A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-77 (SPG77) is caused by homozygous or compound heterozygous mutation in the FARS2 gene (611592) on chromosome 6p25.

Biallelic mutation in the FARS2 gene can also cause combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), a much more severe multisystem disorder.

Spastic paraplegia-77 (SPG77) is an autosomal recessive neurologic disorder characterized by early-childhood onset of spasticity affecting the lower limbs and resulting in gait difficulties. The disorder is progressive and may be associated with childhood seizures, developmental delay, and mitochondrial dysfunction (Yang et al., 2016; Vernon et al., 2015; Vantroys et al., 2017).

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

Yang et al. (2016) reported 4 adult sibs, born of consanguineous Chinese parents, with onset of a pure spastic paraplegia in the first 5 years of life. All had slowly progressive lower limb spasticity, pyramidal weakness with hyperreflexia, and scissoring gait. One patient had extensor plantar responses and another had lower limb amyotrophy. Upper limbs were not affected. Two older patients were unable to walk independently at ages 30 and 41. None had additional neurologic signs, and brain imaging was normal. No additional studies of the patients or of patient tissue were reported.

Vernon et al. (2015) reported 2 sibs, a 5-year-old proband and her 14-year-old brother, with mitochondrial dysfunction and spastic paraplegia who were initially diagnosed with cerebral palsy. The proband had 1 seizure following vaccination in infancy; her EEG and brain imaging were normal at age 3 years. Her brother had several seizures before 6 weeks of age but without recurrence, and brain imaging at age 12 years showed 2 small foci of T2/FLAIR signal in the periventricular white matter and deep white matter of the right posterior frontal lobe. Both sibs showed global developmental delay without regression. Both had retrognathia, prominent incisors, and strabismus; the brother also has ptosis. Both patients showed truncal hypotonia, intention tremor, and dysarthric speech. The proband had elevated plasma lactate on 2 occasions, persistent metabolic acidosis, intermittent elevations in alanine on plasma amino acid analysis, and abnormal qualitative urine organic acid analysis on 2 occasions. Her brother had similar biochemical findings consistent with mitochondrial dysfunction.

Vantroys et al. (2017) reported 2 unrelated patients with mitochondrial dysfunction and spastic paraplegia. Proband 1 was a 19-year-old male who had onset at age 6 months with poor head control. At age 13 months, he could briefly sit independently. He had mild seizures between 15 and 30 months of age without recurrence. He never used words to communicate. At age 15 months, his biochemical findings indicated mitochondrial dysfunction: serum lactate was increased; organic acid profile in urine showed increase in lactate, pyruvate, alpha keto-glutarate, succinate, fumarate, and glutarate; amino acids showed elevations of alanine; and CSF lactate was elevated. At age 8 years, he could use a wheelchair independently, but he lost this ability at age 17 when he also had increasing problems chewing and swallowing, and progressively more apneic episodes. He underwent posterior spinal fusion for progressive scoliosis. Brain imaging showed bilateral, round, focal T2-hyperintense lesions in the anterior part of the mesencephalon. Proband 2 was a 15-year-old female who was small for gestational age and had problems feeding. She had delayed early milestones. She could ambulate with a walker at age 3 years, but at age 6 she lost the ability to ambulate and developed urinary incontinence. She had no seizures. Brain MRI showed extensive T2-hyperintense lesions. At age 15 she had bradykinesia and tremor as well as dystonia but no dysmetria or ataxia. She could communicate with short phrases but with slow and dysarthric speech. Proband 1 showed a complex IV deficiency in skeletal muscle and cultured skin fibroblasts, whereas proband 2 showed a complex I deficiency and low activity of complex IV in cultured skin fibroblasts but normal activities in skeletal muscle.

The transmission pattern of SPG77 in the family reported by Yang et al. (2016) was consistent with autosomal recessive inheritance.

In 4 sibs, born of consanguineous Chinese parents, with SPG77, Yang et al. (2016) identified a homozygous missense mutation in the FARS2 gene (D142Y; 611592.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the mutation resulted in severely impaired enzyme activity compared to wildtype.

In 2 sibs with mitochondrial dysfunction and spastic paraplegia, Vernon et al. (2015) identified compound heterozygous mutations in the FARS2 gene: a missense mutation (R429C; 611592.0006) and an intragenic deletion (611592.0007).

In 2 unrelated patients with mitochondrial dysfunction and spastic paraplegia, Vantroys et al. (2017) identified compound heterozygous mutations in the FARS2 gene (611592.0008-611592.0010). FARS2 catalyzes the charging of the tRNA-phe. Compared to normal control fibroblasts, patient fibroblasts showed a decreased amount of Phe-charged tRNA and a decrease in mitochondrial protein synthesis rate, which affected the assembly of OXPHOS complexes.