Objective: To communicate a novel mutation in the phenylalanyl-tRNA synthetase 2 (FARS2) gene causing spastic paraparesis.

Background: Hereditary spastic paraplegias (HSP) are a complex group of disorders with weakness, spasticity and upper motor neuron signs in the lower limbs as their main symptoms. Spastic paraplegia-77 (SPG77, OMIM#611592) is an autosomal recessive disorder caused by mutations in the FARS2 gene, which encodes for an enzyme taking part in the mitochondrial protein synthesis. The two main phenotypes of FARS2 deficiency are infantile-onset epileptic encephalopathy with lactic acidosis, and later-onset spastic paraplegia [1].

Method: 35-year-old woman with a history of mild fetal distress at birth and slightly delayed acquisition of motor milestones, normal cognition and slowly progressive gait impairment since age 4, with spasticity in the lower limbs requiring oral baclofen, botulinum toxin injections and Achilles tendon lengthening surgery. She had been previously diagnosed of cerebral palsy.
At age 13 she presented a remarkable worsening of those symptoms with speech problems and development of tremor.
On examination, she had mild dysarthria and voice and tongue tremor. In the upper limbs she had a bilateral severe asymmetric postural and kinetic tremor, and in the lower limbs there was mild weakness, spasticity and hyperreflexia. Her gait was spastic and she walked with a cane.

Results: She had low blood folic acid, vitamin D, copper and caeruloplasmin with normal urinary copper. Other blood tests, ophthalmologic evaluation, brain MRI and nerve conduction studies were unremarkable. Whole genome sequencing with a panel of 145 ataxia and spastic paraparesis genes disclosed a homozygous mutation in FARS2 gene exon3, c.G732T;p.K244N, probably pathogenic, with a SIFT and Polyphen2 score of 0 and 1, respectively. Her mother, affected with Parkinson’s disease, was heterozygous for that mutation, and her twin brother and her sister were non-carriers.

Conclusion: The phenotype of FARS2 deficiency is still being depicted [2,3], and this case reflects its heterogeneity. We consider it relevant to communicate this novel mutation and to emphasize the importance of a thorough examination and diagnostic testing in certain patients whose neurologic deficits are attributed to acute fetal distress, especially when later progression of symptoms is observed.

References: 1. Almannai M, Faqeih E, El-Hattab AW, et al. FARS2 Deficiency. 2019 Mar 14. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. 2. Vantroys E, Larson A, Friederich M, et al. New insights into the phenotype of FARS2 deficiency. MolGenet Metab 2017;122:172-181. 3. Yang Y, Liu W, Fang Z, et al. A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia. Hum Mutat 2016;37:165-9.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hereditary-spastic-paraparesis-plus-syndrome-associated-to-a-novel-fars2-gene-mutation/