KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature

Abstract

Background: KARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed.

Results: Herein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects.

Conclusions: With our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity. Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay.

Keywords: Calcifications; KARS; Leukoencephalopathy; Mitochondrial disease.

Fig. 1

MRI in patient B. TOP, Axial T2WI. performed at 1 year and 9 months revealed diffuse hyperintensity in deep cerebellar white matter, middle cerebellar peduncles, brainstem and bi-hemispheric white matter (a, b, c, d). The signal is inhomogeneous for the presence of multiple focal marked hypointensities due to calcifications (e, arrows). BOTTOM, Axial T2WI. performed at 3 years and 10 months showed a dramatic extension of the diffuse signal abnormalities in both hemispheres with full involvement of the posterior arm of the internal capsules, external capsules, U fibers and thalami, with relative sparing of the putamina (h-j). The signal abnormalities extension was also evident in cerebellar white matter, cerebellar peduncles and brainstem (f, g). Bilateral symmetric hyperintensities in the bulbar pyramids and bulbar lateral regions (arrowheads in f), in the superior cerebellar peduncles and in the arciform fibers of their decussation (arrowheads in H) were more evident. The transverse fibers of the pons were prominent and hyperintense (insert in g). Both V cranial nerves appeared swollen and hyperintense (stars in g), as well as the optic chiasm. Calcarine cortex showed a gliotic hyperintensity (black arrows in c). A huge diffuse cerebral atrophy with ventricles and sulci dilatation associated with pronounced cortical thickness was also observed

Fig. 2

Axial CT images of Patient B (a, b, c) and patient C (d, e, f) during different stages of the diseases, showing “rocks” calcifications in the cerebellar white matter (a, d), pons (a), periventricular white matter, thalami (b, e), and in the internal capsules, where they have a peculiar «boomerang appearance» (e, arrows) and centrum semiovale (c, f). Spine sagittal (g) and axial (h) CT of patient A showing extensive «track-like» calcifications along the whole spinal cord, well seen also on axial T2-fast field echo (FFE) MR images at the dorsal level and located in the region of the anterior horns (i). Axial T2-FFE MR image of patient C depicts the bilateral hyperintensities on T2WI in the dorsal lateral columns (j arrows)

Fig. 3

Histological liver changes in patient C: mild sclerotic portal space with irregular venous vessels (a, hematoxylin and eosin stain, 200×); vaguely nodular lobular area with compressed peripheral trabeculae (arrows) can be highlighted by Masson’s trichrome (b, 100×) and Reticulin (c, 100×) stainings, and CD34 immunohistochemistry (d, 100×)