Thymidine kinase 2 and alanyl-tRNA synthetase 2 deficiencies cause lethal mitochondrial cardiomyopathy: case reports and review of the literature

Abstract

Cardiomyopathy is a common manifestation in neonates and infants with mitochondrial disorders. In this study, we report two cases manifesting with fatal mitochondrial hypertrophic cardiomyopathy, which include the third known patient with thymidine kinase 2 deficiency and the ninth patient with alanyl-tRNA synthetase 2 deficiency. The girl with thymidine kinase 2 deficiency had hypertrophic cardiomyopathy together with regression of gross motor development at the age of 13 months. Neurological symptoms and cardiac involvement progressed into severe myopathy, psychomotor arrest, and cardiorespiratory failure at the age of 22 months. The imaging methods and autoptic studies proved that she suffered from unique findings of leucoencephalopathy, severe, mainly cerebellar neuronal degeneration, and hepatic steatosis. The girl with alanyl-tRNA synthetase 2 deficiency presented with cardiac failure and underlying hypertrophic cardiomyopathy within 12 hours of life and subsequently died at 9 weeks of age. Muscle biopsy analyses demonstrated respiratory chain complex I and IV deficiencies, and histological evaluation revealed massive mitochondrial accumulation and cytochrome c oxidase-negative fibres in both cases. Exome sequencing in the first case revealed compound heterozygozity for one novel c.209T>C and one previously published c.416C>T mutation in the TK2 gene, whereas in the second case homozygozity for the previously described mutation c.1774C>T in the AARS2 gene was determined. The thymidine kinase 2 mutations resulted in severe mitochondrial DNA depletion (to 12% of controls) in the muscle. We present, for the first time, severe leucoencephalopathy and hepatic steatosis in a patient with thymidine kinase 2 deficiency and the finding of a ragged red fibre-like image in the muscle biopsy in a patient with alanyl-tRNA synthetase 2 deficiency.

Sideroblastic anemia associated with multisystem mitochondrial disorders

“…The PCR product was sequenced in both directions. Targeted exome sequencing of the characterized mitochondrial‐related genes was performed for P8 using 1.2 μg of gDNA . COX10 (ENSG00000006695 and ENST00000261643) mutations were confirmed by Sanger sequencing in the proband and her parents.…”

Expansion of the clinical spectrum associated with AARS2‐related disorders

“…Two individuals had onset of deterioration in their teens, three individuals had onset in their 20's, and one individual had onset in her 40's (Dallabona et al, ). A handful of reports have implicated AARS2 variants in different phenotypes, such as newborn onset lethal primary pulmonary hypoplasia (Kiraly‐Borri et al, ), infantile‐onset cardiomyopathy (Kamps et al, ; Mazurova et al, ; Sommerville et al, ), childhood‐onset leukoencephalopathy with retinopathy/optic atrophy (Peragallo, Keller, van der Knaap, Soares, & Shankar, ), late adolescence/adult‐onset leukoencephalopathy (Dong et al, ; Szpisjak et al, ; Tang et al, ), adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (Lynch et al, ; Lynch et al, ; Wang, Yu, Zhang, Wang, & Yuan, ), females with ovarian failure and leukoencephalopathy (Hamatani et al, ; Taglia et al, ), and behavioral variant frontotemporal dementia with leukoencephalopathy (Kim et al, ).…”

Novel Alanyl-tRNA Synthetase 2 Pathogenic Variants in Leukodystrophies

“…These mutations can induce multiple neurological disorders, such as epilepsy, autosomal recessive spastic ataxia with leukodystrophy (ARSAL), distal hereditary motor neuropathy (dHMN), hereditary motor neuropathy (HMN), LBSL, pontocerebellar hypoplasia (PCH), and leukodystrophy with thalamic and brainstem involvement and hyperlactatemia (14). However, the AARS2 mutation induces two different mutation-dependent diseases: ovarioleukodystropy (14,15) and lethal mitochondrial cardiomyopathy with lactacidosis (16). Alanyl-transfer RNA synthetase 2 mutation-related leukodystrophy (AARS2-L) is an autosomal recessive neurodegenerative disorder related to AARS2 gene mutation (15).…”