VARS2-linked mitochondrial encephalopathy: two case reports enlarging the clinical phenotype

Abstract

Background Mitochondrial respiratory chain consists of five complexes encoded by nuclear and mitochondrial genomes. Mitochondrial aminoacyl-tRNA synthetases are key enzymes in the synthesis of such complexes. Bi-allelic variants of VARS2 , a nuclear gene encoding for valyl-tRNA (Val-tRNA) synthetase, are associated to several forms of mitochondrial encephalopathies or cardiomyoencephalopathies. Among these, the rare homozygous c.1100C > T (p.Thr367Ile) mutation variably presents with progressive developmental delay, axial hypotonia, limbs spasticity, drug-resistant epilepsy leading, in some cases, to premature death. Yet only six cases, of which three are siblings, harbouring this homozygous mutation have been described worldwide. Case presentation Hereby, we report two additional cases of two non-related young girls from Sardinia, born from non-consanguineous and healthy parents, carrying the aforesaid homozygous VARS2 variant. At onset both the patients presented with worsening psychomotor delay, muscle hypotonia and brisk tendon reflexes. Standard genetic tests were normal, as well as metabolic investigations. Brain MRI showed unspecific progressive abnormalities, such as corpus callosum hypoplasia (patient A) and cerebellar atrophy (patient A and B). Diagnosis was reached by adopting massive parallel next generation sequencing. Notably clinical phenotype of the first patient appears to be milder compared to previous known cases. The second patient eventually developed refractory epilepsy and currently presents with severe global impairment. Because no specific treatment is available as yet, both patients are treated with supporting antioxidant compounds along with symptomatic therapies. Conclusions Given the paucity of clinical data about this very rare mitochondrial encephalopathy, our report might contribute to broaden the phenotypic spectrum of the disorder. Moreover, noteworthy, three out of five pedigrees so far described belong to the Northern Sardinia ethnicity.

Case Report and Review of the Literature: A New and a Recurrent Variant in the VARS2 Gene Are Associated With Isolated Lethal Hypertrophic Cardiomyopathy, Hyperlactatemia, and Pulmonary Hypertension in Early Infancy

“…These additional findings support Bruni et al (1) assumption that "c.1100C>T variant could have a lesser effect to the heart." In the present paper we describe a compound heterozygous case with a recurrent c.1168G>A (15). However, OXPHOS activity was decreased only in six of them (the first patient had low complex IV activity, the second patient had combined complex I + complex IV deficiencies, the third patient had low complex IV activity, the fourth had low complex I activity, the fifth had low complex IV activity, and the sixth showed reduced complex I and III activity).…”

“…Dysfunction of the protein product is responsible for combined oxidative phosphorylation deficiency 20 (OMIM: # 615917) inherited in an autosomal recessive manner. Rare biallelic variants in the VARS2 gene have been associated with severe clinical features as mitochondrial encephalomyopathy or encephalocardiomyopathy in 23 affected individuals from 19 families worldwide (1,4,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). In the present paper we describe a compound heterozygous case with a recurrent c.1168G>A (p.Ala390Thr) and a novel missense variant c.2758T>C (p.Tyr920His) in the VARS2 gene causing isolated hypertrophic cardiomyopathy, hyperlactatemia, and pulmonary hypertension leading to early death.…”

“…Recently, several mutations in VARS2 gene were associated with clinical features such as hypotonia, psychomotor delay, encephalopathy, cardiomyopathy, hyperlactatemia, but the correlation between genotype and phenotype remains unclear (1,15). To date, 19 families with more than 23 affected individuals have been described in the literature worldwide (1,4,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) whereby c.1100C>T (p.Thr367Ile) is the most common variant in the VARS2 gene present in 60.8% (14/23) of the published cases (see Table 2). Common features of homozygous carriers for variant c.1100C>T (p.Thr367Ile) include microcephaly, global psychomotor delay, and hypotonia, less often nystagmus, limb spasticity, and difficulties with feeding.…”

“…In the first 12 months of life, ataxia, dystonic movements, and seizures can occur, which later (from 2 to 4 years) almost always lead to refractory epilepsy and status epilepticus based on mitochondrial encephalopathy (1,6,13). Nevertheless, hypertrophic cardiomyopathy (HCM) has never been observed in these patients (eight patients of which five had no HCM, in three cases the results of cardiologic examination are not available) (1,6,13,15). However, in compound heterozygotes (for variant c.1100C>T (p.Thr367Ile) and another, or two other pathogenic variants, hypertrophic cardiomyopathy was present in 14/15 cases (1,4,(7)(8)(9)(10)(11)(12)14).…”

VARS2 Depletion Leads to Activation of the Integrated Stress Response and Disruptions in Mitochondrial Fatty Acid Oxidation

“…It also possesses the ability to edit mischarged tRNAs, and its variations may lead to mistranslation [3]. Whereas variants in VARS2 have been associated with a better breast cancer prognosis and a higher risk of developing chronic hepatitis B [4,5], homozygous or compound heterozygous mutations in this gene have been found to cause mitochondriopathies, with encephalopathy being the most common, but cardiomyopathy and pulmonary hypertension also occurring [6][7][8][9][10][11][12][13][14]. In the present study, we investigated the consequences and thus the possible disease mechanisms of VARS2 depletion in two different model systems, zebrafish embryos and cultured HEK293A cells.…”