ABSTRACT
Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent research studies focused on genetic diagnosis in patients with CP of unknown etiology. The present study was carried out in 20 families with one family member affected with idiopathic CP. Chromosomal microarray and exome sequencing techniques were performed in all patients. Chromosomal microarray analysis did not show any pathological or probable pathological structural variant. However, the next-generation sequencing study showed a high diagnostic yield. We report 11/20 patients (55%) with different pathogenic or potentially pathogenic variants detected by exome sequencing analysis: five patients with mutations in genes related to hereditary spastic paraplegia, two with mutations in genes related to Aicardi-Goutières syndrome, three with mutations in genes related to developmental/epileptic encephalopathies, and one with a mutation in the PGK1 gene. The accurate and precise patients' selection, the use of a high-throughput genetic platform, the selection of adequate target genes, and the application of rigorous criteria for the clinical interpretation are the most important elements for a good diagnostic performance. Based on our findings, next-generation sequencing should be considered in patients with cryptogenic CP as the first line of genetic workup. IMPACT: Sequencing techniques in CP of uncertain etiology provides a diagnostic yield of 55%. The appropriate selection of cases optimizes the diagnostic yield. NGS facilitate better understanding of new phenotypes of certain genetic diseases.
Subject(s)
Cerebral Palsy/diagnosis , Cerebral Palsy/genetics , DNA Mutational Analysis , Genetic Heterogeneity , Genetic Testing , High-Throughput Nucleotide Sequencing , Mutation , Adolescent , Child , Child, Preschool , Female , Genetic Markers , Genetic Predisposition to Disease , Humans , Male , Phenotype , Predictive Value of Tests , Risk FactorsABSTRACT
INTRODUCTION: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare condition that has only recently been reported. Here we present two new cases belonging to the same family. CASE REPORTS: Case 1: 17-month-old boy with severe underdevelopment in all areas, absence of language and eye contact. The examination revealed microcephaly with spastic tetraparesis. A magnetic resonance imaging scan showed predominantly vermian atrophy of the cerebellum with loss of volume of both nuclei of the putamen and the head of the caudate, and a pattern of hypomyelination of the white matter. Electromyography recording highlighted the presence of a predominantly motor pattern of chronic polyneuropathy. Homovallinic acid and 5-hydroxyindoleacetic acid values were lower than usual. Treatment with levodopa/carbidopa was not effective. Case 2: 11-month-old girl, the sister of the boy in the previous case. The patient presented severe underdevelopment in all areas and microcephaly with spastic tetraparesis was detected in the clinical examination. Magnetic resonance imaging of the head showed findings that could be superimposed upon those of the brother, with hypomyelination, cerebellar atrophy and involvement of the putamen and both caudates; electromyography findings were consistent with motor polyneuropathy of a demyelinating nature. Homovallinic acid and 5-hydroxyindoleacetic acid values in cerebrospinal fluid were lower than usual. Treatment with levodopa/carbidopa was ineffective. CONCLUSIONS: These two new cases help characterise this condition better and reinforce the hypothesis of the genetic origin of the syndrome, given that the two cases occurred in the same family.
TITLE: Hipomielinizacion con atrofia de ganglios basales y de cerebelo. Aportacion de dos nuevos casos a una entidad de descripcion reciente.Introduccion. La hipomielinizacion con atrofia de ganglios basales y de cerebelo (H-ABC) es una rara entidad descrita recientemente. Se presentan dos nuevos casos pertenecientes a una misma familia. Casos clinicos. Caso 1: niño de 17 meses con retraso grave en todas las areas, ausencia de lenguaje y de contacto visual. En la exploracion destacaba una microcefalia con tetraparesia espastica. En la resonancia magnetica cerebral se apreciaba atrofia cerebelosa de predominio vermiano con perdida de volumen de ambos nucleos del putamen y la cabeza del caudado, y patron de hipomielinizacion de la sustancia blanca. En la electromiografia se objetivo un patron de polineuropatia cronica de predominio motor. Presento un descenso de los valores de acido homovalinico y de acido 5-hidroxindolacetico. El tratamiento con levodopa/carbidopa no fue efectivo. Caso 2: niña de 11 meses, hermana del caso anterior. Presentaba un retraso grave en todas las areas y en la exploracion clinica se detecto una microcefalia con tetraparesia espastica. La resonancia magnetica cerebral mostro hallazgos superponibles a los del hermano, con hipomielinizacion, atrofia cerebelosa y afectacion putaminal y de ambos caudados; en la electromiografia, hallazgos compatibles con polineuropatia motora de caracter desmielinizante. Presento un descenso de los valores de acido homovalinico y acido 5-hidroxindolacetico en el liquido cefalorraquideo. El tratamiento con levodopa/carbidopa resulto ineficaz. Conclusiones. Estos dos nuevos casos ayudan a caracterizar mejor esta entidad y refuerzan la hipotesis del origen genetico del sindrome, dado que se trata de dos casos pertenecientes a una misma familia.
