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

Abstract

BackgroundKARS 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.ResultsHerein, 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.ConclusionsWith 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.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0788-4) contains supplementary material, which is available to authorized users.

Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(Pro228Leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis

“…The patient identified by us was diagnosed with MD and was on the more severe end of the clinical spectrum as she died at 20 months of age. Three other patients carrying mutations in KARS were also diagnosed with MD and had either neurological dysfunction or cardiomyopathy with early childhood lethality in the former case (Lieber et al., ; McMillan et al., ; Verrigni et al., ); MD was suspected in the three recent cases reported by (Ardissone et al., ). MD was not reported in the remaining patients, for any of which lethality was also not documented.…”

“…As with other cytosolic or mitochondrial tRNA synthetases, most often the clinical presentation includes a variably severe neurological dysfunction and developmental delay. In more than half of the cases, KARS mutations were associated with hearing loss whether nonsyndromic or part of a neurological phenotype (Ardissone et al., ; Lieber et al., ; Murray et al., ; Santos‐Cortez et al., ; Zhou et al., ). Early onset severe visual loss was detected in five patients (Ardissone et al., ; McMillan et al., ).…”

“…In more than half of the cases, KARS mutations were associated with hearing loss whether nonsyndromic or part of a neurological phenotype (Ardissone et al., ; Lieber et al., ; Murray et al., ; Santos‐Cortez et al., ; Zhou et al., ). Early onset severe visual loss was detected in five patients (Ardissone et al., ; McMillan et al., ). Hypertrophic cardiomyopathy affected two patients carrying different mutations and exhibiting partially overlapping clinical presentations and biochemistry indicative of mitochondrial disorder: developmental delay, lactic acidosis, and combined oxidative phosphorylation (OXPHOS) complex I and IV deficiency (Kohda et al., ; Verrigni et al., ).…”

“…Early onset severe visual loss was detected in five patients (Ardissone et al, 2018;McMillan et al, 2015). Hypertrophic cardiomyopathy affected two patients carrying different mutations and exhibiting partially overlapping clinical presentations and biochemistry indicative of mitochondrial disorder: developmental delay, lactic acidosis, and combined oxidative phosphorylation (OXPHOS) complex I and IV deficiency (Kohda et al, 2016;Verrigni et al, 2017).…”

Mutations inELAC2associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3′‐end processing

“…For P6 and P9 a targeted custom panel (Nextera rapid capture; Illumina) containing genes responsible for mitochondrial disorders was used (Ardissone et al, ). Variant filtering was performed as described in Legati et al ().…”