A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-82 (SPG82) is caused by homozygous or compound heterozygous mutation in the PCYT2 gene (602679) on chromosome 17q25.

Autosomal recessive spastic paraplegia-82 (SPG82) is a progressive neurologic disorder characterized by global developmental delay apparent from infancy, significant motor impairment, and progressive spasticity mainly affecting the lower limbs. Some patients never achieve walking, whereas others lose the ability to walk or walk with an unsteady gait. Additional features include variably impaired intellectual development with language difficulties, ocular anomalies, such as nystagmus and visual impairment, and seizures. Brain imaging shows progressive cerebral and cerebellar atrophy, as well as white matter hyperintensities. Based on the additional abnormalities, the disorder can be classified as a type of complicated SPG (summary by Vaz et al., 2019).

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

Vaz et al. (2019) reported 5 patients from 4 unrelated families, 3 of which were consanguineous, with SPG82. The patients, who ranged in age from 3 to 20 years, presented with delayed motor development associated with progressive spasticity mainly affecting the lower limbs with hyperreflexia and extensor plantar responses. Two patients never achieved walking, 1 lost the ability, and 2 walked with an unsteady ataxic gait. All developed childhood-onset seizures that were mostly controlled, and all had impaired intellectual development, which was severe in 2 and mild in 3; the 2 severely affected individuals were nonverbal. More variable features included poor overall growth, rotary nystagmus, tremor, sensorineural hearing loss, visual impairment, axial hypotonia, poor motor coordination, dysarthria, ankle clonus, scoliosis, and joint contractures in older patients. Brain imaging was normal at first but later showed progressive cerebral and cerebellar atrophy, as well as white matter hyperintensities.

Kaiyrzhanov et al. (2021) reported a patient (case 1) with SPG82 who presented at 3 years of age with reduced vision. At 5 years of age, she was diagnosed with severe early-onset retinal dystrophy and was found to have cataracts. She did not have intellectual impairment. She developed seizures at age 13 years and progressive bilateral sensorineural hearing loss at age 19 years. At age 16 years, she developed a gait abnormality, hyperreflexia, ataxia, and nystagmus. MRIs showed cerebellar atrophy and atrophy of the thoracic spinal cord.

The transmission pattern of SPG82 in the families reported by Vaz et al. (2019) was consistent with autosomal recessive inheritance.

In 5 patients from 4 unrelated families with SPG82, Vaz et al. (2019) identified homozygous or compound heterozygous mutations in the PCYT2 gene (602679.0001-602679.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing through different laboratories, segregated with the disorder in all families. Patient fibroblasts showed significantly decreased, but not absent, PCYT2 activity compared to controls; residual activity ranged from 15 to 20% of controls. Western blot analysis showed absence of the normal 49-kD protein, with variably decreased levels of the normally most abundant protein. Detailed lipidomic studies of patient fibroblasts showed several abnormalities, including accumulation of phosphatidylcholine etherphospholipids (PC(O)), neutral lipid species, and neutral etherlipid species. There was also a decrease in PE(O) (PE etherphospholipids) and PE/PC plasmalogen species. Patient blood samples also showed an abnormal accumulation of PC(O) compared to controls. Since some of the lipid levels did not reach expected levels of change, the authors suggested compensatory biochemical pathways. In summary, Vaz et al. (2019) concluded that etherlipid homeostasis is critical for the development and function of the brain.

In a patient (case 1) with SPG82, Kaiyrzhanov et al. (2021) identified compound heterozygous mutations in the PCYT2 gene (602679.0004 and 602679.0005). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations.