Genetic and Clinical Predictors of Ataxia in Pediatric Primary Mitochondrial Disorders

Juan Se bastian Martin-Saavedra; Sara Reis Teixeira; Cesar Augusto Pinheiro Ferreira Alves; Fabrício Guimarães Gonçalves; Luis Octavio Tierradentro-García; Martin Kidd; Colleen Muraresku; Amy Goldstein; Arastoo Vossough

doi:10.1007/s12311-021-01276-1

Genetic and Clinical Predictors of Ataxia in Pediatric Primary Mitochondrial Disorders

Título traducido de la contribución: Predictores genéticos y clínicos de ataxia en trastornos mitocondriales primarios pediátricos

Juan Se bastian Martin-Saavedra, Sara Reis Teixeira, Cesar Augusto Pinheiro Ferreira Alves, Fabrício Guimarães Gonçalves, Luis Octavio Tierradentro-García, Martin Kidd, Colleen Muraresku, Amy Goldstein, Arastoo Vossough

Producción científica: Contribución a una revista › Artículo de Investigación › revisión exhaustiva

Resumen

La evaluación de la ataxia en niños es un reto en la práctica clínica. Esto es particularmente cierto para condiciones altamente heterogéneas como los trastornos mitocondriales primarios (PMD). Este estudio tiene como objetivo explorar las anomalías cerebelosas y cerebrales identificadas en la RM como posibles predictores de ataxia en pacientes con PMD y, asimismo, determinar el efecto del perfil genético del paciente sobre estos predictores, así como determinar la relación temporal de la ataxia clínica con los hallazgos de la RM. Se evaluaron las características clínicas, radiológicas y genéticas de 111 pacientes con PMD menores de 21 años del Hospital Infantil de Filadelfia. Los datos se extrajeron de las historias clínicas. Neurorradiólogos experimentados realizaron evaluaciones radiológicas ciegas. Para el análisis se utilizó una regresión logística multivariante y estimaciones de ecuaciones generalizadas. La atrofia cerebelosa o la afectación putaminal con mutaciones del ADN mitocondrial (OR 1,18; IC 95%: 1,1-1,3; p < 0,001) y la mutación del ADN nuclear sin atrofia del cerebelo (OR 1,14; IC 95%: 1,0-1,3; p = 0,007) predijeron una mayor probabilidad de padecer ataxia por año de edad. El tracto tegmental central predijo la presencia de ataxia independientemente de la edad y del origen de la variante patogénica (OR 9,8; IC del 95%: 2-74; p = 0,009). La ataxia tendía a preceder al hallazgo de imagen de atrofia cerebelosa. La atrofia cerebelosa y la afectación putaminal en la RM de PMD de inicio pediátrico pueden predecir la presencia de ataxia con la edad en pacientes con mutaciones del ADNmt. Este estudio proporciona probabilidades predichas de tener ataxia por año de edad que pueden ayudar en el asesoramiento familiar y en futuras investigaciones de la población.

Título traducido de la contribución	Predictores genéticos y clínicos de ataxia en trastornos mitocondriales primarios pediátricos
Idioma original	Inglés estadounidense
Páginas (desde-hasta)	116–131
Número de páginas	16
Publicación	Cerebellum
Volumen	21
DOI	https://doi.org/10.1007/s12311-021-01276-1
Estado	Publicada - may. 30 2021

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Neurología
Neurología clínica

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@article{57d97af9ebb8439ba9a0fcee9c886167,

title = "Genetic and Clinical Predictors of Ataxia in Pediatric Primary Mitochondrial Disorders",

abstract = "Evaluation of ataxia in children is challenging in clinical practice. This is particularly true for highly heterogeneous conditions such as primary mitochondrial disorders (PMD). This study aims to explore cerebellar and brain abnormalities identified on MRI as potential predictors of ataxia in patients with PMD and, likewise, to determine the effect of the patient{\textquoteright}s genetic profile on these predictors as well as determination of the temporal relationship of clinical ataxia with MRI findings. We evaluated clinical, radiological, and genetic characteristics of 111 PMD patients younger than 21 years of age at The Children{\textquoteright}s Hospital of Philadelphia. Data was extracted from charts. Blinded radiological evaluations were carried out by experienced neuroradiologists. Multivariate logistic regression and generalized equation estimates were used for analysis.Ataxia was identified in 41% of patients. Cerebellar atrophy or putaminal involvement with mitochondrial DNA (mtDNA) mutations (OR 1.18, 95% CI 1.1–1.3, p < 0.001) and nuclear DNA mutation with no atrophy of the cerebellum (OR 1.14, 95% CI 1.0–1.3, p = 0.007) predicted an increased likelihood of having ataxia per year of age. Central tegmental tract predicted the presence of ataxia independent of age and pathogenic variant origin (OR 9.8, 95% CI 2–74, p = 0.009). Ataxia tended to precede the imaging finding of cerebellar atrophy. Cerebellar atrophy and putaminal involvement on MRI of pediatric-onset PMD may predict the presence of ataxia with age in patients with mtDNA mutations. This study provides predicted probabilities of having ataxia per year of age that may help in family counseling and future research of the population.",

