Novel progressive acrodysostosis-like skeletal dysplasia, cerebellar atrophy, and ichthyosis.

Acrodysostosis refers to a rare heterogeneous group of bone dysplasias that share skeletal features, hormone resistance, and intellectual disability. Two genes have been associated with acrodysostosis with or without hormone resistance (PRKAR1A and PDE4D). Severe intellectual disability has been reported with acrodysostosis but brain malformations and ichthyosis have not been reported in these syndromes. Here we describe a female patient with acrodysostosis, intellectual disability, cerebellar hypoplasia, and lamellar ichthyosis. The patient has an evolving distinctive facial phenotype and childhood onset ataxia. X-rays showed generalized osteopenia, shortening of middle and distal phalanges, and abnormal distal epiphysis of the ulna and radius. Brain magnetic resonance imaging showed cerebellar atrophy without other brainstem abnormalities. Genetic workup included nondiagnostic chromosomal microarray and skeletal dysplasia molecular panels. These clinical findings are different from any recognized form of acrodysostosis syndrome. Whole exome sequencing did not identify rare or predicted pathogenic variants in genes associated with known acrodysostosis, lamellar ichthyosis, and other overlapping disorders. A broader search for rare alleles absent in healthy population databases and controls identified two heterozygous truncating alleles in FBNL7 and PPM1M genes, and one missense allele in the NPEPPS gene. Identification of additional patients is required to delineate the mechanism of this unique disorder.

Determination of genotypic and clinical characteristics of Colombian patients with mucopolysaccharidosis IVA.

BACKGROUND: As mucopolysaccharidosis IVA (MPS IVA) is the most frequent MPS in Colombia, this paper aims to describe its clinical and mutational characteristics in 32 diagnosed patients included in this study. METHODS: Genotyping was completed by amplification and Sanger sequencing of the GALNS gene. The SWISS-model platform was used for bioinformatic analysis, and mutant proteins were generated by homology from the wild-type GALNS code 4FDI template from the Protein Data Bank (PDB) database. Docking was performed using the GalNAc6S ligand (PubChem CID: 193456) by AutoDock Vina 1.0 and visualized in PyMOL and LigPlot+. RESULTS: Eleven variants were identified, and one new pathogenic variant was described in the heterozygous state, which is consistent with genotype c. 319 G> T or p.Ala107Ser. The pathogenic variant c.901G>T or p.Gly301Cys was the most frequent mutation with 51.6% of alleles. Docking revealed affinity energy of -5.9 Kcal/mol between wild-type GALNS and the G6S ligand. Some changes were evidenced at the intermolecular interaction level, and affinity energy for each mutant decreased. CONCLUSION: Clinical variables and genotypic analysis were similar to those reported for other world populations. Genotypic data showed greater allelic heterogeneity than those previously reported. Bioinformatics tools showed differences in the binding interactions of mutant proteins with the G6S ligand, in regard the wild-type GALNS.

Genética clínica comunitaria: exploración de patología genética en Boyacá, Colombia / Clinical community genetics: exploring genetic disorders in Boyacá, Colombia

RESUMEN Objetivo Explorar la presencia de patología genética sindrómica en el Departamento de Boyacá, mediante un acercamiento de medicina genética comunitaria. Materiales y Métodos Un grupo conformado por genetistas, neurólogo pediátrico y genetista bioquímico, llevó a cabo jornadas clínicas en las cuales se evaluaron pacientes con sospecha de enfermedad genética. Se obtuvieron datos demográficos, epidemiológicos y clínicos y se realizó el cálculo de frecuencias de los mismos. En los centros de referencia visitados se realizaron actividades de capacitación al personal médico. Resultados Se encontraron dos agrupamientos genéticos: MPSIII y Síndrome de Ellis Van Creveld, con incidencias mayores a lo reportado en la literatura, además una alta frecuencia de patologías de herencia autosómica recesiva, así como sospecha de síndromes de microdeleción-microduplicación. Conclusiones Se deben establecer mecanismos no convencionales de atención médica para facilitar el acceso a las comunidades a un diagnóstico y tratamiento adecuados en genética. Se espera que el apoyo brindado a los pacientes, familias y personal asistencial de los hospitales a través de las jornadas clínicas y la capacitación, permitan alcanzar este objetivo y a la vez sea un punto de inicio de procesos de prevención primaria y secundaria.(AU)

