@misc{10481/68393,
year = {2021},
month = {3},
url = {http://hdl.handle.net/10481/68393},
abstract = {Ataxia in children is a common clinical sign of numerous neurological disorders consisting
of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia,
describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided
as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia,
which complicates clinical management, particularly on the diagnostic stage. Advances in omics
technologies enable improvements in clinical practice and research, so we proposed a multi-omics
approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile
condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and
untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628
and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants
already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy
was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic
aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome
analysis revealed alterations in our patient’s amino acid, fatty acid and carbohydrate metabolism.
Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C
mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics
approaches to the disease.},
organization = {Fundación Mutua Madrileña, Spain XIII Call on Research
Grants 2016, reference number AP163052016},
publisher = {MDPI},
keywords = {Cerebellar ataxia},
keywords = {Diagnosis},
keywords = {Genomics},
keywords = {Transcriptomics},
keywords = {Metabolomics},
keywords = {Hypomyelination},
keywords = {Leukodystrophy},
keywords = {POLR1C},
title = {Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia},
doi = {10.3390/ijms22062990},
author = {Ching López, Ana and Martínez González, Luis Javier and Arrabal, Luisa and Sáiz, Jorge and Gavilán, Ángela and Barbas, Coral and Lorente Acosta, José Antonio and Roldán, Susana and Sánchez Pérez, María José and Gutiérrez Ríos, Purificación},
}