Clinical and mutational spectrum of Colombian patients with Pelizaeus Merzbacher Disease.

CASE PRESENTATION: Pelizaeus Merzbacher Disease (PMD) is an X-linked developmental defect of myelination that causes childhood chronic spastic encephalopathy. Its genetic etiology can be either a duplication (or other gene dosage alterations) or a punctual mutation at the PLP1 locus. Clinically, it presents with developmental delay, nystagmus and, spasticity, supported by neuroimaging in which the defect of myelination is evident. We present a series of seven Colombian patients diagnosed with this leucodystrophy, describing their genotypic and phenotypic characteristics and heterogeneity. CLINICAL FINDINGS: All patients included were male, 6 months to 16 years of age. Mean age at onset of symptoms was 8 months. Mean age at diagnosis was 5 years 5 months, being classic PMD most frequently diagnosed, as compared to the connatal phenotype. All cases had a primary diagnosis of developmental delay on 100%, and in 28.7% of cases, early onset nystagmus was described. 85.7% of patients had spasticity, 71.4% cerebellar signs, 57.0% hypotonia, and 28.5% had an abnormal movement disorder. Only three patients were able to achieve gait, though altered. In the two patients who had a diagnosis of connatal PMD maturational ages in danger zones according to the WHO Abbreviated Scale of Psychosocial Development were documented. All cases had abnormalities in neuroimages. MOLECULAR ANALYSIS AND RESULTS: Molecular studies were used in the majority of the cases to confirm the diagnosis (85.7 %). For two cases molecular confirmation was not considered necessary given their affected male brothers had already been tested. PLP1 gene dosage alterations (duplications) were found in 28.5 % of the patients (two siblings), whereas three different single nucleotide variants were detected. CLINICAL RELEVANCE: According to these findings, as authors we propose the diagnostic algorithm in Colombian population to begin on a high clinical suspicion, followed by paraclinical extension, moving on to the molecular confirmation by using approaches to simultaneously sequence the PLP1 gene in order to detect point mutations and in/dels and performing a copy number variation analysis for the detection of gene dosage alterations.

DESCRIPCIÓN DEL CASO: La enfermedad de Pelizaeus Merzbacher es una leucodistrofia ligada al X que causa encefalopatía espástica crónica en la infancia. Su etiología es genética, por duplicaciones u otros trastornos de la dosis génica o mutaciones puntuales del gen PLP1, lo que condiciona la formación anormal de las vainas de mielina principalmente en el sistema nervioso central. Clínicamente se caracteriza por un cuadro de retardo del neurodesarrollo, nistagmus y espasticidad, con neuroimágenes que evidencian la dismielinización. Presentamos una serie de siete casos colombianos con esta leucodistrofica en la que describimos fenotípica y genotípicamente la heterogeneidad de esta enfermedad en nuestra población. HALLAZGOS CLÍNICOS: Todos los pacientes analizados fueron de sexo masculino, con edad promedio de inicio de síntomas hacia los ocho meses de vida. La edad media al diagnóstico fue de 5 años 5 meses, siendo más frecuente el diagnóstico de PMD clásica que el tipo connatal. Se describe retardo del desarrollo motor en el 100% de los casos, acompañado de nistagmus en el 28.7%. 85.7% de los casos tenía algún grado de espasticidad, 71.4 % signos cerebelosos, 57.0% hipotonía, y hasta en 28.5% se evidenciaron movimientos anormales. Solo tres pacientes lograron marcha, aunque patológica. En los dos pacientes con la forma connatal se documentó una edad maduracional motora en el rango de Alerta, de acuerdo a la escala abreviada del desarrollo de la OMS. En todos los casos se detectó algún tipo de anormalidad en el estudio imagenológico cerebral. ESTUDIOS MOLECULARES Y RESULTADOS: El diagnóstico molecular se empleó en la mayoría de los casos (85.7%), encontrando alteraciones en la dosis génica en el 28.5% y tres diferentes mutaciones puntuales. RELEVANCIA CLÍNICA: Dados los hallazgos en los resultados del estudio molecular, sugerimos que en el abordaje diagnóstico confirmatorio para la población colombiana se debería contemplar en un mismo tiempo tanto la secuenciación como el estudio de variantes del número de copias del gen afectado, contrario a lo sugerido en literatura mundial en la que se inicia con estudio para duplicación / deleción.

