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2.
Ital J Pediatr ; 45(1): 67, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151476

RESUMO

BACKGROUND: X-linked hypophosphatemic rickets (XLH) is the first cause of inherited hypophosphatemia and is caused by mutation in the PHEX gene, resulting in excessive expression of the phosphaturic factor FGF23. Symptoms are mainly related to rickets in children and osteomalacia in adults and cause several complications that can be highly invalidating. Due to its rarity, XLH is poorly known and diagnosis is frequently delayed. Conventional treatment is based on oral phosphate salts supplementation and activated vitamin D analogs, which however, cannot cure the disease in most cases. OBJECTIVE: Due to the low prevalence of XLH, an experts' opinion survey was conducted across Italian centers to collect data on XLH and on its management. METHODS: A questionnaire was developed by a group of experts to collect data on XLH epidemiology, diagnosis and treatment in Italy. RESULTS: Data from 10 Italian centers (nine of which pediatric) on 175 patients, followed between 1998 and 2017, were included in the survey. Most patients were followed since childhood and 63 children became adults during the investigated period. The diagnosis was made before the age of 1 and between 1 and 5 years in 11 and 50% of cases, respectively. Clinically apparent bone deformities were present in 95% of patients. These were ranked moderate/severe in 75% of subjects and caused growth stunting in 67% of patients. Other frequent complications included bone pain (40%), dental abscesses (33%), and dental malpositions (53%). Treatment protocols varied substantially among centers. Nephrocalcinosis was observed in 34% of patients. Tertiary hyperparathyroidism developed in 6% of patients. CONCLUSIONS: XLH remains a severe condition with significant morbidities.


Assuntos
Raquitismo Hipofosfatêmico Familiar/genética , Doenças Genéticas Ligadas ao Cromossomo X , Padrões de Prática Médica/estatística & dados numéricos , Adolescente , Adulto , Criança , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Raquitismo Hipofosfatêmico Familiar/epidemiologia , Raquitismo Hipofosfatêmico Familiar/terapia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Lactente , Recém-Nascido , Itália/epidemiologia , Masculino , Inquéritos e Questionários
4.
Ital J Pediatr ; 45(1): 53, 2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31029177

RESUMO

BACKGROUND: Angioma serpiginosum is a rare vascular anomaly whose pathogenesis is still unknown. It is characterized by the onset of vascular reddish macules and papules during childhood, lesions are usually monolateral with a linear serpiginous pattern. It is rarely associated with extracutaneous findings. This entity has not yet been included in the classification of the International Society for the Study of Vascular Anomalies. CASE PRESENTATION: We describe the first Italian report of angioma serpiginosum with a congenital symmetrical presentation. The patient had a further extension of macules during puberty involving both of the soles. No extracutaneous manifestations were present. Diagnosis was confirmed with dermoscopy and light microscopy that revealed the typical clusters of dilated, thickened and PAS+ capillaries in the upper dermis. Moreover, Immunohistochemistry showed positive WT-1 staining. Genetic analysis with next generation sequencing did not detected any mutation. CONCLUSIONS: Our patient presented a peculiar symmetrical and planar extension with a serpiginous linear pattern. The proliferative nature of this condition has been widely discussed in literature. In our case immunohistochemistry was positive for Wilms tumor-1, a new endothelial marker expressed during angiogenesis in reparative processes and endothelial tumors. Clinical evolution, histological and immunohistochemical findings suggest that angioma serpiginosum should be considered as a vascular proliferation. For these reasons we think it should be included in the international classification as a tumor.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Dermatopatias Vasculares/congênito , Adolescente , Criança , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Masculino , Dermatopatias Vasculares/diagnóstico , Dermatopatias Vasculares/terapia
7.
JAMA Neurol ; 76(2): 211-216, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30508028