Subject(s)
Basal Ganglia/pathology , Cerebellum/pathology , Hereditary Central Nervous System Demyelinating Diseases , Epilepsy/etiology , Fatal Outcome , Female , Gastrostomy , Hereditary Central Nervous System Demyelinating Diseases/diagnosis , Hereditary Central Nervous System Demyelinating Diseases/genetics , Hereditary Central Nervous System Demyelinating Diseases/pathology , Humans , Infant , Intellectual Disability/etiology , Magnetic Resonance Imaging , Male , Muscle Spasticity , Phenotype , Quadriplegia/etiology , Respiration, Artificial , Respiratory Sounds , Siblings , TracheotomyABSTRACT
Introducción. La hipomielinización con atrofia de ganglios basales y de cerebelo (H-ABC) es una rara entidad descrita recientemente. Se presentan dos nuevos casos pertenecientes a una misma familia. Casos clínicos. Caso 1: niño de 17 meses con retraso grave en todas las áreas, ausencia de lenguaje y de contacto visual. En la exploración destacaba una microcefalia con tetraparesia espástica. En la resonancia magnética cerebral se apreciaba atrofia cerebelosa de predominio vermiano con pérdida de volumen de ambos núcleos del putamen y la cabeza del caudado, y patrón de hipomielinización de la sustancia blanca. En la electromiografía se objetivó un patrón de polineuropatía crónica de predominio motor. Presentó un descenso de los valores de ácido homovalínico y de ácido 5-hidroxindolacético. El tratamiento con levodopa/carbidopa no fue efectivo. Caso 2: niña de 11 meses, hermana del caso anterior. Presentaba un retraso grave en todas las áreas y en la exploración clínica se detectó una microcefalia con tetraparesia espástica. La resonancia magnética cerebral mostró hallazgos superponibles a los del hermano, con hipomielinización, atrofia cerebelosa y afectación putaminal y de ambos caudados; en la electromiografía, hallazgos compatibles con polineuropatía motora de carácter desmielinizante. Presentó un descenso de los valores de ácido homovalínico y ácido 5-hidroxindolacético en el líquido cefalorraquídeo. El tratamiento con levodopa/carbidopa resultó ineficaz. Conclusiones. Estos dos nuevos casos ayudan a caracterizar mejor esta entidad y refuerzan la hipótesis del origen genético del síndrome, dado que se trata de dos casos pertenecientes a una misma familia (AU)
Introduction. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare condition that has only recently been reported. Here we present two new cases belonging to the same family. Case reports. Case 1: 17-month-old boy with severe underdevelopment in all areas, absence of language and eye contact. The examination revealed microcephaly with spastic tetraparesis. A magnetic resonance imaging scan showed predominantly vermian atrophy of the cerebellum with loss of volume of both nuclei of the putamen and the head of the caudate, and a pattern of hypomyelination of the white matter. Electromyography recording highlighted the presence of a predominantly motor pattern of chronic polyneuropathy. Homovallinic acid and 5-hydroxyindoleacetic acid values were lower than usual. Treatment with levodopa/carbidopa was not effective. Case 2: 11-month-old girl, the sister of the boy in the previous case. The patient presented severe underdevelopment in all areas and microcephaly with spastic tetraparesis was detected in the clinical examination. Magnetic resonance imaging of the head showed findings that could be superimposed upon those of the brother, with hypomyelination, cerebellar atrophy and involvement of the putamen and both caudates; electromyography findings were consistent with motor polyneuropathy of a demyelinating nature. Homovallinic acid and 5-hydroxyindoleacetic acid values in cerebrospinal fluid were lower than usual. Treatment with levodopa/carbidopa was ineffective. Conclusions. These two new cases help characterise this condition better and reinforce the hypothesis of the genetic origin of the syndrome, given that the two cases occurred in the same family (AU)