author = "Martin-Saavedra, {Juan Se bastian} and Teixeira, {Sara Reis} and Alves, {Cesar Augusto Pinheiro Ferreira} and Gon{\c c}alves, {Fabr{\'i}cio Guimar{\~a}es} and Tierradentro-Garc{\'i}a, {Luis Octavio} and Martin Kidd and Colleen Muraresku and Amy Goldstein and Arastoo Vossough",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2021",

month = may,

day = "30",

doi = "10.1007/s12311-021-01276-1",

language = "English (US)",

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AU - Martin-Saavedra, Juan Se bastian

AU - Teixeira, Sara Reis

AU - Alves, Cesar Augusto Pinheiro Ferreira

AU - Gonçalves, Fabrício Guimarães

AU - Tierradentro-García, Luis Octavio

AU - Kidd, Martin

AU - Muraresku, Colleen

AU - Goldstein, Amy

AU - Vossough, Arastoo

PY - 2021/5/30

Y1 - 2021/5/30

N2 - Evaluation of ataxia in children is challenging in clinical practice. This is particularly true for highly heterogeneous conditions such as primary mitochondrial disorders (PMD). This study aims to explore cerebellar and brain abnormalities identified on MRI as potential predictors of ataxia in patients with PMD and, likewise, to determine the effect of the patient’s genetic profile on these predictors as well as determination of the temporal relationship of clinical ataxia with MRI findings. We evaluated clinical, radiological, and genetic characteristics of 111 PMD patients younger than 21 years of age at The Children’s Hospital of Philadelphia. Data was extracted from charts. Blinded radiological evaluations were carried out by experienced neuroradiologists. Multivariate logistic regression and generalized equation estimates were used for analysis.Ataxia was identified in 41% of patients. Cerebellar atrophy or putaminal involvement with mitochondrial DNA (mtDNA) mutations (OR 1.18, 95% CI 1.1–1.3, p < 0.001) and nuclear DNA mutation with no atrophy of the cerebellum (OR 1.14, 95% CI 1.0–1.3, p = 0.007) predicted an increased likelihood of having ataxia per year of age. Central tegmental tract predicted the presence of ataxia independent of age and pathogenic variant origin (OR 9.8, 95% CI 2–74, p = 0.009). Ataxia tended to precede the imaging finding of cerebellar atrophy. Cerebellar atrophy and putaminal involvement on MRI of pediatric-onset PMD may predict the presence of ataxia with age in patients with mtDNA mutations. This study provides predicted probabilities of having ataxia per year of age that may help in family counseling and future research of the population.

AB - Evaluation of ataxia in children is challenging in clinical practice. This is particularly true for highly heterogeneous conditions such as primary mitochondrial disorders (PMD). This study aims to explore cerebellar and brain abnormalities identified on MRI as potential predictors of ataxia in patients with PMD and, likewise, to determine the effect of the patient’s genetic profile on these predictors as well as determination of the temporal relationship of clinical ataxia with MRI findings. We evaluated clinical, radiological, and genetic characteristics of 111 PMD patients younger than 21 years of age at The Children’s Hospital of Philadelphia. Data was extracted from charts. Blinded radiological evaluations were carried out by experienced neuroradiologists. Multivariate logistic regression and generalized equation estimates were used for analysis.Ataxia was identified in 41% of patients. Cerebellar atrophy or putaminal involvement with mitochondrial DNA (mtDNA) mutations (OR 1.18, 95% CI 1.1–1.3, p < 0.001) and nuclear DNA mutation with no atrophy of the cerebellum (OR 1.14, 95% CI 1.0–1.3, p = 0.007) predicted an increased likelihood of having ataxia per year of age. Central tegmental tract predicted the presence of ataxia independent of age and pathogenic variant origin (OR 9.8, 95% CI 2–74, p = 0.009). Ataxia tended to precede the imaging finding of cerebellar atrophy. Cerebellar atrophy and putaminal involvement on MRI of pediatric-onset PMD may predict the presence of ataxia with age in patients with mtDNA mutations. This study provides predicted probabilities of having ataxia per year of age that may help in family counseling and future research of the population.

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U2 - 10.1007/s12311-021-01276-1

DO - 10.1007/s12311-021-01276-1

M3 - Research Article

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AN - SCOPUS:85107053587

SN - 1473-4222

VL - 21

SP - 116

EP - 131

JO - Cerebellum

JF - Cerebellum

ER -

Genetic and Clinical Predictors of Ataxia in Pediatric Primary Mitochondrial Disorders

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