Alternative titles; symbols
SNOMEDCT: 723622007; ORPHA: 99015; DO: 0110773;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq22.2 | Spastic paraplegia 2, X-linked | 312920 | X-linked recessive | 3 | PLP1 | 300401 |
A number sign (#) is used with this entry because spastic paraplegia-2 (SPG2) is caused by mutation in PLP1 gene (300401), which encodes myelin proteolipid protein, on chromosome Xq22.
Pelizaeus-Merzbacher disease (PMD; 312080) is an allelic disorder.
The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of Fink et al. (1996) and Fink (1997). Some forms of SPG are considered 'uncomplicated,' i.e., progressive spasticity occurs in isolation; others are considered 'complicated,' i.e., progressive spasticity occurs with other neurologic features. X-linked, autosomal dominant (see 182600), and autosomal recessive (see 270800) forms of SPG have been described.
For discussion of genetic heterogeneity of X-linked SPG, see 303350.
Johnston and McKusick (1962) reported a kindred in which the disorder began as 'pure' spastic paraparesis, but the patients later developed nystagmus, dysarthria, sensory disturbance, and mental retardation, with half the patients having optic atrophy. Later symptoms included muscle wasting, joint contractures, and a requirement for crutches or wheelchair by early adult life. Johnston and McKusick (1962) observed early onset, slow progression, and long survival with eventual involvement of the cerebellum, cerebral cortex and optic nerves as features of the X-linked recessive form. Thurmon et al. (1971) studied 2 rather extensively affected kindreds with X-linked spastic paraplegia, one of which was previously reported by Johnston and McKusick (1962).
Ginter et al. (1974) examined the central nervous system at autopsy in 1 patient from the Johnston-McKusick kindred. Degeneration of both corticospinal and spinocerebellar traits was found. Many of the affected members showed cerebellar signs.
Keppen et al. (1987) studied a large family in which 12 males had X-linked recessive uncomplicated spastic paraplegia. The disorder was characterized by hyperreflexia and spastic gait. Intelligence was normal, and there were no other complicating features such as optic atrophy or spinocerebellar manifestations.
Goldblatt et al. (1989) described a family with complicated X-linked spastic paraplegia with manifestations including nystagmus, optic atrophy, intellectual handicap, and mild ataxia of the arms.
Bonneau et al. (1993) reported a 3-generation family in which some members had a complicated form of spastic paraplegia with mental retardation, whereas others had mild spastic paraplegia and normal intelligence. One presumably heterozygous female had spastic paraparesis.
Naidu et al. (1997) presented the case of a boy first examined at the age of 3.5 years for toe walking and frequent falls that had begun when he was 2 years old. He had intact cognition, delayed walking, progressive spastic paraparesis, and congenital nystagmus. The patient was found to have the same PLP1 mutation as in the family of Johnston and McKusick (1962) (see MOLECULAR GENETICS) and genealogic connections were subsequently established. Differences from the disorder in other members of the kindred were observed. His condition began at birth, whereas in the other boys it began when they began to walk or later. Most significantly, his MRI scan demonstrated patchy leukodystrophy, but this was to a lesser degree than usually seen in connatal Pelizaeus-Merzbacher disease. Nystagmus was of earlier onset than usual. The patient also had lysinuria as did his otherwise unaffected sister and mother, with normal urinary excretions of cystine, arginine, and ornithine, and no hyperammonemia. Since these individuals were clinically asymptomatic with a normal MRI scan and wildtype PLP alleles, the lysinuria was thought to be a benign finding segregating independently of the PLP mutation in this kindred. The lysinuria was thought to be very similar to that described by Whelan and Scriver (1968); see 222690.
Gorman et al. (2007) reported a boy with SPG2 due to a hemizygous mutation in the PLP1 gene (300401.0026). He presented at age 10 years with poor school performance, diplopia, and clumsiness after an upper respiratory infection. MRI showed multifocal areas of T2 white matter hyperintensities. Treatment with high-dose intravenous methylprednisolone resulted in clinical improvement. Over the next few years, he had episodes of neurologic deterioration characterized by nystagmus, dysmetria, ataxia, tremor, and progressive cognitive decline. These episodes responded temporarily to methylprednisolone treatment, suggesting an inflammatory process. The patient even fulfilled the criteria for relapsing-remitting multiple sclerosis (MS; 128200), including the presence of oligoclonal bands in the CSF. His mother, who carried the mutation, developed tremor and incoordination in her late forties, although this was complicated by alcohol abuse. A grandfather with the mutation was asymptomatic except for mild tremor.
Linkage studies by Keppen et al. (1987) demonstrated location of the locus for this disorder, designated SPG2, on the middle of the long arm of the X chromosome. The markers to which this pure form of spastic paraplegia was linked (DXS17 and another marker identified by probe YNH3) are located in the Xq21-q22 region. Goldblatt et al. (1989) described a family with complicated X-linked spastic paraplegia and tight linkage to a marker located at Xq13-q21.1.