RESUMO

Importance: Anecdotal evidence suggests that deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in ameliorating dystonia in X-linked dystonia parkinsonism (XDP), a disease that is usually refractive to medical therapy. Objective: To determine the efficacy of GPi-DBS in a cohort of patients with XDP in a prospective study and identify predictors of postoperative outcomes. Design, Setting, and Participants: This observational prospective cohort study enrolled patients in February 2013 and was completed in December 2014. The patients were followed up for up to 46 months. Patients from the Philippines were treated in a single center in Lübeck, Germany and followed up in the Philippines. Sixteen men with XDP (mean [SD] age, 40.9 [7.3] years; disease duration, 1-6 years) from the Philippines with predominant dystonia were selected. Exposures: All patients underwent bilateral GPi-DBS in Lübeck, Germany. Main Outcomes and Measures: Clinical assessment included the motor parts of the Burke-Fahn-Marsden scale (BFMDRS-M) and the Unified Parkinson's Disease Rating Scale (UPDRS-III). T1-based basal ganglia volumetry was performed and correlated with postoperative outcomes. Results: The study participants included 16 Filipino men (mean age, 40.9 years). Masked video ratings revealed significant improvements of dystonia severity 1 week (-55%; range, -94% to 59%; P < .01) and 6 months (-59%; range, -100% to 22%; P < .001) after surgery. The UDPRS-III score also improved, albeit to a lesser extent (-19%; range, -54% to 95%; and -27%; range, -70% to 124%; respectively). Unmasked long-term follow-up confirmed the continued efficacy of GPi-DBS up to 46 months after surgery. Important secondary end points improved, including activities of daily living, pain severity, weight, and quality of life. Caudate atrophy was a predictor of a less beneficial outcome (r = 0.817, P = .004). Conclusions and Relevance: Internal globus pallidus DBS had a positive association in XDP with predominant dystonia (the primary end point) and contributed to an improved quality of life (the secondary end point). The response to DBS occurred within 1 week. Given the inverse correlation of postoperative benefit and caudate atrophy, GPi-DBS should be considered early during the disease course. Close international collaboration, training, and funding from multiple sources enabled the sustainable follow-up of patients with XDP in the Philippines.


Assuntos
Estimulação Encefálica Profunda/métodos , Distúrbios Distônicos/terapia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Globo Pálido , Adulto , Núcleo Caudado/patologia , Seguimentos , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Filipinas
8.
Transfusion ; 58 Suppl 3: 3056-3064, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30536429

RESUMO

Primary immunodeficiency (PID) diseases result from genetic defects of the immune system that increase a patient's susceptibility to infections. The types of infections that occur in patients with PID diseases are dictated largely by the nature of the immunodeficiency, which can be defined by dysfunction of cellular or humoral defenses. An increasing number of PID diseases, including those with both cellular and humoral defects, have antibody deficiency as a major feature, and as a result can benefit from immunoglobulin replacement therapy. In fact, the most common PID diseases worldwide are antibody deficiencies and include common variable immunodeficiency, congenital agammaglobulinemia, hyper-IgM syndrome, specific antibody deficiency, and Good syndrome. Although immunoglobulin replacement therapy is the cornerstone of treatment for the majority of these conditions, a thorough understanding of the specific infections for which these patients are at increased risk can hasten diagnosis and guide additional therapies. Moreover, the infection trends in some patients with PID disease who have profound defects of cellular immunity, such as autosomal-dominant hyper-IgE syndrome (Job/Buckley syndrome) or dedicator of cytokinesis 8 (DOCK8) deficiency, suggest that select patients might benefit from immunoglobulin replacement therapy even if their immunodeficiency is not limited to antibody defects. In this review, we provide an overview of the predisposition to infections seen in PID disease that may benefit from immunoglobulin replacement therapy.


Assuntos
Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/terapia , /imunologia , Agamaglobulinemia/complicações , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/terapia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Síndromes de Imunodeficiência/classificação , Síndromes de Imunodeficiência/imunologia , Fatores de Risco
9.
Stereotact Funct Neurosurg ; 96(5): 320-326, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30481788

RESUMO

BACKGROUND: X-linked dystonia parkinsonism (XDP) causes adult-onset progressive dystonia and parkinsonism, which may not respond to pharmacotherapy. OBJECTIVE: Previous case reports have reported beneficial effects from bilateral pallidal (GPi) deep brain stimulation (DBS). Here, we report the long-term clinical outcomes of 3 patients treated at our center. METHODS: All patients presented with medication refractory dystonia and parkinsonism. They were followed prospectively. Clinical evaluations included the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS). Adverse events were recorded. RESULTS: The average length of follow-up was 45.7 months. No serious adverse events occurred. All patients experienced an immediate and sustained improvement in dystonia. Mean percentage improvement in motor subscores of BFMDRS was 63.5% at the last follow-up visit. Parkinsonism was less responsive to neuromodulation, with a mean improvement in UPDRS-III of 39.5%. Standard pallidal stimulation parameters were used. Freezing of gait developed after DBS therapy in 2 patients, stimulation-induced in one and due to disease progression in the other. CONCLUSION: Bilateral pallidal DBS resulted in significant and sustained improvement in dystonia and moderate improvement in parkinsonism. Pallidal DBS represents an important treatment option for XPD for the management of motor symptoms.


