ABSTRACT
Background and Objectives: Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by the loss or presence of point pathogenic variants in the SMN1 gene. The main positive modifier of the SMA phenotype is the number of copies of the SMN2 gene, a paralog of SMN1, which only produces around 10%-15% of functional SMN protein. The SMN2 copy number is inversely correlated with phenotype severity; however, discrepancies between the SMA type and the SMN2 copy number have been reported. The presence of SMN2-SMN1 hybrids has been proposed as a possible modifier of SMA disease. Methods: We studied 31 patients with SMA, followed at a single center and molecularly diagnosed by Multiplex Ligand-Dependent Probe Amplification (MLPA), with a specific next-generation sequencing protocol to investigate their SMN2 genes in depth. Hybrid characterization also included bioinformatics haplotype phasing and specific PCRs to resolve each SMN2-SMN1 hybrid structure. Results: We detected SMN2-SMN1 hybrid genes in 45.2% of the patients (14/31), the highest rate reported to date. This represents a total of 25 hybrid alleles, with 9 different structures, of which only 4 are detectable by MLPA. Of particular interest were 2 patients who presented 4 SMN2-SMN1 hybrid copies each and no pure SMN2 copies, an event reported here for the first time. No clear trend between the presence of hybrids and a milder phenotype was observed, although 5 of the patients with hybrid copies showed a better-than-expected phenotype. The higher hybrid detection rate in our cohort may be due to both the methodology applied, which allows an in-depth characterization of the SMN genes and the ethnicity of the patients, mainly of African origin. Discussion: Although hybrid genes have been proposed to be beneficial for patients with SMA, our work revealed great complexity and variability between hybrid structures; therefore, each hybrid structure should be studied independently to determine its contribution to the SMA phenotype. Large-scale studies are needed to gain a better understanding of the function and implications of SMN2-SMN1 hybrid copies, improving genotype-phenotype correlations and prediction of the evolution of patients with SMA.
ABSTRACT
Epilepsy surgery may be a curative therapy for patients with drug-resistant epilepsies when focal lesions or foci are identified. Genetic testing is not yet routinely included in many presurgical evaluation programs although recent evidence support that finding a germline genetic mutation could help to better delineate the patient candidacy to surgery and provide valuable information on the expected surgery outcome. In this study, we report nine patients presenting drug-resistant focal epilepsy enrolled in presurgical evaluation. We show how the identification of genetic pathogenic variant in epilepsy known genes led to the interruption of the presurgical work-up and ruled out surgery in 7 of them. We observed that the co-existence of some recurrent clinical characteristics as early seizures' onset, frequent precipitating factors including fever, and developmental delay or intellectual disability may be useful markers for germline genetic pathogenic variants. In this group, genetic assessment should be mandatory during presurgical work up, mainly in patients with negative magnetic resonance imaging (MRI) or doubtful structural lesions. The integration of next generation targeted sequencing into the presurgical evaluation can improve the selection of candidates for resective surgery and fosters a personalized medicine approach with a better outcome. PLAINE LANGUAGE ABSTRACT: Genetic testing is not yet systematically included in the pre-surgical assessment of patients with drug-resistant focal epilepsies. In this study, through the description of nine patients, we underline how the integration of genomics into the presurgical work up can help in evaluating the patient candidacy to surgery and provide valuable information on expected surgery outcome.
ABSTRACT
El liquen estriado es una genodermatosis inflamatoria lineal de carácter benigno que suele ser autolimitada. Habitualmente se presenta en la edad preescolar y es más frecuente en el sexo femenino. Clínicamente se caracteriza por pápulas de 2 a 4 mm de diámetro que forman bandas siguiendo las líneas de Blaschko. Suelen ser lesiones únicas y unilaterales. Afecta generalmente a las extremidades. El diagnóstico suele ser clínico y no requiere pruebas complementarias. Presentamos el caso de una niña de seis años con una lesión lineal en la extremidad inferior formada por pápulas rosadas que siguen las líneas de Blaschko y se extienden desde el maléolo interno al muslo, sin antecedente traumáticos. No existen otros antecedentes patológicos de interés. Ante este tipo de lesiones se debe realizar el diagnóstico diferencial con las patologías que siguen las líneas de Blaschko como nevus epidérmico verrucoso lineal, incontinencia pigmenti, enfermedad de Darier lineal, poroqueratosis lineal e hipomelanosis de Ito, entre otras, aunque la morfología es muy típica y en los casos de lesiones únicas, en niñas, lineales y en extremidades inferiores no ofrece grandes problemas diagnósticos
Lichen striatus is a linear self-limited inflammatory genodermatosis. It mostly affects preschoolers, more often in females. It is characterized by pagues of 2-4 mm organized in linear bands following the lines of Blaschko. These findings are usually unique and unilateral, affecting principally extremities. The diagnosis is clinical, no requiring complementary tests. We present the case of a six-year-old girl with a linear lesion consisting in pink papules following the Blaschko's lines, starting in the internal malleolus of the lower extremity and spreading to the thigh. No history of traumatic event at that level. No other pathological background of interest. Comments: the differential diagnosis of lichen striatus includes other dermatoses that follow the Blaschko lines such as inflammatory linear verrucous epidermal naevus, incontinentia pigmenti, linear Darier's disease, linear porokeratosis, or hypomelanosis of Ito. The morphology of the lesions is characteristic, so cases of single lesions, linear, in lower extremities and in girls should not offer great diagnostic problems
Subject(s)
Humans , Female , Child , Lichenoid Eruptions/diagnosis , Skin Diseases, Papulosquamous/diagnosis , Nevus/diagnosis , Dermatitis/diagnosis , Diagnosis, DifferentialABSTRACT
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