Classic and Atypical Late Infantile Neuronal Ceroid Lipofuscinosis in Latin America: Clinical and Genetic Aspects, and Treatment Outcome with Cerliponase Alfa.

Introduction: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), is a neurodegenerative autosomal recessive disease caused by TPP1 gene variants, with a spectrum of classic and atypical phenotypes. The aim of treatment is to slow functional decline as early as possible in an attempt to improve quality of life and survival. This study describes the clinical characteristics as well as the response to treatment with cerliponase alfa. Materials and methods: A retrospective study was conducted in five Latin-American countries, using clinical records from patients with CLN2. Clinical follow-up and treatment variables are described. A descriptive and bivariate statistical analysis was performed. Results: A total of 36 patients were observed (range of follow-up of 61-110 weeks post-treatment). At presentation, patients with the classic phenotype (n = 16) exhibited regression in language (90%), while seizures were the predominant symptom (87%) in patients with the atypical phenotype (n = 20). Median age of symptom onset and time to first specialized consultation was 3 (classical) and 7 (atypical) years, while the median time interval between onset of symptoms and treatment initiation was 4 years (classical) and 7.5 (atypical). The most frequent variant was c.827 A > T in 17/72 alleles, followed by c.622C > T in 6/72 alleles. All patients were treated with cerliponase alfa, and either remained functionally stable or had a loss of 1 point on the CLN2 scale, or up to 2 points on the Wells Cornel and Hamburg scales, when compared to pretreatment values. Discussion and conclusion: This study reports the largest number of patients with CLN2 currently on treatment with cerliponase alfa in the world. Data show a higher frequency of patients with atypical phenotypes and a high allelic proportion of intron variants in our region. There was evidence of long intervals until first specialized consultation, diagnosis, and enzyme replacement therapy. Follow-up after the initiation of cerliponase alfa showed slower progression or stabilization of the disease, associated with adequate clinical outcomes and stable functional scores. These improvements were consistent in both clinical phenotypes.

Genotype and Phenotype Characterization of Patients with Mucopolysaccharidosis IV-A in Chile.

Introduction: Morquio syndrome or mucopolysaccharidosis type IV-A (MPS IV-A) is an autosomal recessive disease caused by biallelic variants in the GALNS gene, encoding the lysosomal enzyme GalN6S, responsible for glycosaminoglycan keratan sulfate and chondroitin-6-sulfate degradation. Studies have shown that the degree of evolutionary and chemical divergence of missense variants in GalN6S when compared to ancestral amino acids is associated with the severity of the syndrome, suggesting a genotype-phenotype correlation. There is little information on Latin American patients with MPS IV-A that replicate these findings. This study aimed to characterize the phenotype and genotype from patients with MPS IV-A, who are under Enzyme Replacement Therapy at the Children's Neuropsychiatry Service of the Hospital Clínico San Borja Arriarán, Santiago, Chile, and to determine if there is any association between genotype and phenotype with those findings. Methods: Information was collected from medical charts, all patients went through a GalN6S enzymatic activity measurement in leukocytes from peripheral blood, and the GALNS gene was sequenced for all cases. Results: 12 patients with MPS IV-A were recruited, all patients presented multisystem involvement, mostly skeletal, and 75% of cases underwent surgical interventions, and cervical arthrodesis was the most frequent procedure. In regards of the genotype, the two most frequent variants were c.319+2T>C (n = 10, 41.66%) and p.(Arg386Cys) (n = 8, 33.33%), the first one was previously described in 2018 in a patient from Chile [Bochernitsan et al., 2018]. Conclusion: This is the first time that a genotype-phenotype correlation has been studied by analyzing the variants effect on the molecular structure of human GalN6S and the evolutionary conservation degree of affected residues in a cohort of patients in Chile. Albeit our work could not find statistically significant associations, we may infer that the evolutionary conservations of affected amino acids and the effect of variants on enzyme structure may play a main role. Further analyzes should consider a meta-analysis of published cases with genotype data and larger samples and include other variables that could provide more information. Finally, our data strongly suggest that variant c.319+2T>C could have a founder effect in Chilean patients with MPS IV-A.

