Pure or complex autosomal dominant spastic paraplegia
-Rare genetic disease
-Rare neurologic disease
Comment:
REEP1 is an ER protein within the DP1/Yop1p superfamily. Members of the DP1/Yop1p protein family form higher-order oligomeric structures. REEP1 forms higher-order oligomers as well (PMID:20200447).
Mutations in the receptor expression enhancing protein 1 (REEP1) gene have recently been reported to be associated with an autosomal dominant HSP phenotype (SPG31) (PMID:19034539).
Zuchner et al. (2006) described 2 multigenerational Caucasian families with an autosomal dominant form of uncomplicated spastic paraplegia. All patients studied had typical signs of spastic paraplegia mainly characterized by proximal weakness of the lower extremities with brisk ... Zuchner et al. (2006) described 2 multigenerational Caucasian families with an autosomal dominant form of uncomplicated spastic paraplegia. All patients studied had typical signs of spastic paraplegia mainly characterized by proximal weakness of the lower extremities with brisk reflexes and spastic gait abnormalities. The upper extremities showed normal tone and only very mild weakness of the small hand muscles. The sensory system was not involved. No additional neurologic symptoms were present that suggested cerebellar or visual involvement. The average age of onset in one pedigree was 27.7 years. In the second smaller family, the average age of onset was 11.8 years. However, some affected individuals developed symptoms in their fifties and sixties. Hewamadduma et al. (2009) reported 3 unrelated British families with genetically confirmed SPG31. In 1 family, the age of onset ranged between 15 and 30 years and was associated with spasticity affecting all 4 limbs, pes cavus, severe gait disturbance, lower limb muscle atrophy, and loss of distal joint position and vibration sense. All required a wheelchair by age 30 to 35 years. The proband of the second family developed progressive unsteadiness of gait with increased tone and hyperreflexia in the upper and lower limbs at the age of 25. Her gait deteriorated significantly, and she became wheelchair-bound. She also had mild distal sensory loss. There was no muscle wasting. The proband of the third family had difficulty in walking and running since age 9 years. At age 27, she had severe spastic tetraparesis with bulbar dysfunction, including dysarthria and dysphagia. Hewamadduma et al. (2009) noted that SPG31 can be associated with both pure and complicated phenotypes.
On the basis of emerging pathways for spastic paraplegia and conserved protein domains contained in proteins that cause neurodegenerative diseases, Zuchner et al. (2006) chose 9 candidate genes in the critical linkage region. Sequencing all exons and flanking ... On the basis of emerging pathways for spastic paraplegia and conserved protein domains contained in proteins that cause neurodegenerative diseases, Zuchner et al. (2006) chose 9 candidate genes in the critical linkage region. Sequencing all exons and flanking intronic and UTR sequences of these genes, they identified a single-bp deletion in the REEP1 gene, 507delC, in 1 family (609139.0001). In a second family they found a splice site mutation, 182-2A-G (609139.0002). These sequence changes resulted in frameshifts leading to altered stop codons. For additional REEP1 mutations, Zuchner et al. (2006) screened a sample of 90 independent HSP-affected families of European descent, neither selected for pure HSP phenotype nor tested for mutations in other HSP genes. They identified 4 more mutations that led to significant sequence changes in REEP1. Altogether Zuchner et al. (2006) found that REEP1 mutations occurred in 6.5% of patients with HSP in their sample, making it the third most common HSP gene. Since REEP1 is widely expressed and localized to mitochondria, the findings underscored the importance of mitochondrial function in neurodegenerative disease. Beetz et al. (2008) identified 16 different mutations, including 14 novel mutations, in the REEP1 gene (see, e.g., 609139.0003-609139.0004) in 16 (3.0%) of 535 unrelated patients with familial or sporadic SPG. Small frameshift mutations were the most common type of REEP1 mutation. Most patients with confirmed SPG31 had a pure phenotype, although some also reported impaired distal vibration sense, urge incontinence, or distal amyotrophy. There was a bimodal distribution of age onset: most (71%) patients had onset in the first or second decade, whereas the rest had onset after age 30 years. Mutations were distributed throughout the gene, except for exon 3, and there were no apparent genotype/phenotype correlations. Beetz et al. (2008) postulated haploinsufficiency as the main molecular genetic mechanism. In affected members of 3 unrelated British families with SPG31, Hewamadduma et al. (2009) identified 2 different heterozygous mutations in the REEP1 gene (609139.0003 and 609139.0005). The REEP1 mutation frequency in their overall cohort of 133 probands was 2.3%.