ABSTRACT Objectives To explore the incidence of syndromic genetic pathologies in Boyacá, Colombia, through a community genetics approach. Materials and Methods A group made up by different medical specialists (geneticists, a pediatric neurologist, and a biochemical geneticist) developed clinical campaigns, in which patients with clinical suspicion of genetic diseases were involved. Demographic, epidemiological and clinical data were collected, and frequency calculations were made based on the collected data. Several training workshops for health personnel were done in each center visited. Results Two genetic clusters were found: mucopolysaccharidosis type III, and Ellis-Van Creveld Syndrome, both of them with higher incidences than those found in the literature. Also, a high frequency of autosomal recessive diseases was found, as well as microdeletion/microduplication syndromes. Conclusions Conventional mechanisms of medical attention must be established, in order to facilitate the access to an appropriate diagnosis and treatment. This work intended to provide support to patients, families and health care services personnel through the workshops and clinical campaigns, and to become a starting point to develop primary and secondary prevention processes.(AU)

[Clinical community genetics: exploring genetic disorders in Boyacá, Colombia]. / Genética clínica comunitaria: exploración de patología genética en Boyacá, Colombia.

OBJECTIVES: To explore the incidence of syndromic genetic pathologies in Boyacá, Colombia, through a community genetics approach. MATERIALS AND METHODS: A group made up by different medical specialists (geneticists, a pediatric neurologist, and a biochemical geneticist) developed clinical campaigns, in which patients with clinical suspicion of genetic diseases were involved. Demographic, epidemiological and clinical data were collected, and frequency calculations were made based on the collected data. Several training workshops for health personnel were done in each center visited. RESULTS: Two genetic clusters were found: mucopolysaccharidosis type III, and Ellis-Van Creveld Syndrome, both of them with higher incidences than those found in the literature. Also, a high frequency of autosomal recessive diseases was found, as well as microdeletion/microduplication syndromes. CONCLUSIONS: Conventional mechanisms of medical attention must be established, in order to facilitate the access to an appropriate diagnosis and treatment. This work intended to provide support to patients, families and health care services personnel through the workshops and clinical campaigns, and to become a starting point to develop primary and secondary prevention processes.

OBJETIVO: Explorar la presencia de patología genética sindrómica en el Departamento de Boyacá, mediante un acercamiento de medicina genética comunitaria. MATERIALES Y MÉTODOS: Un grupo conformado por genetistas, neurólogo pediátrico y genetista bioquímico, llevó a cabo jornadas clínicas en las cuales se evaluaron pacientes con sospecha de enfermedad genética. Se obtuvieron datos demográficos, epidemiológicos y clínicos y se realizó el cálculo de frecuencias de los mismos. En los centros de referencia visitados se realizaron actividades de capacitación al personal médico. RESULTADOS: Se encontraron dos agrupamientos genéticos: MPSIII y Síndrome de Ellis Van Creveld, con incidencias mayores a lo reportado en la literatura, además una alta frecuencia de patologías de herencia autosómica recesiva, así como sospecha de síndromes de microdeleción-microduplicación. CONCLUSIONES: Se deben establecer mecanismos no convencionales de atención médica para facilitar el acceso a las comunidades a un diagnóstico y tratamiento adecuados en genética. Se espera que el apoyo brindado a los pacientes, familias y personal asistencial de los hospitales a través de las jornadas clínicas y la capacitación, permitan alcanzar este objetivo y a la vez sea un punto de inicio de procesos de prevención primaria y secundaria.

Charcot Marie Tooth disease (CMT4A) due to GDAP1 mutation: report of a colombian family / Enfermedad de Charcot Marie Tooth (CMT4A) por mutacion en el gen GDAP1: reporte de una familia colombiana

