ORPHA: 99013; DO: 0110816;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16q24.3 | Spastic paraplegia 7, autosomal recessive | 607259 | Autosomal dominant; Autosomal recessive | 3 | PGN | 602783 |
A number sign (#) is used with this entry because spastic paraplegia-7 (SPG7) is caused by homozygous or compound heterozygous mutation in the paraplegin gene (SPG7; 602783) on chromosome 16q24. Some patients with the disorder carry heterozygous SPG7 mutations.
Hereditary spastic paraplegia (SPG) is characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons. There is considerable genetic heterogeneity. Inheritance is most often autosomal dominant (see 182600), but X-linked (see 312920) and autosomal recessive (see 270800) forms occur.
SPG7 shows phenotypic variability between families. Some cases are pure, whereas other are complicated with additional neurologic features (Warnecke et al., 2007).
De Michele et al. (1998) reported a large consanguineous family with autosomal recessive spastic paraplegia with age of onset between 25 and 42 years (mean 30 +/- 8 years). Abnormal gait was the presenting symptom in all cases, and it was associated with leg pains in 1 patient. Weakness and extensor plantar response were absent in 1 patient with the shortest duration of disease at the time of observation. Vibration sense was frequently decreased in the lower limbs. Hypernasal and slowed speech was present in 2 patients and dysphagia in 1. Urinary urgency was present in 3 patients, scoliosis and pes cavus in 2, and pale optic disc in 2. There were no cerebellar or extrapyramidal signs in any of the 6 affected individuals (3 persons in each of 2 sibships who were related as double first cousins, having been born from brothers married to sisters).
Casari et al. (1998) reported 2 affected brothers from a small village in southern Italy who showed typical signs of pure SPG with an age of onset of 26 years. Casari et al. (1998) reported a French family with autosomal recessive complicated SPG characterized by progressive weakness and spasticity of the lower limbs, decreased perception of sharp stimulation, diminished vibratory sense, and urinary incontinence. Mean age of onset was 34 years. These patients also had optic atrophy (3 of 3 examined), cortical atrophy (1 of 3 examined), and cerebellar atrophy (2 of 3 examined). Muscle biopsies showed ragged-red fibers and abnormal mitochondrial structure with no reaction to cytochrome c oxidase, consistent with a defect in mitochondrial respiration.
Elleuch et al. (2006) reported a Moroccan family in which 4 sibs had SPG7. Age at onset ranged from 28 to 32 years with instability and stiff legs, which rapidly progressed to lower limb spasticity and weakness with hyperreflexia. Three patients could not run, and 1 could walk only with help. All had pes cavus, but none had extensor plantar responses. One patient had nystagmus, another had cerebellar signs, and a third had bladder dysfunction; none had decreased visual acuity. Two patients had impaired sensation at the ankles.
Warnecke et al. (2007) reported a consanguineous Turkish family in which 3 sibs had a complicated form of SPG7. Age at onset ranged from 10 to 25 years, with gait disturbances in 2 sibs and dysarthria in 1. Clinical features included lower limb spasticity, pyramidal signs, lower limb hyperreflexia, supranuclear palsy, nystagmus, and cerebellar dysarthria. Two of the sibs, who were more severely affected, also had ataxia and extensor plantar responses, and 1 had urinary incontinence. Neuropsychologic evaluations showed severe deficits in attention and executive function in all sibs. The more severely affected sibs also showed impaired working memory and verbal learning. However, none of the sibs reported cognitive deficits. Brain MRI showed cerebellum atrophy and mild frontal cortical atrophy. Diffusion tensor imaging showed decreased white matter in the corticospinal tracts, frontal lobes, and midbrain. There was no evidence of peripheral neuropathy or optic atrophy. Molecular analysis identified a homozygous mutation in the SPG7 gene (602783.0006). Warnecke et al. (2007) suggested that the diffuse involvement may reflect mitochondrial dysfunction.