By multipoint linkage analysis, Bonneau et al. (1993) located the SPG2 locus at Xq21. Bonneau et al. (1993) suggested that there is variable clinical expression of a single gene at the SPG2 locus, accounting for both complicated and uncomplicated forms of X-linked spastic paraplegia.
While narrowing the genetic interval containing the SPG2 gene in the X-linked SPG family reported by Bonneau et al. (1993), Saugier-Veber et al. (1994) found that the gene for proteolipid protein was the closest marker, implicating PLP as a possible candidate gene. In an affected male, they found a his139-to-tyr mutation in exon 3B of the PLP gene (300401.0012) and showed that it segregated with the disease (maximum lod = 6.63 at theta = 0.00). The PLP gene encodes 2 myelin proteins, PLP and DM20; the his139-to-tyr mutation resulted in a mutant PLP, but a normal DM20. Saugier-Veber et al. (1994) concluded that SPG2 and Pelizaeus-Merzbacher disease are allelic disorders.
Kobayashi et al. (1994) demonstrated that the family with X-linked SPG described by Johnston and McKusick (1962) showed linkage of the disease phenotype to markers in the region Xq21.3-q24 which includes the PLP locus. By SSCP and direct sequencing methods, they found a T-to-C transition in exon 4 of the PLP gene in affected males in this family, which altered isoleucine to threonine at residue 186 (300401.0013). The ile186-to-thr mutation altered both the PLP and DM20 protein products, in contrast to the his139-to-tyr X-linked SPG mutation which altered only PLP.
Cailloux et al. (2000) investigated 28 SPG families without large PLP duplications or deletions by PCR amplification and sequencing of the 7 coding regions and the splice sites of the PLP gene. Abnormalities were identified in 4 (14%) of the cases. Clinical severity was found to be correlated with the nature of the mutation when compared to the more severe allelic PMD. The 4 mutations identified were either splice site mutations or changes in the PLP-specific intracytoplasmic B-C loop of the protein (exon 3B).
Inoue (2005) provided a detailed review of SPG2 and the PLP1 gene.
Lee et al. (2006) reported a patient with a mild form of SPG2 who also had a peripheral axonal neuropathy. Although there were no mutations, duplications, or deletions in the PLP1 gene, detailed molecular analysis detected a small duplication of less than 150 kb approximately 136 kb downstream of the PLP1 gene in the patient and his unaffected mother. Lee et al. (2006) suggested that the duplication resulted in silencing of the PLP1 gene by position effect since the patient's relatively mild phenotype resembled that seen with PLP1-null mutations.
Nixon and Connelly (1968) described hind-leg paralysis as an X-linked trait in the Syrian hamster. This may be homologous to X-linked spastic paraplegia in man.
The mutation in the PLP1 gene (300401.0013) identified in affected patients with SPG2 by Kobayashi et al. (1994) is identical to the mutation identified in the 'rumpshaker' mouse model (Schneider et al., 1992). 'Rumpshaker' is an allele of the 'jimpy' locus. 'Jimpy' mice are clinically similar to PMD and show failure of development and differentiation of oligodendrocytes leading to early death. 'Rumpshaker' mice, although myelin-deficient like other jimpy mutants, have normal longevity and a full complement of morphologically normal oligodendrocytes. Affected mice show a generalized tremor at about 12 days of age, which generally becomes confined to the rear end. The differences between 'rumpshaker' and other 'jimpy' alleles suggested a dual function of PLP: it is required for early development and survival of oligodendrocytes, and also in the terminal stages of myelin compaction.
Blumel et al. (1957) reported a likely case of X-linked spastic paraplegia.
From Maine, Baar and Gabriel (1966) reported a kindred with 13 affected males in 3 generations and 5 sibships. Mental retardation and death before age 1 year were features. The oldest survivor was aged 44 years. Bundey and Griffiths (1977) published an X-linked recessive pedigree of spastic athetosis that they concluded was probably the same condition as that reported by Baar and Gabriel (1966). A total of 7 males were thought to be affected. The proband developed athetosis of all 4 limbs and spasticity in the legs by 11 months. He had occasional grand mal seizures and occasional myoclonus. He was never able to stand or walk. At age 13 he was moderately retarded. Uric acid metabolism in him and other affected members of the pedigree was normal.
Gutmann et al. (1990) presented extensive studies of a family in which 5 brothers in a sibship of 7 had complicated hereditary spastic paraparesis with evidence on magnetic resonance imaging of bilateral posterior periventricular white matter lesions. The findings did not appear to be consistent with any other well-described spastic paraplegia condition. Three of the 4 living brothers showed red-green color vision defects. Preliminary RFLP analysis demonstrated no linkage to St14 (DXS52).