Background: Mutations of GDAP1 gene cause autosomal dominant and autosomal recessive Charcot-Marie-Tooth disease and more than 40 different mutations have been reported. The recessive Q163X mutation has been described in patients of Spanish ancestry, and a founder mutation in South American patients, originating in Spain has been demonstrated. Objective: We describe physical and histological features, and the molecular impact of mutation Q163X in a Colombian family. Methods: We report two female patients, daughters of consanguineous parents, with onset of symptoms within the first two years of life, developing severe functional impairment, without evidence of dysmorphic features, hoarseness or diaphragmatic paralysis. Electrophysiology tests showed a sensory and motor neuropathy with axonal pattern. Sequencing of GDAP1 gene was requested and the study identified a homozygous point mutation (c.487 C>T) in exon 4, resulting in a premature stop codon (p.Q163X). This result confirms the diagnosis of Charcot-Marie-Tooth disease, type 4A. Results: The patients were referred to Physical Medicine and Rehabilitation service, in order to be evaluated for ambulation assistance. They have been followed by Pulmonology service, for pulmonary function assessment and diaphragmatic paralysis evaluation. Genetic counseling was offered. The study of the genealogy of the patient, phenotypic features, and electrophysiological findings must be included as valuable tools in the clinical approach of the patient with Charcot-Marie-Tooth disease, in order to define a causative mutation. In patients of South American origin, the presence of GDAP1 gene mutations should be considered, especially the Q163X mutation, as the cause of CMT4A disease.

Antecedentes: Las mutaciones del gen GDAP1 son causantes de la enfermedad de Charcot Marie Tooth tanto autosómica dominante como recesiva, y se han reportado más de 40 mutaciones distintas. La mutación recesiva Q163X ha sido descrita en pacientes de ascendencia española y se ha demostrado una mutación fundadora originaria de España en pacientes de origen suramericano. Describimos las características físicas e histológicas y el impacto molecular de la mutación Q163X en una familia colombiana. Objetivo: Se describe el impacto de la mutación Q163X en las características físicas, histológicas y moleculares en una familia colombiana. Métodos: Se describe dos pacientes de sexo femenino, hijas de padres consanguíneos, quienes presentaron inicio de síntomas en los dos primeros años de vida, mostrando deterioro funcional severo, sin evidencia de dismorfía, disfonía o parálisis diafragmática. Los estudios de electrofisiología mostraron una neuropatía sensitiva y motora con patrón axonal. Se solicitó la secuenciación del gen GDAP1, y el estudio identificó una mutación homocigota puntual (c. 487 C>T) en el exón 4, causando un codón de parada prematuro (p. Q163X). Este resultado confirma el diagnóstico de Enfermedad de Charcot Marie Tooth, tipo 4A (recesiva, tipo axonal). Resultados: Las pacientes fueron remitidas al servicio de Fisiatría para evaluación de métodos de asistencia para deambulación. Ellas reciben seguimiento por el servicio de Neumología, quienes vigilan la función pulmonar y el desarrollo de parálisis diafragmática. Se brindó asesoramiento genético. La genealogía del paciente, las características fenotípicas y los hallazgos en los estudios electrofisiológicos son herramientas valiosas en el enfoque clínico del paciente con CMT, de forma que se pueda plantear una posible mutación causal. Se debe considerar la presencia de mutaciones en el gen GDAP1 en pacientes de origen suramericano, en especial la mutación Q163X, como causa de CMT4A.

Charcot Marie Tooth disease (CMT4A) due to GDAP1 mutation: report of a Colombian family.

BACKGROUND: Mutations of GDAP1 gene cause autosomal dominant and autosomal recessive Charcot-Marie-Tooth disease and more than 40 different mutations have been reported. The recessive Q163X mutation has been described in patients of Spanish ancestry, and a founder mutation in South American patients, originating in Spain has been demonstrated. OBJECTIVE: We describe physical and histological features, and the molecular impact of mutation Q163X in a Colombian family. METHODS: We report two female patients, daughters of consanguineous parents, with onset of symptoms within the first two years of life, developing severe functional impairment, without evidence of dysmorphic features, hoarseness or diaphragmatic paralysis. Electrophysiology tests showed a sensory and motor neuropathy with axonal pattern. Sequencing of GDAP1 gene was requested and the study identified a homozygous point mutation (c.487 C>T) in exon 4, resulting in a premature stop codon (p.Q163X). This result confirms the diagnosis of Charcot-Marie-Tooth disease, type 4A. RESULTS: The patients were referred to Physical Medicine and Rehabilitation service, in order to be evaluated for ambulation assistance. They have been followed by Pulmonology service, for pulmonary function assessment and diaphragmatic paralysis evaluation. Genetic counseling was offered. The study of the genealogy of the patient, phenotypic features, and electrophysiological findings must be included as valuable tools in the clinical approach of the patient with Charcot-Marie-Tooth disease, in order to define a causative mutation. In patients of South American origin, the presence of GDAP1 gene mutations should be considered, especially the Q163X mutation, as the cause of CMT4A disease.