Clinical and mutational spectrum of Colombian patients with Pelizaeus Merzbacher Disease / Heterogeneidad clínica y mutacional en pacientes colombianos con Pelizaeus Merzbacher

Abstract Case Presentation: Pelizaeus Merzbacher Disease (PMD) is an X-linked developmental defect of myelination that causes childhood chronic spastic encephalopathy. Its genetic etiology can be either a duplication (or other gene dosage alterations) or a punctual mutation at the PLP1 locus. Clinically, it presents with developmental delay, nystagmus and, spasticity, supported by neuroimaging in which the defect of myelination is evident. We present a series of seven Colombian patients diagnosed with this leucodystrophy, describing their genotypic and phenotypic characteristics and heterogeneity. Clinical Findings: All patients included were male, 6 months to 16 years of age. Mean age at onset of symptoms was 8 months. Mean age at diagnosis was 5 years 5 months, being classic PMD most frequently diagnosed, as compared to the connatal phenotype. All cases had a primary diagnosis of developmental delay on 100%, and in 28.7% of cases, early onset nystagmus was described. 85.7% of patients had spasticity, 71.4% cerebellar signs, 57.0% hypotonia, and 28.5% had an abnormal movement disorder. Only three patients were able to achieve gait, though altered. In the two patients who had a diagnosis of connatal PMD maturational ages in danger zones according to the WHO Abbreviated Scale of Psychosocial Development were documented. All cases had abnormalities in neuroimages. Molecular Analysis and Results: Molecular studies were used in the majority of the cases to confirm the diagnosis (85.7 %). For two cases molecular confirmation was not considered necessary given their affected male brothers had already been tested. PLP1 gene dosage alterations (duplications) were found in 28.5 % of the patients (two siblings), whereas three different single nucleotide variants were detected. Clinical Relevance: According to these findings, as authors we propose the diagnostic algorithm in Colombian population to begin on a high clinical suspicion, followed by paraclinical extension, moving on to the molecular confirmation by using approaches to simultaneously sequence the PLP1 gene in order to detect point mutations and in/dels and performing a copy number variation analysis for the detection of gene dosage alterations.

Resumen Descripción del caso: La enfermedad de Pelizaeus Merzbacher es una leucodistrofia ligada al X que causa encefalopatía espástica crónica en la infancia. Su etiología es genética, por duplicaciones u otros trastornos de la dosis génica o mutaciones puntuales del gen PLP1, lo que condiciona la formación anormal de las vainas de mielina principalmente en el sistema nervioso central. Clínicamente se caracteriza por un cuadro de retardo del neurodesarrollo, nistagmus y espasticidad, con neuroimágenes que evidencian la dismielinización. Presentamos una serie de siete casos colombianos con esta leucodistrofica en la que describimos fenotípica y genotípicamente la heterogeneidad de esta enfermedad en nuestra población. Hallazgos clínicos: Todos los pacientes analizados fueron de sexo masculino, con edad promedio de inicio de síntomas hacia los ocho meses de vida. La edad media al diagnóstico fue de 5 años 5 meses, siendo más frecuente el diagnóstico de PMD clásica que el tipo connatal. Se describe retardo del desarrollo motor en el 100% de los casos, acompañado de nistagmus en el 28.7%. 85.7% de los casos tenía algún grado de espasticidad, 71.4 % signos cerebelosos, 57.0% hipotonía, y hasta en 28.5% se evidenciaron movimientos anormales. Solo tres pacientes lograron marcha, aunque patológica. En los dos pacientes con la forma connatal se documentó una edad maduracional motora en el rango de Alerta, de acuerdo a la escala abreviada del desarrollo de la OMS. En todos los casos se detectó algún tipo de anormalidad en el estudio imagenológico cerebral. Estudios Moleculares y Resultados: El diagnóstico molecular se empleó en la mayoría de los casos (85.7%), encontrando alteraciones en la dosis génica en el 28.5% y tres diferentes mutaciones puntuales. Relevancia clínica: Dados los hallazgos en los resultados del estudio molecular, sugerimos que en el abordaje diagnóstico confirmatorio para la población colombiana se debería contemplar en un mismo tiempo tanto la secuenciación como el estudio de variantes del número de copias del gen afectado, contrario a lo sugerido en literatura mundial en la que se inicia con estudio para duplicación / deleción.

