FARS2 haploinsufficiency: from early onset malignant hyperthermia to childhood epilepsy partialis continua and adult intellectual disability

Background: FARS2 encodes the mitochondrial phenylalanine-tRNA synthetase, which charges tRNA with phenylalanine in mitochondrial DNA translation. 12 patients were described with FARS2 mutations who exhibited early Alpers-like encephalopathy or infantile onset epilepsy, global developmental delay with dysarthria and tremor, liver and eye abnormalities or spastic paraplegia. This report further characterizes the FARS2-related phenotype with marked intrafamilial variability. Case report and results: Four siblings were born from non-consanguineous parents. Patient 1 abruptly died at age 15 months in acute conditions including seizures, high fever, disseminated intravascular coagulation, high liver enzymes and rhabdomyolysis. Patient 2 is currently 22 years of age. She exhibited learning difficulties since early childhood and was diagnosed with intel- lectual disability. She developed epilepsy since the age 12 years and has tremor of upper extremities. Patient 3 is healthy. Patient 4 had learning and behavioural disturbances. At 6 years of age, he presented with an acute episode of hypotonia and pallor. In the following year, recurrent contact losses were noted. At age 8 years, he died from a sudden encephalitic episode with epilepsia partialis continua and severe necrotic lesions on brain MRI. Array CGH revealed a maternally inherited 70 kb deletion in FARS2. FARS2 sequencing found a novel paternally inherited heterozygous mutation, c.467 > T (p.Thr156Met). These combined FARS2 abnormalities were detected in patient 2 and are expected in early expired patient 1. Healthy patient 3 is heterozygous for the paternal mutation. Discussion: Our data further characterize FARS2 phenotype emphasizing high intrafamilial phenotypic variability. This is the third case of FARS2 disease caused by combination of a 6p25.1 deletion with a novel missense mutation, demonstrating that routine array CGH can be the first step prompting the identification of this recessive disorder