Leukodystrophy with Calcifications and Central Nervous System Atrophy: Expansion of the Phenotypic Spectrum Regarding Autosomal Recessive AARS Mutations?

Background/Purpose: In a female patient developmental regression occurred in the second year of life leading to spastic tetraparesis, dysphagia, optic atrophy and epilepsy. Imaging studies showed progressive leukodystrophy, brain and spinal atrophy, cerebral and cerebellar calcifications as well as lactate peak in MR spectroscopy. Electrophysiological studies showed pathologic evoked visual and somato-sensory potentials. Extensive diagnostics did not reveal causes for acquired or known genetic leukodystrophies. Respiratory chain analysis in muscle tissue showed diminished activities for complexes I, II/III and IV.

Methods: Through whole exome sequencing compound-heterozygous missense-variants in the AARS gene were identified, which encodes for the cytosolic alanyl-tRNA synthetase. Mutations in the aminoacyl-tRNA-synthetase (ARS) coding genes are associated with varying neurological phenotypes with strict genotype-phenotype correlations (cytosolic ARS: autosomal-dominant peripheral neuropathies; mitochondrial ARS: autosomal-recessive mitochondrial syndromes affecting the central nervous system, respectively with cardiomyopathy, ophthalmoplegia).

Results: As of late two AARS-associated diseases have been described: autosomal-dominant Charcot-Marie-Tooth disease (CMT2N) and autosomal-recessive early infantile epileptic encephalopathy (EIEE29). Compared with the characteristics of the three described EIEE29 patients (congenital microcephaly, refractory myoclonic epilepsy, extrapyramidal symptoms, peripheral neuropathy, congenital vertical tali, failure to thrive, progressive diffuse brain atrophy, hypomyelination) our patient shows only marginal phenotypic similarities.

Conclusion: Therefore, our diagnostics give evidence of a new phenotype of an AARS-associated disease with progressive leukodystrophy, atrophy and calcifications of the central nervous system with normocephaly, epilepsy, optic atrophy, and combined respiratory chain defect. If ongoing functional studies prove the causal role of the AARS variants in our patient this would be the first autosomal-recessive ARS-related disease with varying phenotypes.