Síndrome de Williams: características clínicas de tres casos / Williams syndrome: clinical characteristics of three cases

El Síndrome de Williams (SW) es un síndrome genético generado por la deleción del gen de la Elastina y genes contiguos del cromosoma 7q11.23. Tiene una incidencia de 1:7500-20.000 recién nacidos vivos. Se caracteriza por un conjunto de síntomas y signos con compromiso multiorgánico y un fenotipo conductual distintivo. Objetivo: Describir la clínica del SW en relación a tres casos clínicos. Método: Estudio descriptivo retrospectivo de fichas clínicas de pacientes estudiados y tratados entre el 2006 y 2012. Resultados: Tres varones con rango de edad entre 4 y 6 años. Todos presentaron dismorfias características y se asociaron a cardiopatía congénita: estenosis aórtica supravalvular. En los rasgos de personalidad destacaron alta sociabilidad y habilidades en lenguaje expresivo, RM leve a moderado y mala coordinación motora. Conclusión: Todos nuestros pacientes presentaron características concordantes con las descritas para SW. Existen alteraciones funcionales cerebrales en pacientes con SW que tienen relación con el perfil cognitivo observado.

Williams Syndrome (WS) is a genetic disorder caused by deletion of elastine gene and contiguous genes of chromosome 7q11.2. It has an incidence of 1:7.500-20.000 newly born. It is characterized by a group of symptoms and signs with multiorganic involvement and a distinctive behavioural phenotype. Objective: To describe the clinical manifestations of WS in relation to three case reports. Method: review of clinical reports of patients diagnosed and treated between 2006 and 2012. Results: Three boys aged 5-9 years, all of them presented distinctive appearance, associated to congenital heart disease: aortic supravalvular stenosis. Behavioral features included high sociability and expressive language skills, mental retardation and poor motor coordination. Conclusions: All of our patients had clinical characteristics corresponding to the ones described for WS in the literature. The peculiar cognitive profile is presumed to be related to functional brain alterations described in WS.

Calidad de vida en pacientes con discapacidad motora según factores sociodemográficos y salud mental / Quality of life in motor-handicapped patients according to socio-demographic factors and mental health

It is estimated that there are presently over one thousand million people worldwide living with some kind of disability. In Chile, there are very few studies on this topic without conceptual uniformity. Since 2004, the prevalence is estimated in 12,9 percent (1). Objectives: Study a sample population taken from the Metropolitan Region of Santiago, Chile, of individuals over 18 years of age who have some kind of motor disability, and observe the relationship with quality of life according to different indicators: time with their disability, mental health and sociodemographic factors. Methodology: This study is a descriptive, transverse correlation. The questionnaires used were the SF- 36 questionnaire for Quality of Life, the Barthel Index for motor disability and the GHQ12 Goldbergfor mental illness. Results: No significant results were found between individuals with an altered mental health (Goldberg ≥ 5) and individuals with some level of dependence on the Barthel Index Scale (Fisher Test = 0.34). There is a 10-point difference in the physical component of the SF-36 questionnaire between individuals with mental health alteration and those without: however, this value is not statistically significant (p = 0.06). Quality of life is lower with regard to the physical component of the SF- 36 as educational level rises: these results are statistically significant. Conclusion: There is no statistical significance between quality of life and mental health alterations in disabled people. We cannot establish a relationship between altered mental health and motor disability. This study shows us the tremendous scope for research on different types of disabilities and their correlation with mental health that still remains. There are still very few studies about the latter and the time individuals have been with this condition, the differences that exist between rehabilitation centers or the differences in mental health and quality of life observed...

Las cifras mundiales de discapacidad estiman más de un millón de afectados. En Chile existen escasos estudios respecto al tema, sin uniformidad de conceptos y desde el 2004 se considera que la prevalencia es de 12,9 por ciento (4). Objetivos: Estudiar a individuos con discapacidad motora mayores de 18 años de la región Metropolitana y observar la relación entre su calidad de vida con el tiempo de discapacidad, salud mental y factores socio-demográficos. Metodología: Estudio descriptivo correlacional de corte trasversal. Se utilizaron las encuestas SF 36 para la calidad de vida, el índice de Barthel para discapacidad y la escala GHQ12 de Goldberg para la salud mental. Resultados: No se encontró una correlación estadísticamente significativa entre individuos con salud metal alterada (Goldberg ≥ 5) e individuos con algún nivel de dependencia en la escala de Barthel (Fisher = 0,34). Existe una diferencia de 10 puntos en relación al componente físico del SF-36, entre individuos con y sin alteración de la salud mental, sin embargo, esta cifra no es significativa (p = 0,06). A mayor nivel educacional, existe una menor calidad de vida según el componente físico del SF-36, con significancia estadística. Conclusiones: No se encontró diferencias significativas en relación a la salud mental y la calidad de vida de los pacientes discapacitados. No podemos inferir la relación entre salud mental alterada y discapacidad motora. Este trabajo nos muestra la necesidad de ampliar la investigación sobre la salud mental en relación a: Diversos tipos de discapacidad, tiempo de evolución de esta condición, diferencia que existe entre los distintos centros y variación entre las personas con discapacidad física que asisten o no a un centro de rehabilitación.