Mutations in the ER-shaping protein reticulon 2 (SPG12 / RTN2) cause the axon-degenerative disorder hereditary spastic paraplegia type 12 (HSP12) (PMID:22232211).
Spastic paraplegia-12 is an autosomal dominant neurodegenerative disorder characterized by lower limb spasticity and hyperreflexia, resulting in walking difficulties. Some patients may have urinary symptoms and distal sensory impairment. The age at onset is variable and can range ... Spastic paraplegia-12 is an autosomal dominant neurodegenerative disorder characterized by lower limb spasticity and hyperreflexia, resulting in walking difficulties. Some patients may have urinary symptoms and distal sensory impairment. The age at onset is variable and can range from childhood to adulthood (summary by Montenegro et al., 2012). For a general description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
Reid et al. (2000) reported a Welsh family with autosomal dominant spastic paraplegia. Montenegro et al. (2012) reported follow-up of this family, which included 9 affected individuals. The mean age at onset was 6.8 years (range, 5-22 years), ... Reid et al. (2000) reported a Welsh family with autosomal dominant spastic paraplegia. Montenegro et al. (2012) reported follow-up of this family, which included 9 affected individuals. The mean age at onset was 6.8 years (range, 5-22 years), and all had moderate lower limb spasticity and weakness. Two had lower limb muscle wasting. Other features included hyperreflexia and extensor plantar responses; 3 patients had bladder disturbances. Orlacchio et al. (2002) reported a large nonconsanguineous Italian family in which 16 members in 4 generations were affected with a rapidly progressive form of spastic paraplegia. Mean age of onset was 14 years, and most patients required use of a wheelchair within 4 years after onset. Other clinical features included lower limb hyperreflexia, bilateral extensor plantar responses, lower urinary tract symptoms, and decreased vibration sense. There was a trend toward earlier age of onset in subsequent generations.
In affected members of the families with SPG12 reported by Reid et al. (2000) and Orlacchio et al. (2002), Montenegro et al. (2012) identified a heterozygous truncating mutation in the RTN2 gene (603183.0001). Heterozygous mutations in the gene ... In affected members of the families with SPG12 reported by Reid et al. (2000) and Orlacchio et al. (2002), Montenegro et al. (2012) identified a heterozygous truncating mutation in the RTN2 gene (603183.0001). Heterozygous mutations in the gene were found in 2 additional unrelated patients with later onset of the disorder (603183.0002 and 603183.0003). One of the unrelated patients was ascertained from a cohort of 342 patients of mixed European descent and 160 Japanese patients, all with spastic paraplegia who did not have mutations in the SPAST gene (604277).