ANTECEDENTES: Las mutaciones del gen GDAP1 son causantes de la enfermedad de Charcot Marie Tooth tanto autosómica dominante como recesiva, y se han reportado más de 40 mutaciones distintas. La mutación recesiva Q163X ha sido descrita en pacientes de ascendencia española y se ha demostrado una mutación fundadora originaria de España en pacientes de origen suramericano. Describimos las características físicas e histológicas y el impacto molecular de la mutación Q163X en una familia colombiana. OBJETIVO: Se describe el impacto de la mutación Q163X en las características físicas, histológicas y moleculares en una familia colombiana. MÉTODOS: Se describe dos pacientes de sexo femenino, hijas de padres consanguíneos, quienes presentaron inicio de síntomas en los dos primeros años de vida, mostrando deterioro funcional severo, sin evidencia de dismorfía, disfonía o parálisis diafragmática. Los estudios de electrofisiología mostraron una neuropatía sensitiva y motora con patrón axonal. Se solicitó la secuenciación del gen GDAP1, y el estudio identificó una mutación homocigota puntual (c. 487 C>T) en el exón 4, causando un codón de parada prematuro (p. Q163X). Este resultado confirma el diagnóstico de Enfermedad de Charcot Marie Tooth, tipo 4A (recesiva, tipo axonal). RESULTADOS: Las pacientes fueron remitidas al servicio de Fisiatría para evaluación de métodos de asistencia para deambulación. Ellas reciben seguimiento por el servicio de Neumología, quienes vigilan la función pulmonar y el desarrollo de parálisis diafragmática. Se brindó asesoramiento genético. La genealogía del paciente, las características fenotípicas y los hallazgos en los estudios electrofisiológicos son herramientas valiosas en el enfoque clínico del paciente con CMT, de forma que se pueda plantear una posible mutación causal. Se debe considerar la presencia de mutaciones en el gen GDAP1 en pacientes de origen suramericano, en especial la mutación Q163X, como causa de CMT4A.

Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru.

Mucopolysaccharidosis type I (MPSI) is a rare autosomal recessive disorder caused by mutations in the gene encoding the lysosomal enzyme α-l-iduronidase (IDUA), which is instrumental in the hydrolysis of the glycosaminoglycans, dermatan and heparan sulfate. The accumulation of unhydrolyzed glycosaminoglycans leads to pathogenesis in multiple tissue types, especially those of skeletal, nervous, respiratory, cardiovascular, and gastrointestinal origin. Although molecular diagnostic tools for MPSI have been available since the identification and characterization of the IDUA gene in 1992, Colombia, Ecuador, and Peru have lacked such methodologies. Therefore, the mutational profile of the IDUA gene in these countries has largely been unknown. The goal of this study was to characterize genotypes in 14 patients with MPSI from Colombia, Ecuador, and Peru. The most common mutation found at a frequency of 42.8% was W402X. Six patients presented with seven novel mutations, a high novel mutational rate in this population (32%). These novel mutations were validated using bioinformatic techniques. A model of the IDUA protein resulting from three of the novel missense mutations (Y625C, P385L, R621L) revealed that these mutations alter accessible surface area values, thereby reducing the accessibility of the enzyme to its substrates. This is the first characterization of the mutational profile of the IDUA gene in patients with MPSI in Colombia, Ecuador, and Peru. The findings contribute to our understanding of IDUA gene expression and IDUA enzyme function, and may help facilitate early and improved diagnosis and management for patients with MPSI.

