Alternative titles; symbols
SNOMEDCT: 764686003; ORPHA: 100996; DO: 0110768;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q24.1 | Spastic paraplegia 15, autosomal recessive | 270700 | Autosomal recessive | 3 | ZFYVE26 | 612012 |
A number sign (#) is used with this entry because of evidence that spastic paraplegia-15 (SPG15) is caused by homozygous or compound heterozygous mutation in the gene encoding spastizin (ZFYVE26; 612012) on chromosome 14q24.
Spastic paraplegia-15 (SPG15) is an autosomal recessive neurodegenerative disorder characterized by progressive spasticity primarily affecting the lower limbs. It is a complex form of spastic paraplegia, associated with other neurologic dysfunction, including variable mental retardation, hearing and visual defects, and thin corpus callosum (summary by Goizet et al., 2009).
For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).
Louis-Bar and Pirot (1945) described 2 brothers with macular degeneration and spastic paraplegia referred to by the authors as 'Strumpell type.' A third brother was said to have a forme fruste of spastic paraplegia. They could find no report of similar cases. Family 1 of Ledic and Van Bogaert (1960) may be identical.
Kjellin (1959) reported 2 pairs of brothers from 2 kindreds who had spastic paraplegia, distal amyotrophy of the hands, mental retardation, and central retinal degeneration. Mental retardation in all patients was present since birth, and onset of spastic paraplegia was in the third decade.
Mahloudji and Chuke (1968) reported a female with late-onset spastic paraplegia and retinal degeneration more striking peripherally. A sister was identically affected, and another sister had only spastic paraplegia. Follow-up studies by Stieffel and Todorov (1974) showed that the third sister had developed the typical retinal changes and that out of the sibship of 11, two more (5 in all) were affected. The affected persons were mentally dull. Onset was between ages 30 and 36 years.
Hughes et al. (2001) studied 2 Irish families with autosomal recessive SPG complicated by additional symptoms of pigmented maculopathy, distal amyotrophy, dysarthria, mental retardation, and further intellectual deterioration.
Sachdev et al. (2005) reported a 32-year-old woman with dysarthria, spastic paraplegia, and dementia. Fundus examination showed yellow retinal lesions and fluorescein angiography demonstrated retinal flecks. Isolated flecks were observed in both her parents, suggesting that carriers of this presumably autosomal recessive disorder may have mild manifestations.
Elleuch et al. (2007) reported 3 large consanguineous Arab families with an autosomal recessive spastic paraplegia showing linkage to the SPG15 locus. Age at onset ranged from 10 to 19 years. Clinical features included spastic paraplegia, saccadic pursuit, cognitive impairment, cerebellar signs, and thin corpus callosum in those studied by MRI. Variable features included axonal peripheral neuropathy, extrapyramidal signs, and white matter abnormalities. Decreased visual acuity was not found. Elleuch et al. (2007) emphasized the clinical variability of SPG15.
Boukhris et al. (2008) reported 3 consanguineous Tunisian families of Arab origin with SPG15. Age at onset ranged from 8 to 16 years, and all had slowly progressive lower limb spasticity and mental impairment. Distal amyotrophy was observed in 3 patients and pes cavus in 2 patients. Some patients had mild upper limb involvement. Three had dysarthria, and 2 had axonal and demyelinating polyneuropathy. There was no ocular involvement.
Goizet et al. (2009) reported 11 patients from 8 families with SPG15, including a family reported by Boukhris et al. (2008). The mean age at onset was 13 years (range, 4 to 18 years), and most presented with gait disturbances, such as stumbling, tripping, and stiffness in the lower limbs. Three patients presented with learning disabilities and mental retardation. After a mean disease duration of 18.8 years, all had a moderate to severe disorder, with 6 of 10 being wheelchair-bound, and 9 having mental impairment. All patients had lower limb hyperreflexia, spasticity, and extensor plantar responses, and most had severe weakness. Other variable signs included pseudobulbar dysarthria (7 of 10), bladder dysfunction (4 of 10), nystagmus (4 of 10), upper limb spasticity with weakness (4 of 10), distal or diffuse amyotrophy (5 of 10), and axonal peripheral neuropathy (5 of 9). Three of 7 patients had degenerative retinal changes on funduscopy. All 7 patients examined had brain abnormalities, most commonly thin corpus callosum and white matter hyperintensities. Less common features included hand tremor and decreased vibration sense, each in 2 patients, and cerebellar ataxia, upper limb distal amyotrophy, pes cavus, epilepsy, frontotemporal dementia, behavioral disturbances, limited lateral ocular movements, and diabetes in 1 patient each.
