A Comprehensive Review of Fragile X Syndrome and Fragile X Premutation Associated Conditions in Africa.

Fragile X syndrome (FXS) is a genetic disorder caused by a mutation in the fragile X messenger ribonucleoprotein 1 (FMR1) gene and known to be a leading cause of inherited intellectual disability globally. It results in a range of intellectual, developmental, and behavioral problems. Fragile X premutation-associated conditions (FXPAC), caused by a smaller CGG expansion (55 to 200 CGG repeats) in the FMR1 gene, are linked to other conditions that increase morbidity and mortality for affected persons. Limited research has been conducted on the burden, characteristics, diagnosis, and management of these conditions in Africa. This comprehensive review provides an overview of the current literature on FXS and FXPAC in Africa. The issues addressed include epidemiology, clinical features, discrimination against affected persons, limited awareness and research, and poor access to resources, including genetic services and treatment programs. This paper provides an in-depth analysis of the existing worldwide data for the diagnosis and treatment of fragile X disorders. This review will improve the understanding of FXS and FXPAC in Africa by incorporating existing knowledge, identifying research gaps, and potential topics for future research to enhance the well-being of individuals and families affected by FXS and FXPAC.

Ovarian reserve in patients with FMR1 gene premutation and the role of fertility preservation.

INTRODUCTION: Women with premutation (PM) of the FMR1 gene may suffer from reduced ovarian reserve or even premature ovarian insufficiency (POI). We studied hormonal and ultrasound ovarian reserve, fertility and fertility preservation outcomes in these patients. PATIENTS AND METHOD: Retrospective cohort study of 63 female FMR1 premutation carriers. RESULTS: Sixty-three female patients bearing an FMR1 premutation were included. Median age was 30 years [26.5-35]. Median number of CGG triplets was 83 [77.2-92]. Before diagnosis of PM, 19 women (30%) had had in all 35 pregnancies, resulting in 20 births, including 7 affected children. After diagnosis of PM, 17 women (26.1%) had in all 23 pregnancies, at a median age of 34.5 years [32.2-36.0]: 2 after pre-implantation genetic diagnosis, 3 after oocyte donation, 18 spontaneously, and 5 ending in medical termination for fragile X syndrome. Thirty-three patients (52.4%) had POI diagnosis (median age, 30 years [27-34]) with median FSH level 84 IU/L [50.5-110] and median AMH level 0.08ng/mL [0.01-0.19]. After POI diagnosis, 8 women had in all 9 pregnancies: 3 following oocyte donation, and 6 spontaneous in 5 women (15.1%). Eight of the 9 pregnancies resulted in a live birth (including 2 affected children) and 1 in medical termination for trisomy 13. The median age of the 30 patients without POI was 31 years [25.2-35.0]. Thirteen women (20.6%) underwent fertility preservation, at a median age of 29 years [24-33]: FSH 7.7 IU/L [6.8-9.9], AMH 1.1ng/mL [0.95-2.1], antral follicle count 9.5 [7.7-14.7]. A median 15 oocytes [10-26] were cryopreserved in a median 2 cycles [1-3]. At the time of writing, no oocytes had yet been thawed for in-vitro fertilization. CONCLUSIONS: This study shows the importance of early fertility preservation after diagnosis of FMR1 premutation in women, due to early deterioration of ovarian reserve. Genetic counseling is essential in these patients, as spontaneous pregnancies are not uncommon, even in cases of impaired ovarian reserve, and can lead to birth of affected children.

Fragile X syndrome in the largest world clustering. I. Genetic epidemiology and founder effect outline.

The FMR1 5' regulation gene region harbors a CGG trinucleotide repeat expansion (CGG-TRE) that causes Fragile X syndrome (FXS) when it expands to more than 200 repetitions. Ricaurte is a small village in southwestern Colombia, with an FXS prevalence of 1 in 38 men and 1 in 100 women (~100 times higher than the worldwide reported prevalence), defining Ricaurte as the largest FXS cluster in the world. In the present study, using next-generation sequencing of whole exome capture, we genotype 55 individuals from Ricaurte (49 with either full mutation or with premutation), four individuals from neighboring villages (with either the full mutation or with the premutation), and one unaffected woman, native of Ricaurte, who did not belong to any of the affected families. With advanced clustering and haplotype reconstruction, we modeled a common haplotype of 33 SNPs spanning 83,567,899 bp and harboring the FMR1 gene. This reconstructed haplotype was found in all the men from Ricaurte who carried the expansion, demonstrating that the genetic conglomerate of FXS in this population is due to a founder effect. The definition of this founder effect and its population outlining will allow a better prediction, follow-up, precise and personalized characterization of epidemiological parameters, better knowledge of the disease's natural history, and confident improvement of the clinical attention, life quality, and health interventions for this community.

