SPG28 is an autosomal recessive neurodegenerative disorder characterized by early-onset, slowly progressive lower-limb spasticity resulting in walking difficulties. Some patients also have distal sensory impairment (summary by Tesson et al., 2012).
For a general phenotypic description ... SPG28 is an autosomal recessive neurodegenerative disorder characterized by early-onset, slowly progressive lower-limb spasticity resulting in walking difficulties. Some patients also have distal sensory impairment (summary by Tesson et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.
Bouslam et al. (2005) reported a consanguineous Moroccan family in which 3 members had pure spastic paraplegia with distal sensory loss in the lower limbs; 1 had mild upper limb involvement. Features included hyperreflexia of the lower limbs, ... Bouslam et al. (2005) reported a consanguineous Moroccan family in which 3 members had pure spastic paraplegia with distal sensory loss in the lower limbs; 1 had mild upper limb involvement. Features included hyperreflexia of the lower limbs, extensor plantar responses, lower limb weakness, and difficulty walking. Age at onset ranged from 6 to 15 years, and the disorder was slowly progressive. The patient with earliest onset also had pes cavus and scoliosis. Tesson et al. (2012) reported 3 patients from 2 unrelated families with SPG28. Two Turkish brothers, born of consanguineous parents, showed progressive spastic gait with onset around adolescence. One brother also had a cerebellar oculomotor disturbance with saccadic eye pursuit. An unrelated 62-year-old French woman had spastic paraplegia since infancy and also had an axonal neuropathy.
In 3 affected members of the consanguineous Moroccan family with autosomal recessive SPG28 originally reported by Bouslam et al. (2005), Tesson et al. (2012) identified a homozygous mutation in the DDHD1 gene (614603.0001). The mutation, which was identified ... In 3 affected members of the consanguineous Moroccan family with autosomal recessive SPG28 originally reported by Bouslam et al. (2005), Tesson et al. (2012) identified a homozygous mutation in the DDHD1 gene (614603.0001). The mutation, which was identified by exome sequencing of the candidate region and confirmed by Sanger sequencing, was not present in several large control databases. Biallelic mutations in the DDHD1 gene (614603.0002-614603.0004) were identified in affected individuals from 2 additional families with a similar phenotype. In the same study, Tesson et al. (2012) identified pathogenic mutations in the CYP2U1 gene (610670) as a cause of SPG56 (615030). 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. Loss of DDHD1 function could result in reduced phospholipase A1 activity, causing increased phospholipid in the mitochondrial membrane that may disrupt its function. DDHD1 also works in the endoplasmic reticulum to form lipid messengers; these phospholipids and fatty acids can serve as precursors of a variety of lipid messengers and thus 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.