The transmission pattern of spastic paraplegia in the families reported by Hughes et al. (2001) was consistent with autosomal recessive inheritance.
In 2 families with autosomal recessive SPG, Hughes et al. (2001) obtained evidence for linkage to a locus on chromosome 14q distinct from the SPG3 locus (182600) for autosomal dominant SPG. A lod score of 4.20 was found at zero recombination with D14S77. Haplotype construction of nearby markers confirmed the existence of this novel locus, designated SPG15, and narrowed it to a 19-cM interval on chromosome 14q22-q24.
Elleuch et al. (2007) refined the SPG15 locus to a 5.3-Mb interval on chromosome 14q between markers D14S981 and rs8688 by genomewide linkage analysis and haplotype reconstruction of 3 large consanguineous families of Arab origin with a phenotype consistent with SPG15. Direct sequencing excluded mutations in the GPHN (603930) and SLC8A3 (607991) genes.
Mannan et al. (2006) failed to identify mutations in the coding or flanking intronic sequences of the RTN1 gene (600865) on chromosome 14q23.1 in 2 index patients from the SPG15 families reported by Hughes et al. (2001).
In affected individuals from 8 families with SPG15, Hanein et al. (2008) identified 6 different homozygous mutations in the ZFYVE26 gene (see, e.g., 612012.0001-612012.0004). The families had previously been reported by Hughes et al. (2001), Elleuch et al. (2007), Casali et al. (2004), and Boukhris et al. (2008).
Goizet et al. (2009) identified 12 different biallelic truncating mutations in the ZFYVE26 gene (see, e.g., 612012.0005-612012.0006) in affected members of 8 families with SPG15.
Boukhris et al. (2009) identified a molecular basis for hereditary spastic paraplegia in 13 (34.2%) of 38 unrelated families from southern Tunisia with the disorder. The most common forms of SPG were SPG11 in 7 (18.4%) families and SPG15 in 4 (10.5%) families. SPG4 (182601) and SPG5 (270800) were present in 1 family each.
Goizet et al. (2009) reported that among a larger cohort of patients with SPG and thin corpus callosum from France, Belgium, Austria, North Africa, and the Middle East, SPG15 was the second most common type, accounting for 11.5%, after SPG11 (604360), which accounted for 59%. They calculated that SPG15 accounts for about 4% of autosomal recessive hereditary spastic paraplegias, and SPG11 accounts for about 21%.