Report of a novel mutation in the SLC26A2 gene found in a Colombian adult patient with diastrophic dysplasia / Reporte de una nueva mutación en el gen SLC26A2 en un paciente adulto colombiano con displasia diastrófica

Summary Background. Diastrophic dysplasia is an osteochondrodysplasia belonging to the group of dysplasias caused by mutations in the diastrophic dysplasia sulfate transporter. This sindrome is a micromelic dysplasia with multiple bone deformities of the hands, feet, knees and spine. Objective. Describe the first report of diastrophic displasia in Colombia Materials and methods. In this paper a Colombian adult patient with diastrophic dysplasia whose clinical diagnosis was confirmed at the molecular level is reported. Results. In this first report of diastrophic dysplasia in Colombia we found that the patient was compound heterozygote for the already reported Arg279Trp substitution and an unpublished mutation, a Ser157Thr substitution in the SLC26A2 gene. Conclusion. Bioinformatic analysis on the latter mutation suggested that it could correspond to a deleterious mutation because it is in a highly conserved domain of the sulfate transporter.

Resumen Antecedentes. La displasia diastrófica es una osteocondrodisplasia que pertenece al grupo de las enfermedades genéticas del esqueleto causadas por mutaciones en los transportadores de sulfato. Se presenta como una displasia micromélica con afectación de múltiples huesos y deformidades en manos, pies, rodillas y columna vertebral. Objetivo. Describir el primer reporte de displasia diastrófica en Colombia. Materiales y métodos. Se reporta un adulto colombiano con esta displasia, con confirmación clínica, radiológica y molecular. Resultados. En este primer reporte colombiano, se encontró que la paciente presentó una mutación heterocigota compuesta, de Arg279Trp y Ser157Thr, esta última no reportada previamente, en el gen SLC26A2. Conclusión. El análisis bioinformático de la mutación nueva sugiere que podría corresponder a una mutación deletérea dado que el dominio afectado en el transportador de sulfatos es altamente conservado.

Análisis genotípico de 11 pacientes colombianos con Síndrome de Apert / Genotypic analysis of 11 Colombian Apert syndrome patients

Antecedentes. El síndrome de Apert (SA) es una de las craneosinostosis sindrómicas más severas que afecta el neuro y viscerocraneo y además presenta alteraciones multisistémicas con repercusiones en aspectos físicos (aspecto general y talla baja), sensoriales (hipoacusia y trastornos visuales), cognoscitivos (retardo mental o trastornos del aprendizaje) y de inclusión laboral (sindactilia severa en manos y pies). Su etiología es la mutación del receptor 2 del factor de crecimiento fibroblástico (FGFR2) y se hereda de forma autosómica dominante. Materiales y métodos. Se analizaron clínica y molecularmente 11 pacientes con sospecha de SA. Se realizó estudio mutacional mediante RFLP para el gen FGFR2. Resultados. Se confirmaron molecularmente los 11 pacientes con SA, cuyas edades oscilaron desde los 0 a 32 años. Todos los pacientes presentaron el fenotipo clásico. Se encontró un 63.6% de pacientes con la mutación S252W y 36.4% con P253R. Discusión. De los pacientes analizados, llamo la atención la presencia de talla baja y RM/RGD en algunos de ellos. Desde el punto de vista genotípico, las frecuencias mutacionales para S252W y P253R no mostraron diferencias con relación a lo reportado mundialmente. Aunque no se disponen de datos de la incidencia de esta patología a nivel local, este estudio podría ser el primer acercamiento para fines epidemiológicos en Colombia.

Background. Apert Syndrome (AS) is one of the most severe syndromic craniosynostosis affecting neuro and viscerocranium and presenting with multisystemic anomalies altering physical aspects (general looks and short stature), sensorineural aspects (deafness and visual problems), cognitive development (mental retardation or trouble learning) and work inclusion (severe syndactyly in hands and feet). Its aetiology relies on mutation of the Fibroblast Growth Factor Receptor type 2 (FGFR2) gene, inherited by an autosomal dominant path. Materials and methods. 11 patients with suspicion of AS were clinically evaluated and molecularly tested for mutations in FGFR2 by RFLP. Results. Patients with AS from 0 to 32 years old were analized for mutations in FGFR2 gene. All of them had the classical phenotype of the disease. 63.6% of the patients had the S252W mutation while 36.4% had the P253R mutation. Discussion. Of all patients enrolled in this study it is notwworthy that some of them had short stature, while others had mental retardation or global development delay. Mutational frequencies for S252W and P253R did not show difference according to what has been reported worldwide. Although there is no data about the incidence of this disease locally, this study could be a first approach to its epidemiology in Colombia.