mutation detection is complex, due to the large gene size, the large variety of mutations and the presence of pseudogenes. Using Ion Torrent PGM™ Platform, 73 mutations were identified in 79 NF1 Italian patients, 51% of which turned out to be novel mutations. Pathogenic status of each variant was classified using "American College of Medical Genetics and Genomics" guidelines criteria, thus enabling the classification of 96% of the variants identified as being pathogenic. The use of Next Generation Sequencing has proven to be effective as for costs, and time for analysis, and it allowed us to identify a patient with NF1 mosaicism. Furthermore, we designed a new approach aimed to quantify the mosaicism percentage using electropherogram of capillary electrophoresis performed on Sanger method.


Assuntos
Manchas Café com Leite/genética , Neurofibromatose 1/genética , Neurofibromina 1/genética , Anormalidades da Pele/genética , Adolescente , Adulto , Manchas Café com Leite/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Itália , Masculino , Pessoa de Meia-Idade , Mosaicismo , Mutação , Neurofibromatose 1/patologia , Análise de Sequência de DNA , Anormalidades da Pele/patologia
19.
BMC Oral Health ; 16(1): 114, 2016 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-27809836

RESUMO

BACKGROUND: This study was aimed to investigate the prevalence of dental anxiety in a population of patients with Borderline Intellectual Functioning (BIF) and patients with mild and moderate intellectual disability (ID), and how dental anxiety correlated with their age and gender. METHODS: The sample was made of 700 patients, 287 females and 413 males, 6-to-47 years old, either with borderline intellectual functioning or mild/moderate intellectual disabilities. All patients were administered the Dental Anxiety Scale to assess their level of dental anxiety. RESULTS: Moderate Anxiety was the most prevalent dental anxiety category for patients with intellectual borderline functioning (15.56 %) and mild intellectual disabilities(18.79 %), while Severe Anxiety was the most prevalent category for patients with moderate intellectual disabilities(21 %). Overall, a statistically significant difference (p < 0.001) between the three groups (BIF, Mild-ID and Moderate-ID) was found. Also, the correlation analysis between participants' age and dental anxiety was statistically significant (p < 0.001); indeed, dental anxiety turned out to decrease with the increasing of the age. Moreover, the analysis between gender and dental anxiety was found to be significant as well (p < 0.001), where higher prevalence of dental anxiety was found in females. CONCLUSIONS: To our knowledge, this is the first study on dental anxiety carried out in the field of intellectual disability. Results show that the higher the level of intellectual disability - and consequently the lower the cognitive functioning - the higher the percentage and the severity of dental anxiety.


Assuntos
Ansiedade ao Tratamento Odontológico , Deficiência Intelectual , Adolescente , Adulto , Criança , Feminino , Humanos , Deficiências da Aprendizagem , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
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