Assuntos
Estimulação Encefálica Profunda/tendências , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/terapia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Globo Pálido/fisiologia , Adulto , Estimulação Encefálica Profunda/métodos , Distúrbios Distônicos/complicações , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/terapia , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
10.
Clin Transl Gastroenterol ; 9(10): 201, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30385752

RESUMO

OBJECTIVE: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disease caused by mutations in the forkhead box protein 3 gene (FOXP3), which encodes a key regulator of immune tolerance. The aim of this study was to describe the clinical heterogeneity of the disease in a national French cohort. METHODS: Multicenter retrospective study of patients diagnosed with IPEX syndrome caused by mutations in FOXP3. RESULTS: Thirty children from 26 families were included. Age at disease onset (median [first to third quartile]) was 1.5 mo [0-84] and at death 3.5 years [0-10.5] (n = 15) indicating a high heterogeneity. Initial presentation was diarrhoea (68%), type 1 diabetes (T1D; 25%), skin lesions (7%) and nephropathy (3%). During the course of the disease the following main symptoms were observed: diarrhoea (100%), skin lesions (85%), T1DM (50%), severe food allergies (39%), haematological disorders (28%), nephropathies (25%), hepatitis (14%) as well as the presence of a variety of autoantibodies. Immunosuppressive mono- or combination therapy led to improvement in eight children. Three boys displayed a stable disease course without any immunosuppressive medication. Overall 10-year survival rate was 43% (42% in transplanted patients and 52% in patients on immunosuppressive therapy). Five out of 22 identified FOXP3 mutations have not been described yet: c.-23 + 1G > A, c.-23 + 5G > A, c.264delC, c.1015C > T and c.1091A > G. The first two produced atypical, attenuated phenotypes. Missense and frameshift mutations affecting the forkhead domain were associated with poor survival (Gehan-Wilcoxon p = 0.002). CONCLUSION: The broad phenotypic heterogeneity of IPEX raises questions about modifying factors and justifies early FOXP3 sequencing in suspected cases.


Assuntos
Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Enteropatias/genética , Poliendocrinopatias Autoimunes/genética , Autoanticorpos/sangue , Variação Biológica da População , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diarreia/genética , Fatores de Transcrição Forkhead/imunologia , França , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Imunossupressão , Lactente , Recém-Nascido , Enteropatias/imunologia , Enteropatias/terapia , Nefropatias/genética , Masculino , Mutação , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/terapia , Estudos Retrospectivos , Dermatopatias Genéticas/genética , Taxa de Sobrevida , Síndrome
11.
Clin Immunol ; 197: 219-223, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30368009

RESUMO

Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation.


Assuntos
Agamaglobulinemia/imunologia , Autoimunidade/imunologia , Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/congênito , Diarreia/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças do Sistema Imunitário/congênito , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Agamaglobulinemia/terapia , Anemia Hemolítica Autoimune/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Diarreia/genética , Diarreia/terapia , Eczema/imunologia , Família , Feminino , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Heterozigoto , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Switching de Imunoglobulina/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Enteropatias/imunologia , Masculino , Pessoa de Meia-Idade , Linhagem , Pneumonia/imunologia , Recidiva , Sinusite/imunologia , Adulto Jovem
12.
Curr Opin Allergy Clin Immunol ; 18(6): 453-458, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30299399

RESUMO

PURPOSE OF REVIEW: Conventional gene therapy has been a successful, curative treatment modality for many primary immune deficiencies with significant improvements in the last decade. However, the risk of leukemic transformation with viral-mediated gene addition still remains, and unregulated gene addition is not an option for certain diseases in which the target gene is closely controlled. The recent bloom in genome modification platforms has created the opportunity to site-specifically correct mutated DNA base pairs or insert a corrective cDNA minigene while maintaining gene expression under control of endogenous regulatory elements. RECENT FINDINGS: There is an abundance of ongoing research utilizing programmable nucleases to facilitate site-specific gene correction of many primary immune deficiencies including X-linked severe combined immune deficiency, X-linked chronic granulomatous disease, Wiskott-Aldrich syndrome, X-linked hyper-IgM syndrome, X-linked agammaglobulinemia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked. In all, these studies have demonstrated the ability to integrate corrective DNA sequences at a precise location in the genome at rates likely to either cure or ameliorate disease. SUMMARY: Gene editing for primary immune deficiency (PID) has advanced to the point to that translation to clinical trials is likely to occur in the next several years. At the current pace of research in DNA repair mechanisms, stem cell biology, and genome-editing technology, targeted genome modification represents the next chapter of gene therapy for PID.