Boukhris, A., Feki, I., Denis, E., Miladi, M. I., Brice, A., Mhiri, C., Stevanin, G. Spastic paraplegia 15: linkage and clinical description of three Tunisian families. Mov. Disord. 23: 429-433, 2008. [PubMed: 18098276] [Full Text: https://doi.org/10.1002/mds.21848]
Boukhris, A., Stevanin, G., Feki, I., Denora, P., Elleuch, N., Miladi, M. I., Goizet, C., Truchetto, J., Belal, S., Brice, A., Mhiri, C. Tunisian hereditary spastic paraplegias: clinical variability supported by genetic heterogeneity. Clin. Genet. 75: 527-536, 2009. [PubMed: 19438933] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01176.x]
Casali, C., Valente, E. M., Bertini, E., Montagna, G., Criscuolo, C., De Michele, G., Villanova, M., Damiano, M., Pierallini, A., Brancati, F., Scarano, V., Tessa, A., and 11 others. Clinical and genetic studies in hereditary spastic paraplegia with thin corpus callosum. Neurology 62: 262-268, 2004. [PubMed: 14745065] [Full Text: https://doi.org/10.1212/wnl.62.2.262]
Elleuch, N., Bouslam, N., Hanein, S., Lossos, A., Hamri, A., Klebe, S., Meiner, V., Birouk, N., Lerer, I., Grid, D., Bacq, D., Tazir, M., Zelenika, D., Argov, Z., Durr, A., Yahyaoui, M., Benomar, A., Brice, A., Stevanin, G. Refinement of the SPG15 candidate interval and phenotypic heterogeneity in three large Arab families. Neurogenetics 8: 307-315, 2007. [PubMed: 17661097] [Full Text: https://doi.org/10.1007/s10048-007-0097-x]
Goizet, C., Boukhris, A., Maltete, D., Guyant-Marechal, L., Truchetto, J., Mundwiller, E., Hanein, S., Jonveaux, P., Roelens, F., Loureiro, J., Godet, E., Forlani, S., and 12 others. SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum. Neurology 73: 1111-1119, 2009. [PubMed: 19805727] [Full Text: https://doi.org/10.1212/WNL.0b013e3181bacf59]
Hanein, S., Martin, E., Boukhris, A., Byrne, P., Goizet, C., Hamri, A., Benomar, A., Lossos, A., Denora, P., Fernandez, J., Elleuch, N., Forlani, S., Durr, A., Feki, I., Hutchinson, M., Santorelli, F. M., Mhiri, C., Brice, A., Stevanin, G. Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am. J. Hum. Genet. 82: 992-1002, 2008. [PubMed: 18394578] [Full Text: https://doi.org/10.1016/j.ajhg.2008.03.004]
Hughes, C. A., Byrne, P. C., Webb, S., McMonagle, P., Patterson, V., Hutchinson, M., Parfrey, N. A. SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q. Neurology 56: 1230-1233, 2001. [PubMed: 11342696] [Full Text: https://doi.org/10.1212/wnl.56.9.1230]
Kjellin, K. Familial spastic paraplegia with amyotrophy, oligophrenia, and central retinal degeneration. Arch. Neurol. 1: 133-140, 1959. [PubMed: 14409555] [Full Text: https://doi.org/10.1001/archneur.1959.03840020007002]
Ledic, P., Van Bogaert, L. Cerebellar and spastic heredo-degeneration with macular degeneration. J. Genet. Hum. 9: 140-157, 1960. [PubMed: 13760186]
Louis-Bar, D., Pirot, G. Sur une paraplegie spasmodique avec degenerescence maculaire chez deux freres. Ophthalmologica 109: 32-43, 1945.
Macrae, W., Stieffel, J., Todorov, A. B. Recessive familial spastic paraplegia with retinal degeneration. Acta Genet. Med. Gemellol. 23: 249-252, 1974.
Mahloudji, M., Chuke, P. O. Familial spastic paraplegia with retinal degeneration. Johns Hopkins Med. J. 123: 142-144, 1968. [PubMed: 5672932]
Mannan, A. U., Boehm, J., Sauter, S. M., Rauber, A., Byrne, P. C., Neesen, J., Engel, W. Spastin, the most commonly mutated protein in hereditary spastic paraplegia interacts with reticulon 1 an endoplasmic reticulum protein. Neurogenetics 7: 93-103, 2006. [PubMed: 16602018] [Full Text: https://doi.org/10.1007/s10048-006-0034-4]
Sachdev, A., Proudlock, F. A., Abbott, R., Gottlob, I. Kjellin syndrome: first case with retinal changes in carriers. Neurology 65: 1110 only, 2005. [PubMed: 16217069] [Full Text: https://doi.org/10.1212/01.wnl.0000182290.78138.69]
Stieffel, J. W., Todorov, A. B. Recessive spastic paraplegia with retinal degeneration. Birth Defects Orig. Art. Ser. X(4): 343-344, 1974.