Eriksen et al. (2022) described a 57-year-old man, born to first-cousin Caucasian parents, with childhood optic nerve atrophy and SPG7. Bilateral progressive vision loss bagan at age 6 years, and a diagnosis of idiopathic optic nerve atrophy was made at the age of 20. The findings of spastic paraplegia were subtle, and the diagnosis was not suspected until the likely pathogenic SPG7 mutation was identified. At age 52 years, the patient had an episode of aphasia and convulsions without loss of consciousness. Neurologic evaluation at that time included brain MRI, CT angiography, and an EEG, which were all normal. He was noted to have a broad-based gait. At age 57, he had further acute vision loss and noted that he had had 2 episodes of transient aphasia in previous months. Ophthalmologic examination showed poor visual function limited to light perception bilaterally. He had left esotropia, conjugate gaze palsy, and pendular nystagmus. Funduscopic examination showed pale optic discs with slightly increased cupping. Cerebral CT and MRI showed late sequelae of multiple lacunar infarcts and generalized cerebral and cerebellar atrophy. Identification of the likely pathogenic variant in the SPG7 gene led to neurologic evaluation, which showed somewhat reduced tongue movements, mild right dysdiadokokinesia, increased muscle tone in the lower limbs, mildly reduced muscle strength in the ankle dorsiflexors, and broad-based gait with mild ataxia. The authors speculated that the cerebral stroke-like changes could be secondary to involvement of a mitochondrial membrane protein in SPG7.
Although SPG7 has classically been considered to show an autosomal recessive mode of inheritance, there is also evidence for autosomal dominant transmission in some families (Sanchez-Ferrero et al., 2013).
In a large consanguineous family with SPG, De Michele et al. (1998) demonstrated linkage to 16q24.3, with markers D16S413 (maximum lod score 3.37 at a recombination fraction of 0.00) and D16S303 (maximum lod score 3.74 at a recombination fraction of 0.00). Multipoint analysis localized the disease gene in the most telomeric region, with a lod score of 4.2.
Casari et al. (1998) found that all affected individuals from the SPG7 family reported by De Michele et al. (1998) were homozygous for a 9.5-kb deletion (602783.0003) in the SPG7 gene.
In 1 of 2 brothers from a small village in southern Italy who had autosomal recessive hereditary pure spastic paraplegia, Casari et al. (1998) identified a homozygous 2-bp deletion in the paraplegin cDNA (602783.0001), resulting in a frameshift that abolished approximately 60% of the protein. In a French family with SPG, they identified homozygosity for a 1-bp insertion (602783.0002) in all affected sibs; the mother was heterozygous for the mutation.
In 4 affected sibs from a Moroccan family with SPG7, Elleuch et al. (2006) identified compound heterozygosity for 2 mutations in the SPG7 gene (602783.0004-602783.0005).
In 1 (0.7%) of 136 index patients with autosomal recessive SPG, Elleuch et al. (2006) identified 2 mutations in the SPG7 gene. Twenty families had at least 1 variant in the SPG7 gene that was not found in 550 control chromosomes. In 4 of these families, mutations were predicted to be highly deleterious, suggesting that they may have contributed to the phenotype. The authors identified several additional rare variants in the SPG7 gene, which were of undetermined significance.
Arnoldi et al. (2008) identified 7 different SPG7 mutations (see, e.g., 602783.0007-602783.0009) in 6 (4.4%) of 135 Italian patients with spastic paraplegia. Four of the patients were heterozygous for the mutations, which fell within conserved domains of the protein and were not found in controls.
In 7 of 98 Dutch patients with apparently sporadic upper motor neuron disease symptoms, Brugman et al. (2008) identified homozygosity or compound heterozygosity for 6 mutations in the SPG7 gene that were of known or probable pathogenicity. Six patients had lower limb involvement only, and 1 patient had both upper and lower limb involvement. Three patients developed cerebellar signs, including dysarthria and gait ataxia, late in the disease course. None had bulbar involvement. Two patients with pure spastic paraparesis carried a single pathogenic mutation in the SPG7 gene.
Sanchez-Ferrero et al. (2013) sequenced the SPG7 gene in 285 Spanish patients with spastic paraplegia who were negative for mutations in the SPAST (604277) and ATL1 (606439) genes. Fourteen SPG7 mutations, including 12 novel mutations, were identified in 14 patients. The mutations included 2 large deletions, 5 missense changes, 4 nonsense mutations, 2 frameshift insertion/deletions, and 1 splice site mutation. Thirteen patients had only a single heterozygous mutation, suggesting a dominant effect for some SPG7 mutations. Functional studies were not performed to assess the biologic significance. An A510V (rs61755320) substitution (602783.0012) was found in 8 patients (3%): 4 carried A510V in compound heterozygous state with another SPG7 mutation, 1 was homozygous for A510V, and 3 patients were heterozygous for A510V. The A510V substitution was also identified in 1% of controls. All patients had adult onset of the disorder, but only 35% had a complicated phenotype.
