Dados do Trabalho

Título

Genetic leukoencephalopathy: a diagnostic challenge

RESUMO

Case presentation

C. A. S., male, 35 years old, presented in 2014 with depressive symptoms, developing visuospatial and executive impairment, as well as behavioral disorder, after a few months. He presented worsening of cognition over the years. In 2019 he developed gait ataxia with early falls, becoming wheelchair bound within few months. He became totally dependent for daily life activities since then. In 2021 he developed dysarthria and dysphagia. There was no consanguinity nor similar cases in the family. Physical exam: awake, bulbar dysarthria, disconnected words, spastic tretraparesis, bilateral Babinski sign, dysmetria in four limbs.
Brain MRI showed diffuse confluent white matter T2/FLAIR hyperintensity and cortical atrophy. The possibility of leukodystrophy was raised. Genetic testing showed heterozygous mutations in the mitochondrial gene alanyl-tRNA synthetase 2 (AARS2).
The patient passed away in April 2022.

Discussion

The diagnostic evaluation of genetic leukoencephalopathy includes screening test that should be performed to rule out the main causes: biochemical for inborn errors of metabolism, spinal fluid analysis, magnetic resonance of the brain and spinal cord, and genetic testing, if possible.
Diseases associated with mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) enzymes are a group of genetic leukoencephalopathies associated mainly with three specific clinical diseases: aspartyl-tRNA synthetase (DARS2), mitochondrial glutamate tRNA synthetase (EARS2) and AARS2. [1].
AARS2 is associated with a rare autosomal recessive leukodystrophy. In adults the most prevalent phenotype, first described in 2014, is characterized by premature ovarian failure in women and progressive leukodystrophy [2]. The age of onset is usually around 25 years, with cognitive decline, neuropsychiatric changes, pyramidal and extrapyramidal signs, ataxia and neuropathy [2,3]. Some cases have been described with developmental delay or motor problems in childhood [2].

Conclusions

This case report illustrates the diagnostic challenge presented by the primary leukodystrophies, which is only possible with a genetic study, unfortunately difficult to obtain in our country.
The possibility of identifying a specific mutation related to leukodystrophy is the first step that will allow the development of targeted therapeutic treatment for this group of diseases, that are currently associated with high morbidity and mortality.

Palavras Chave

leukoencephalopathy; leukodystrophy; AARS2; genetic