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). ... 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). 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 ... 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.
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 ... 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.