Gene expression analysis in peripheral blood cells of patients with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC): identification of NRF2 pathway activation.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare disease that is inherited in an autosomal dominant manner. Affected patients may develop from cutaneous and uterine leiomyomas to type 2 papillary renal cell carcinoma (Schmidt and Linehan, Int J Nephrol Renovasc Dis 7:253-260, 2014). HLRCC is caused by germline mutations in the FH gene, which produces the fumarate hydratase protein that participates in the tricarboxylic acid cycle during the conversion of fumarate to malate. In FH-deficient cells, high concentrations of fumarate lead to a series of intricate events, which seem to be responsible for the malignant transformation (Yang et al., J Clin Invest 123(9):3652-3658, 2013) (Bardella et al., J Pathol 225(1):4-11, 2011). Among these events, one that is gaining attention is the pathological activation of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which has been found in several types of cancer and is implicated in the expression of genes associated with antioxidant responses (Linehan and Rouault, Clin Cancer Res 19(13):3345-3352, 2013). In this article, we present the results of a gene expression analysis performed on peripheral blood cells from patients with HLRCC syndrome, where upregulation of numerous NRF2 targets and the differential expression of two key genes, Jun dimerization protein 2 (JDP2) and Phosphoglycerate mutase family member 5 (PGAM5), which are involved in the control of this pathway, was observed.

Hereditary leiomyomatosis and renal cell cancer syndrome: identification and clinical characterization of a novel mutation in the FH gene in a Colombian family.

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome (HLRCC) is a rare disease and since the first report, it has been found in just over 200 families approximately, around the world (Smit et al. in Clin Genet 79:49-59, 2009). Patients in Colombia or in Latin America have not been described, as far as we know. HLRCC is inherited in an autosomal dominant manner, and it is caused by heterozygous germline mutations in the FH gene, which encodes the fumarate hydratase enzyme. It is characterized mainly by the appearance of cutaneous and uterine leiomyomas, and an early-onset, aggressive form of type 2- papillary renal cell carcinoma (Smit et al. in Clin Genet 79:49-59, 2009; Schmidt and Linehan in Int J Nephrol Renovasc Dis 7:253-260, 2014]. We report a Colombian family with HLRCC syndrome, with a novel mutation in FH gene (c.1349_1352delATGA) in which cutaneous leiomyomas have not been found, but other clinical manifestations such as type 2- papillary renal cell carcinoma, uterine leiomyomas and rare tumors were present. This investigation constitutes the first report of HLRCC syndrome in Colombia, and probably in Latin America.

Metachondromatosis: Clinical and radiological diagnosis and differential diagnosis / Metacondromatosis: diagnóstico clínico, radiológico y diagnóstico diferencial

The clinical case of a 9-year-old patient derived from Orthopedics to the Institute of Genetics at Universidad Nacional de Colombia due to a longstanding medical history of multiple bony outgrowths that required surgical management without etiologic diagnosis is presented in this paper. A possible diagnosis of metachondromatosis is suggested based on the clinical course, the family history, and the findings of the biopsy and regular growth parameters. On the other hand, differential diagnoses were compared taking into account the most common enchondromatosis type, based on data obtained during physical examination, radiological signs and other variables. This comparison was grounded on the review of existing literature on this type of entities.

En el presente artículo se presenta el caso clínico de una paciente de 9 años de edad remitida al Instituto de Genética de la Universidad Nacional de Colombia desde el servicio de Ortopedia por cuadro clínico de larga data, consistente en múltiples excrecencias óseas que han requerido manejo quirúrgico sin diagnóstico etiológico. Se Plantea la posibilidad de metacondromatosis como diagnóstico, basándose en el curso clínico, la historia familiar, los hallazgos en biopsia y los parámetros normales de crecimiento; también se compararon los diagnósticos diferenciales dentro de las encondromatosis más frecuentes teniendo en cuenta datos tomados del examen físico, signos radiológicos y otras variables, esta comparación se basó en la revisión bibliográfica de la literatura existente actualmente sobre este tipo de entidades.

Case studies of two families with MIDD and MELAS: heteroplasmy level in m. 3243A>G mutation and the first report on m.3271T>C mutation in Colombia / Dos familias con midd y melas: nivel de heteroplasmia de la mutación m. 3243a>g y primer reporte de la mutación m.3271t>c en colombia

MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MIDD syndrome (maternally inherited diabetes and deafness) are mitochondrial diseases caused in most cases by the same mutation m.3243A> G, which affects the gene MT-TL1. The cases of two families with MELAS are presented here. In the first case, the m.3243A>G mutation was detected and the heteroplasmy level in blood, urine and oral mucosa were determined, finding a great phenotypic variability: the patient had higher heteroplasmy in the three tissues compared against oligosymptomatic relatives, and the mother had high blood sugar levels and hearing loss, suggesting a phenotype near to MIDD. In the second family, the m.3271T>C mutation was detected, which constitutes the first case reported in Colombia. These findings suggest that MIDD and MELAS, often described as distinct entities, are part of the same entity with variable expressivity partially depending on heteroplasmy.

El síndrome MELAS (encefalomiopatía mitocondrial, acidosis láctica y episodios similares a isquemia cerebral) y el síndrome MIDD (diabetes y sordera de herencia materna) son enfermedades mitocondriales producidas en la mayor parte de los casos por una misma mutación: la m.3243A>G que afecta al gen MT-TL1. Se presentan los casos de dos familias con MELAS. En la primera se detecta la mutación m.3243A>G y se determina el nivel de heteroplasmia en sangre, orina y mucosa oral, con lo que se evidencia una gran variabilidad fenotípica: la paciente tenía una mayor heteroplasmia en los tres tejidos en comparación con sus familiares oligosintomáticos y la madre tenía una glicemia elevada e hipoacusia, sugiriendo un fenotipo cercano al MIDD. En la segunda familia se detecta la mutación m.3271T>C, siendo el primer caso reportado en Colombia. Estos hallazgos sugieren que el MIDD y el MELAS, descritos frecuentemente como entidades distintas, hacen parte de una misma entidad con expresividad variable dependiendo en parte de la heteroplasmia.

[Prevalence and characterisation of the newborn suffering craniofacial anomalies at the Instituto Materno Infantil in Bogotá]. / Prevalencia y Caracterización de los Recién Nacidos con Anomalías Craneofaciales en el Instituto Materno Infantil de Bogotá

OBJECTIVES: Determining the frequency and characteristics of newborn suffering craniofacial abnormalities who were attending the Instituto Materno Infantil (IMI) in Bogotá. METHODS: Data was gathered regarding the newborn suffering such alterations who attended IMI from March 1st 2000 to August 15th 2001. The variables analysed were: being born in or having been remitted to the IMI, social strata, origin, general and specific risk factors, gender, correlation between weight and gestational age, clinical and aetiological diagnosis of the anomaly, karyotype and condition on leaving IMI. RESULTS: There was 2.7% prevalence for congenital defects and 0.6% for craniofacial abnormalities. 69% of the 52 patients had specific risk factors, 38% had been preterm, 33% had suffered retarded intra-uterine growth, 65% had cleft palates, 55.8% multiple abnormalities and 46% syndromes. Aetiological diagnosis was established in 38%; 12% had chromosomopathy. Eighteen children (35%) died, death being attributed to their defect in 13 of them, six by chromosomopathy. This study revealed the use of karyotype in making an aetiological diagnosis and determining prognosis. Mortality for the group suffering craniofacial abnormalities was threefold that of other hospitalised neonatal patients. Significant statistical association was shown between mortality and preterm condition, retarded growth, chromosomopathy and a diagnosis of multiple defects and/or syndromes. CONCLUSIONS: Prematurity, retarded growth, multiple defects, syndrome diagnosis and chromosomopathy revealed a mortality risk profile.