Assuntos
Agamaglobulinemia , Edição de Genes/métodos , Doenças Genéticas Ligadas ao Cromossomo X , Terapia Genética/métodos , Síndrome de Wiskott-Aldrich , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Animais , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/imunologia , Síndrome de Wiskott-Aldrich/terapia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia
13.
Pan Afr Med J ; 30: 9, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123412

RESUMO

Rickets are abnormalities of mineralization that can lead to bone fractures and deformities. Vitamin-resistant rickets is defined as any rickets not prevented by regular, early and prolonged administration of vitamin D and not cured by a sufficient total dose. The aim of our work is to describe the clinical, paraclinical and therapeutic aspects of X-linked hypophosphatemic rickets (XLHR), which is the most common cause of hereditary rickets and on the other hand to highlight the interest not only of the early care but also the regular long-term monitoring of these children.


Assuntos
Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Vitamina D/administração & dosagem , Adolescente , Criança , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/terapia , Seguimentos , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Masculino
16.
Rinsho Ketsueki ; 59(4): 401-406, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29743399

RESUMO

A 45-year-old man presented with fatigue and pain in the finger joints. Despite having a history of suspected sideroblastic anemia since the age of 18 years, he had not been followed up for years. Upon presentation, laboratory data revealed microcytic anemia and elevated serum ferritin levels. In addition, ringed sideroblasts were increased in the bone marrow. A liver biopsy revealed hemochromatosis and cirrhosis. Furthermore, genetic analysis revealed that he harbored the ALAS2 R452H mutation, leading to the diagnosis of X-linked sideroblastic anemia (XLSA). Accordingly, oral folate or vitamin (Vit) B12 was administered, but his anemia did not respond. However, his hemoglobin level increased from 7 to 11 g/dl with an additional prescription of oral VitB6, which facilitated the patient to undergo phlebotomy to ameliorate organ dysfunctions caused by iron overload. Previous research has revealed that ALAS2 R452 mutations confer poor responses to VitB6 therapy. Hence, accrual of patients with an unexpectedly better response, which was observed in our case, may help elucidate the pathogenesis of and therapies for XLSA.


Assuntos
Anemia Sideroblástica/terapia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Vitamina B 6/uso terapêutico , 5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
17.
Hum Gene Ther Clin Dev ; 29(2): 69-79, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29664709

RESUMO

Chronic granulomatous disease (CGD) is a debilitating primary immunodeficiency affecting phagocyte function due to the absence of nicotinamide dinucleotide phosphate (NADPH) oxidase activity. The vast majority of CGD patients in the Western world have mutations within the X-linked CYBB gene encoding for gp91phox (NOX2), the redox center of the NADPH oxidase complex (XCGD). Current treatments of XCGD are not entirely satisfactory, and prior attempts at autologous gene therapy using gammaretrovirus vectors did not provide long-term curative effects. A new strategy was developed based on the use of the lentiviral vector G1XCGD expressing high levels of the gp91phox transgene in myeloid cells. As a requisite for a clinical trial approval, standardized non-clinical studies were conducted in vitro and in mice in order to evaluate the pharmacodynamics and biosafety of the vector and the biodistribution of G1XCGD-transduced cells. Transduced CD34+ cells derived from XCGD patients engrafted and differentiated similarly to their non-transduced counterparts in xenograft mouse models and generated therapeutically relevant levels of NADPH activity in myeloid cells expressing gp91phox. Expression of functional gp91phox in hematopoietic cells did not affect their homing properties, which engrafted at high levels in mice. Extensive in vitro and in vivo genotoxicity studies found no evidence for adverse mutagenesis related to vector treatment. These studies paved the way for the approval of clinical trials in Europe and in the United States for the treatment of XCGD patients with G1XCGD gene-modified autologous hematopoietic cells.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Doença Granulomatosa Crônica/genética , NADPH Oxidase 2/genética , NADPH Oxidases/genética , Animais , Ensaios Clínicos como Assunto , Regulação da Expressão Gênica/efeitos dos fármacos , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Terapia Genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/efeitos adversos , Doença Granulomatosa Crônica/patologia , Doença Granulomatosa Crônica/terapia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Xenoenxertos , Humanos , Lentivirus/genética , Camundongos , NADPH Oxidase 2/administração & dosagem
19.
Klin Monbl Augenheilkd ; 235(3): 281-289, 2018 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-29390235