In a 57-year-old man, born to first-cousin Caucasian parents, with childhood optic nerve atrophy and SPG7, Eriksen et al. (2022) identified a homozygous mutation in the SPG7 gene (M1?; 602783.0013). The patient had onset of vision loss at age 6 years, but findings of spastic paraplegia were subtle and the diagnosis was not suspected until the likely pathogenic variant in the SPG7 gene was identified. The authors noted that the SPG7 gene should be added to the workup of suspected hereditary optic neuropathy.
Arnoldi, A., Tonelli, A., Crippa, F., Villani, G., Pacelli, C., Sironi, M., Pozzoli, U., D'Angelo, M. G., Meola, G., Martinuzzi, A., Crimella, C., Redaelli, F., Panzeri, C., Renieri, A., Comi, G. P., Turconi, A. C., Bresolin, N., Bassi, M. T. A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum. Mutat. 29: 522-531, 2008. [PubMed: 18200586] [Full Text: https://doi.org/10.1002/humu.20682]
Brugman, F., Scheffer, H., Wokke, J. H. J., Nillesen, W. M., de Visser, M., Aronica, E., Veldink, J. H., van den Berg, L. H. Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes. Neurology 71: 1500-1505, 2008. [PubMed: 18799786] [Full Text: https://doi.org/10.1212/01.wnl.0000319700.11606.21]
Casari, G., De Fusco, M., Ciarmatori, S., Zeviani, M., Mora, M., Fernandez, P., De Michele, G., Filla, A., Cocozza, S., Marconi, R., Durr, A., Fontaine, B., Ballabio, A. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93: 973-983, 1998. [PubMed: 9635427] [Full Text: https://doi.org/10.1016/s0092-8674(00)81203-9]
De Michele, G., De Fusco, M., Cavalcanti, F., Filla, A., Marconi, R., Volpe, G., Monticelli, A., Ballabio, A., Casari, G., Cocozza, S. A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3. Am. J. Hum. Genet. 63: 135-139, 1998. [PubMed: 9634528] [Full Text: https://doi.org/10.1086/301930]
Elleuch, N., Depienne, C., Benomar, A., Ouvrard Hernandez, A. M., Ferrer, X., Fontaine, B., Grid, D., Tallaksen, C. M. E., Zemmouri, R., Stevanin, G., Durr, A., Brice, A. Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia. Neurology 66: 654-659, 2006. [PubMed: 16534102] [Full Text: https://doi.org/10.1212/01.wnl.0000201185.91110.15]
Eriksen, K. O., Wigers, A. R., Wedding, I. M., Erichsen, A. K., Baroy, T., Soberg, K., Jorstad, O. K. A novel homozygous variant in the SPG7 gene presenting with childhood optic nerve atrophy. Am. J. Ophthal. Case Rep. 26: 101400, 2022. [PubMed: 35243150] [Full Text: https://doi.org/10.1016/j.ajoc.2022.101400]
Sanchez-Ferrero, E., Coto, E., Beetz, C., Gamez, J., Corao, A. I., Diaz, M., Esteban, J., del Castillo, E., Moris, G., Infante, J., Menendez, M., Pascual-Pascual, S. I., Lopez de Munain, A., Garcia-Barcina, M. J., Alvarez, V. SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V. Clin. Genet. 83: 257-262, 2013. [PubMed: 22571692] [Full Text: https://doi.org/10.1111/j.1399-0004.2012.01896.x]
Warnecke, T., Duning, T., Schwan, A., Lohmann, H., Epplen, J. T., Young, P. A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation. Neurology 69: 368-375, 2007. Note: Erratum: Neurology 69: 1065 only, 2007. [PubMed: 17646629] [Full Text: https://doi.org/10.1212/01.wnl.0000266667.91074.fe]