A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-56 with or without pseudoxanthoma elasticum (SPG56) is caused by homozygous or compound heterozygous mutation in the CYP2U1 gene (610670) on chromosome 4q25.

Spastic paraplegia-56 with or without pseudoxanthoma elasticum (SPG56) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive lower-limb spasticity resulting in walking difficulties. Upper limbs are often also affected, and some patients may have a subclinical axonal neuropathy (summary by Tesson et al., 2012). Some patients also have pseudoxanthoma elasticum (Legrand et al., 2021).

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

Tesson et al. (2012) reported 5 unrelated families with autosomal recessive spastic paraplegia. Two were consanguineous and of Saudi Arabian origin. The other families were of Italian, Egyptian, or mixed Spanish/Vietnamese descent. Affected individuals developed spastic paraplegia, often involving the upper limbs, in the first decade (range, birth to age 8 years). Features included delayed walking, toe walking, unsteady gait, spastic gait, hyperreflexia of the lower limbs, and extensor plantar responses. Two patients had dystonic posturing of the upper limbs, and 3 had cognitive impairment or mental retardation. Five patients also had evidence of a subclinical axonal neuropathy, predominantly in the lower limbs. Brain MRI showed white matter lesions in 3 patients and a thin corpus callosum in 1 patient. During follow-up, 2 sibs with white matter lesions developed calcifications in the globus pallidus. Symptom severity varied widely, even within the same family.

Pujol et al. (2021) reported clinical characteristics in 23 patients, aged 2 to 45 years, with SPG56. Most of the patients presented at less than 3 years of age with delayed motor milestones. Predominant lower limb manifestations were seen; however, 13 patients also had upper limb involvement. Seventeen patients had cognitive impairment. All adult patients who had ophthalmologic examination were found to have macular dystrophy. Brain MRIs in 15 patients showed white matter abnormalities in the periventricular region with a radial distribution.

Legrand et al. (2021) reported 3 patients with pseudoxanthoma elasticum and complicated spastic paraplegia with mutation in the CYP2U1 gene. Patient 1 presented with vision loss and maculopathy at 12 years of age. At age 25 she developed an unsteady gait, and 2 years later she was diagnosed with pseudoxanthoma elasticum of her neck and axillae. At age 30 she had spastic ataxia with dysarthria and kinetic ataxia. Brain MRI and CT demonstrated bipallidal calcifications and cerebellar atrophy. Ophthalmologic examination demonstrated angioid retinal streaks, reduced retinal thickness, and signs of choroidal neovascularization. Patient 2 presented at 33 years of age with pain in the lower extremities that spread to her upper extremities. She had cognitive decline, spastic gait, tremor, and muscle weakness. Brain MRI showed basal ganglia calcifications. At age 37 she was diagnosed with pseudoxanthoma elasticum of her neck, axillae, and antecubital fossa. Patient 3 had slowly progressive spastic paraplegia starting at the age of 2 years. Brain CT at age 6 showed subcortical white matter calcifications. At age 27 she had spasticity of all 4 limbs. She developed visual impairment due to fibrotic scarring of the macula at age 7 years. At age 12 she developed pseudoxanthoma elasticum in multiple areas including the neck, abdomen, axillae, and groin.

Pujol et al. (2021) performed lipidomic analysis of blood from 7 patients and showed a significant increase in CoQ10 and CoQ9. The oxidized form of CoQ10 was significantly increased in the patients compared to controls. Studies in CSF from 3 patients showed elevated neopterin levels, which Pujol et al. (2021) considered likely to be markers of folate deficiency.

The transmission pattern of spastic paraplegia in the families reported by Tesson et al. (2012) was consistent with autosomal recessive inheritance.

By genomewide linkage analysis of a large consanguineous Saudi Arabian kindred with autosomal recessive spastic paraplegia, Tesson et al. (2012) found linkage to a region on chromosome 4q25 (maximum multipoint lod score of 4.76). A second affected Saudi family also showed linkage to this region. Both families shared a homozygous haplotype, yielding a 3.8-Mb candidate region between markers D4S3256 and D4S2940.

In affected members of 2 consanguineous Saudi Arabian families with autosomal recessive spastic paraplegia, Tesson et al. (2012) identified a homozygous mutation in the CYP2U1 gene (D316V; 610670.0001). The mutation was found by linkage analysis followed by exome sequencing of the candidate region. Sequencing of this gene in 94 additional SPG patients identified biallelic mutations in 3 families (610670.0002-610670.0005). In the same study, Tesson et al. (2012) identified pathogenic mutations in the DDHD1 gene (614603) as a cause of SPG28 (609340). Both the DDHD1 and CYP2U1 gene products were expressed concomitantly in the developing mouse brain, and both showed partial mitochondrial localization. Mutant cells from SPG28 and SPG56 patients showed significantly lower mitochondrial respiration activity, lower ATP levels, and increased cytosolic hydrogen peroxide compared to controls. However, isolated catalytic activities of each of the respiratory chain complexes, measured after disruption of the mitochondrial membrane, were similar to controls. SPG56 fibroblasts showed structural abnormalities, suggesting a defect in mitochondrial membrane organization. CYP2U1 can catalyze the hydroxylation of arachidonic acid and related long-chain fatty acids, which are mediators of signaling pathways and may affect signaling of hormones or neurotransmitters. In addition, accumulation of reactive oxygen species may contribute to neurodegeneration. The study indicated that both DDHD1 and CYP2U1 are involved in the same pathway related to lipid metabolism and disruption of mitochondrial function, suggesting a common disease pathway in SPG.

In a patient with SPG56 and pseudoxanthoma elasticum from a cohort of 47 patients who had zero or only 1 mutation in the ABCC6 gene (603234), Legrand et al. (2021) identified compound heterozygous missense mutations in the CYP2U1 gene (610670.0005 and 610670.0006). The mutations were identified by whole-exome sequencing. Sequencing of the CYP2U1 gene in the rest of the cohort identified 2 additional patients with SPG56 and biallelic mutations (610670.0007-610670.0009).

Tesson et al. (2012) referred to this disorder as SPG49. However, Oz-Levi et al. (2012) also used the designation SPG49 (615031) to refer to a disorder caused by mutation in the TECPR2 gene (615000). Because the study by Oz-Levi et al. (2012) was accepted for publication before that of Tesson et al. (2012), the disorder caused by mutation in the CYP2U1 gene is referred to here as SPG56.

Pujol et al. (2021) characterized a Cyp2u1 knockout (Cyp2u1 -/-) mouse model with a homozygous deletion in exon 2. At 2 months of age mutant mice showed a significant defect in short-term memory, which slightly progressed over time. At 18 months of age the mutant mice developed photoreceptor cone degeneration. Proteomics analysis of hippocampi from the mutant mice demonstrated deregulation of MTHFD1L (611427), implicating folate metabolism in disease pathogenesis. Mutant mice were treated starting in utero with sodium formate supplementation, which resulted in no cognitive defects at 2 months of age.