Características físicas e bucais na síndrome do X frágil: revisão de literatura / Physical and oral characteristics of fragile X syndrome: literature review

Introdução: A síndrome do cromossomo X frágil é uma síndrome genética que acomete principalmente indivíduos do sexo masculino. O nome desta síndrome ocorre como consequência de um estreitamento da extremidade distal do braço longo do cromossomo X, local chamado de sítio frágil. O presente trabalho apresenta uma revisão de literatura, apresentando etiologia, prevalência, métodos de diagnósti-co, características comportamentais, características físicas gerais e de interesse odontológico, além das considerações acerca do atendimento, realizado pelo cirurgião-dentista, em portadores da síndrome do X frágil. Revisão de literatura: As principais características comportamentais são o déficit de atenção, a dificuldade na interação social, a timidez, a ansiedade, a labilidade emocional e os movimentos este-reotipados de mãos. Os achados de interesse odontológico mais prevalentes na literatura foram palato ogival, prog-natismo mandibular, macroglossia, hipoplasia de esmalte e má oclusão. Discussão: Não foram encontrados muitos artigos voltados para a análise facial e odontológica destes pacientes. O atendimento deste público é um desafio para o cirurgião-dentista devido às características comportamentais e fisiológicas apresentadas. Conclusão: o conhecimento das características desta síndrome pelo profissional é impor-tante, pois a síndrome comumente se associa à doenças sistêmicas que podem influenciar no plano de tratamento, além de alterações orofaciais importantes.

Introduction: The fragile X syndrome is a genetic syn-drome that mainly affects males. The name of this syn-drome occurs as a consequence of a narrowing of the distal end of the long arm of the X chromosome, a site called the fragile site. This paper presents a review of the literature, presenting etiology, prevalence, diagnostic methods, behavioral characteristics, general physical characteristics and dental interest, as well as considera-tions about the care provided by the dentist in patients with fragile X syndrome. Literature review: The main behavioral characteristics are attention deficit, difficulty in social interaction, shyness, anxiety, emotional lability and stereotyped hand movements. The most prevalent findings of dental interest in the literature were the ogival palate, mandibular prognathism, macroglossia, enamel hypoplasia and malocclusion. Discussion: There were not many articles focused on facial and dental analysis of these patients. The care of this public is a challenge for the dentist due to the behavioral and physiological characteristics presented. Conclusion: professional know-ledge of the characteristics of this syndrome is important, as the syndrome is commonly associated with systemic diseases that may influence the treatment plan, as well as major orofacial changes.

Metabolic screening and metabolomics analysis in the Intellectual Developmental Disorders Mexico Study / Tamiz bioquímico y metabolómico en el estudio de los trastornos del desarrollo intelectual en México

Abstract: Objective: Inborn errors of metabolism (IEM) are genetic conditions that are sometimes associated with intellectual developmental disorders (IDD). The aim of this study is to contribute to the metabolic characterization of IDD of unknown etiology in Mexico. Materials and methods: Metabolic screening using tandem mass spectrometry and fluorometry will be performed to rule out IEM. In addition, target metabolomic analysis will be done to characterize the metabolomic profile of patients with IDD. Conclusion: Identification of new metabolomic profiles associated with IDD of unknown etiology and comorbidities will contribute to the development of novel diagnostic and therapeutic schemes for the prevention and treatment of IDD in Mexico.

Resumen: Objetivo: Los errores innatos del metabolismo (EIM) son condiciones genéticas que pueden asociarse con trastornos del desarrollo intelectual (TDI). El objetivo de este estudio es contribuir a la caracterización metabólica de los pacientes con TDI de etiología desconocida. Material y métodos: Se realizará un tamiz metabólico mediante espectrometría de masas-tándem y fluorometría para descartar EIM; además, se analizará el perfil metabolómico de los pacientes con TDI. Conclusión: La identificación de perfiles metabolómicos asociados con los TDI de etiología desconocida contribuirá al desarrollo de nuevos esquemas diagnósticos y terapéuticos para la prevención y tratamiento de los TDI en México.

Primeras manifestaciones clínicas de un síndrome de X frágil en la comunidad / First clinical manifestations of a case of fragile X syndrome in the community

Fundamento: el síndrome del X frágil es el más común de los trastornos de retraso mental ligados al cromosoma X.Objetivo: presentar las primeras manifestaciones clínicas de un caso de síndrome de X frágil que no comenzó con retardo del desarrollo psicomotor.Caso clínico: paciente que es remitido a consulta de genética por presentar macrocráneo y orejas displásicas en forma de copa. Al año y seis meses presentó retardo del desarrollo psicomotor. El examen físico, los exámenes complementarios dieron el diagnóstico de un síndrome del X Frágil. Se le puso tratamiento en consulta de estimulación temprana y el paciente mejoró el desarrollo psicomotor.Conclusiones: la aparición de macrocefalia y el retardo del desarrollo psicomotor contribuyeron a realizar el diagnóstico oportuno de esta enfermedad. La estimulación temprana permitió avances en el desarrollo psicomotor del paciente(AU)

Background: fragile X Syndrome is the most common mental retardations disorders linked to X chromosome.Objective: to show the first clinical manifestations of a case of Fragile X Syndrome case that did not began with psychomotor development retardation.Clinical case: a patient who is transferred to genetic consult for presenting macrocranium, dysplastic ears in form of cup. Aged one year and six month old, he had psychomotor development retardation. Physical examinations and complementary test confirmed Fragile X Syndrome diagnosis. The patient was treated in early stimulation consult which improved the psychomotor development retardation.Conclusions: the presence of macrocephaly and later psychomotor development retardation helped to make the appropriate diagnosis of that disorder. Early stimulation permitted advances in psychomotor development in this patient(AU)

Sindrome do X fragil: relato de caso em dois irmaos / Fragile X syndrome: case report in two brothers

Objetivos: Alertar os pediatras para o fenótipo dos pacientes portadores da Síndrome do X Frágil, devido a sua alta incidência e aos graus variáveis de incapacidade que podem decorrer da mesma. Métodos: Relato de caso de dois irmäos que apresentavam achados clássico da Síndrome do X Frágil (retardo mental, orelhas proeminentes, macrorquidismo, dentre outros), comprovados por estudo citogenético. Resultados: O diagnóstico da síndrome é baseado na presenca de uma proporçäo variável de células com sítio frágil no cromossomo X na regiäo Xq27.3. A análise do DNA confirmou a presença de sítio frágil no cromossomo X em 14 por cento das metáfases dos irmäos e em 1 por cento nas da mäe. Detectaram-se, também, dois primos maternos portadores da síndrome, confirmada em estudo genético...

Fragile x syndrome among mentally retarded children Guadeloupe, French West Indies

Fragile x syndrome (FXS) is the most frequent cause of inherited mental retardation (1:1500 males, 1:2500 females) and affects all ethnic groups. Recent demonstration of an original genetic basis, involving expansion of a (CGG)n repeat in affected individuals, has allowed development of efficient, specific and sensitive laboratory procedures of DNA analysis. Diagnosis of FXS has important implications in terms of genetic counselling. We have conducted a screening survey of FXS (and FRAXE) in Guadeloupe, among 138 boys and 88 girls affected with moderate to severe mental retardation and attending special schools. Using the procedure described by Wang et al (1995), with modifications, in order to estimate prevalence of FXS among these children and compare it to prevalences observed among Caucasian populations identify FXS index cases allowing for genetic counseling for their families and evaluate systematic screening for FXS and FRAXE using DNA analysis. We found a prevalence of FXS of 5.7 percent among boys and 0 percent among girls (3.5 percent overall); none of these cases was already known. No FRAXE case was identified. These results are consistent with other similar surveys concerning Caucasian populations. This study, like others, has demonstrated the efficiency, acceptablility and usefulness on DNA analysis for FXS screening (AU)