Prevalencia y caracterización de los recién nacidos con anomalías craneofaciales en el Instituto Materno Infantil de Bogotá / Prevalence and characterisation of the newborn suffering craniofacial anomalies at the Instituto Materno Infantil in Bogotá

Objetivos Determinar la frecuencia y caracterizar los neonatos nacidos con anomalías craneofaciales atendidos en el Instituto Materno Infantil (IMI). Métodos Se recolectaron los datos de nacidos o remitidos al IMI, estrato, procedencia, factores de riesgo general y específico, género, edad gestacional, correlación peso y edad gestacional, diagnóstico de la anomalía, cariotipo y condición al egreso de los neonatos con anomalías craneofaciales atendidos entre 1 de Marzo de 2000 y 15 de Agosto de 2001. Resultados La prevalencia de anomalía congénita fue 2,7 por ciento y de anomalía craneofacial 0,6 por ciento. De 52 pacientes, 69 por ciento tenía factores de riesgo específico, 38 por ciento era prematuro y 33 por ciento tenía retardo del crecimiento intrauterino; 65 por ciento correspondió a hendiduras, 55,8 por ciento a anomalía múltiple y 46 por ciento a síndromes. Se estableció diagnóstico etiológico en 38 por ciento de los casos; 12 por ciento tenía cromosomopatía. Fallecieron 18 niños (35 por ciento) y en 13 la muerte se atribuyó a la anomalía, 6 de éstos tenían cromosomopatía. Se evidenció la utilidad del cariotipo para hacer diagnóstico etiológico y establecer pronóstico. Los neonatos con anomalías craneofaciales tuvieron 3 veces más riesgo de morir que el resto de neonatos hospitalizados. Se demostró asociación estadísticamente significativa de la mortalidad con prematurez, retardo de crecimiento, cromosomopatía y diagnósticos de anomalía múltiple y síndrome. Conclusiones Prematurez, retardo de crecimiento, anomalía múltiple, diagnóstico de síndrome y cromosomopatía evidencian un perfil de riesgo para mortalidad.

Objectives Determining the frequency and characteristics of newborn suffering craniofacial abnormalities who were attending the Instituto Materno Infantil (IMI) in Bogotá. Methods Data was gathered regarding the newborn suffering such alterations who attended IMI from March 1 st 2000 to August 15 th 2001. The variables analysed were: being born in or having been remitted to the IMI, social strata, origin, general and specific risk factors, gender, correlation between weight and gestational age, clinical and aetiological diagnosis of the anomaly, karyotype and condition on leaving IMI. Results There was 2,7 percent prevalence for congenital defects and 0,6 percent for craniofacial abnormalities. 69 percent of the 52 patients had specific risk factors, 38 percent had been preterm, 33 percent had suffered retarded intra-uterine growth, 65 percent had cleft palates, 55,8 percent multiple abnormalities and 46 percent syndromes. Aetiological diagnosis was established in 38 percent; 12 percent had chromosomopathy. Eighteen children (35 percent) died, death being attributed to their defect in 13 of them, six by chromosomopathy. This study revealed the use of karyotype in making an aetiological diagnosis and determining prognosis. Mortality for the group suffering craniofacial abnormalities was threefold that of other hospitalised neonatal patients. Significant statistical association was shown between mortality and preterm condition, retarded growth, chromosomopathy and a diagnosis of multiple defects and/or syndromes. Conclusions Prematurity, retarded growth, multiple defects, syndrome diagnosis and chromosomopathy revealed a mortality risk profile.