Case presentation: A 15-month-old girl evolved with fever and tremors associated with ataxy after vaccination
of hepatitis A, DTP, OPV y tetraviral. She was born via cesarean, uneventfully. Parents
are consanguineous. Her mother had Specific Hypertensive Pregnancy Disease (SHPD)
during pregnancy. No history of previous hospitalizations, regular medications, and
allergies. Neuropsychomotor development (NPMD): she sat at 6 months, babbles and waves,
and didn’t walk but stood with support by 12 months. The cranial magnetic resonance
imaging (MRI), electroencephalogram (EEG), and cerebral spinal fluid were normal.
Diagnostic hypothesis: acute cerebellitis. An intravenous combination of ceftriaxone
and acyclovir was given for 10 days, evolving with an improvement in tremors. It was
prescribed clonazepam for ambulatorial use. After 3 months, the fever began again,
getting worse the tremors and ataxia. Physical exam: without trunk support; decreased
muscle strength in lower and upper limbs (LL. and UP.), with hypertonia, reflexes,
and distal clonus in LL.; tongue and chin tremors. Genetic analysis, Next Generation
Sequencing (NGS), by Movement Program, identified compound homozygous mutations in
the WARS2 gene, being the paternally inherited missense variant: c.754C>T, (p.Arg252Cys)
with uncertain significance.
Discussion: Protein translation is critical for all forms of life, and aminoacyl transfer RNA
(tRNA) synthetases (ARSs) play an important role in this process. ARSs ensure the
incorporation of correct amino acids in the growing polypeptide chain during protein
synthesis. Each protein-genic amino acid is coupled to its corresponding tRNA by a
specific ARS. Mitochondrial ARSs are encoded by separate nuclear genes and an increasing
proportion of ARS genes has been associated with human disease. WARS2 is a mitochondria-specific
AR named tryptophanyl-RNA synthetase 2 and its deficiency can cause heterogeneous
clinical presentations (e.g., muscle weakness, peripheral neuropathy, movement disorder,
epilepsy), but developmental cognitive delay and complex movement disorders are prevalent
mark, and the absence of epileptic seizures can increase patient survival. NGS techniques
became widely available and, are a powerful tool to unravel the heterogenic genetic
background of MD.
Final comments: In children with otherwise unexplained progressive hyperkinetic movement disorders,
WARS2-related mitochondrial disease should be included in the list of differential
diagnoses.