RESUMO

Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous group of non-progressive retinal disorder with largely normal fundus appearance. The mode of inheritance can be autosomal dominant (adCSNB), autosomal recessive (arCSNB) or X-chromosomal (XLCSNB). Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity. The Riggs and Schubert-Bornschein form of CSNB can be discriminated by electroretinography. While the Riggs form represents a dysfunction of the rods, a signal transmission defect from photoreceptors to bipolar cell is described in patients with the more frequently occurring Schubert-Bornschein form. The Schubert-Bornschein form can be further divided into incomplete (icCSNB) and complete (cCSNB) showing different electroretinograms (ERGs). While patients with cCSNB show a dysfunction of the ON-signaling pathway, patients with icCSNB show a dysfunction of the ON- and OFF-signaling pathways, affecting visual acuity as well. Using classical linkage, candidate gene analyses and more recent next-generation sequencing approaches, to date, mutations in 13 different genes have been associated with this disease. In vitro and in vivo models showed a correlation of the phenotype of patients with the expression, protein localization and function of the respective molecules: genes, mutated in patients with the Riggs form of CSNB have an important role in the rod phototransduction cascade. Genes mutated in patients with icCSNB, code for proteins important for glutamate neurotransmitter release at the synaptic cleft of the photoreceptors. Genes mutated in patients with cCSNB, code for proteins important for glutamate uptake and further signal transmission to the ON-bipolar cells. Preliminary in vivo studies showed that CSNB may be cured by gene therapy. These studies concerning CSNB are important for the precise diagnosis of patients with this disease, but are also helpful in deciphering key molecules essential for signal transmission from photoreceptors to bipolar cells. So far, it is a poorly understood field.


Assuntos
Oftalmopatias Hereditárias/diagnóstico , Fundo de Olho , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Miopia/diagnóstico , Cegueira Noturna/diagnóstico , Aberrações Cromossômicas , Eletrorretinografia , Oftalmopatias/classificação , Oftalmopatias/diagnóstico , Oftalmopatias/genética , Oftalmopatias Hereditárias/classificação , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/terapia , Genes Dominantes , Genes Recessivos , Genes Ligados ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/classificação , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Terapia Genética , Genótipo , Miopia/classificação , Miopia/genética , Miopia/terapia , Cegueira Noturna/classificação , Cegueira Noturna/genética , Cegueira Noturna/terapia , Fenótipo
20.
Am J Med Genet A ; 176(3): 733-738, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29392821

RESUMO

Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD syndrome) is a rare X-linked dominant genodermatosis caused by mutations in the NAD(P) dependent steroid dehydrogenase-like protein gene. Its defect leads to accumulation of toxic metabolic intermediates upstream from the pathway block and to the deficiency of bulk cholesterol, probably leading to altered keratinocyte membrane function, resulting in the phenotype seen in CHILD syndrome. Symptomatic treatment using emollients and retinoids to reduce scaling has long been used until recently, whereby new therapeutic means based on the pathogenesis-targeted therapy have been developed. We subsequently chose to use the same pathogenesis-based therapy using a 2% cholesterol and 2% lovastatin cream with or without glycolic acid in two of our patients. Improvement in CHILD skin lesions was seen as early as 4 weeks after initiation. The addition of glycolic acid helped improve the penetrance of the cholesterol and lovastatin cream into the thick waxy scales. Our study confirms the efficacy of the pathogenesis-targeted therapy and introduces the possibility of modifying its formula by adding glycolic acid in order to improve the treatment.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Eritrodermia Ictiosiforme Congênita/diagnóstico , Eritrodermia Ictiosiforme Congênita/genética , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , 3-Hidroxiesteroide Desidrogenases/genética , Anormalidades Múltiplas/terapia , Biópsia , Criança , Colesterol/administração & dosagem , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Eritrodermia Ictiosiforme Congênita/terapia , Deformidades Congênitas dos Membros/terapia , Lovastatina/administração & dosagem , Mutação , Fenótipo , Pele/patologia , Resultado do Tratamento
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