Baar, H. S., Gabriel, A. M. Sex-linked spastic paraplegia. Am. J. Ment. Defic. 71: 13-18, 1966. [PubMed: 5964018]
Blumel, J., Evans, E. B., Eggers, G. W. N. Hereditary cerebral palsy: a preliminary report. J. Pediat. 50: 454-458, 1957. [PubMed: 13406703] [Full Text: https://doi.org/10.1016/s0022-3476(57)80255-8]
Bonneau, D., Rozet, J.-M., Bulteau, C., Berthier, M., Mettey, R., Gil, R., Munnich, A., Le Merrer, M. X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus. J. Med. Genet. 30: 381-384, 1993. [PubMed: 8320699] [Full Text: https://doi.org/10.1136/jmg.30.5.381]
Bundey, S., Griffiths, M. I. Recurrence risks in families of children with symmetrical spasticity. Dev. Med. Child Neurol. 19: 179-191, 1977. [PubMed: 870357] [Full Text: https://doi.org/10.1111/j.1469-8749.1977.tb07968.x]
Cailloux, F., Gauthier-Barichard, F., Mimault, C., Isabelle, V., Courtois, V., Girard, G., Dastugue, B., Boespflug-Tanguy, O., Clinical European Network on Brain Dysmyelinating Disease. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Europ. J. Hum. Genet. 8: 837-845, 2000. [PubMed: 11093273] [Full Text: https://doi.org/10.1038/sj.ejhg.5200537]
Fink, J. K., Heiman-Patterson, T., Bird, T., Cambi, F., Dube, M.-P., Figlewicz, D. A., Haines, J. L., Hentati, A., Pericak-Vance, M. A., Raskind, W., Rouleau, G. A., Siddique, T. Hereditary spastic paraplegia: advances in genetic research. Neurology 46: 1507-1514, 1996. [PubMed: 8649538] [Full Text: https://doi.org/10.1212/wnl.46.6.1507]
Fink, J. K. Advances in hereditary spastic paraplegia. Curr. Opin. Neurol. 10: 313-318, 1997. [PubMed: 9266155] [Full Text: https://doi.org/10.1097/00019052-199708000-00006]
Ginter, D. N., Konigsmark, B. W., Abbott, M. H. X-linked spinocerebellar degeneration. Birth Defects Orig. Art. Ser. X(4): 334-336, 1974.
Goldblatt, J., Ballo, R., Sachs, B., Moosa, A. X-linked spastic paraplegia: evidence for homogeneity with a variable phenotype. Clin. Genet. 35: 116-120, 1989. [PubMed: 2470540] [Full Text: https://doi.org/10.1111/j.1399-0004.1989.tb02915.x]
Gorman, M. P., Golomb, M. R., Walsh, L. E., Hobson, G. M., Garbern, J. Y., Kinkel, R. P., Darras, B. T., Urion, D. K., Eksioglu, Y. Z. Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation. Neurology 68: 1305-1307, 2007. [PubMed: 17438221] [Full Text: https://doi.org/10.1212/01.wnl.0000259522.49388.53]
Gutmann, D. H., Fischbeck, K. H., Kamholz, J. Complicated hereditary spastic paraparesis with cerebral white matter lesions. Am. J. Med. Genet. 36: 251-257, 1990. [PubMed: 2368815] [Full Text: https://doi.org/10.1002/ajmg.1320360222]
Inoue, K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 6: 1-16, 2005. [PubMed: 15627202] [Full Text: https://doi.org/10.1007/s10048-004-0207-y]
Johnston, A. W., McKusick, V. A. A sex-linked recessive form of spastic paraplegia. Am. J. Hum. Genet. 14: 83-94, 1962. [PubMed: 14452137]
Keppen, L. D., Leppert, M. F., O'Connell, P., Nakamura, Y., Stauffer, D., Lathrop, M., Lalouel, J.-M., White, R. Etiological heterogeneity in X-linked spastic paraplegia. Am. J. Hum. Genet. 41: 933-943, 1987. [PubMed: 3479019]
Kobayashi, H., Hoffman, E. P., Marks, H. G. The rumpshaker mutation in spastic paraplegia. (Letter) Nature Genet. 7: 351-352, 1994. [PubMed: 7522741] [Full Text: https://doi.org/10.1038/ng0794-351]
Lee, J. A., Madrid, R. E., Sperle, K., Ritterson, C. M., Hobson, G. M., Garbern, J., Lupski, J. R., Inoue, K. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann. Neurol. 59: 398-403, 2006. [PubMed: 16374829] [Full Text: https://doi.org/10.1002/ana.20732]
Naidu, S., Dlouhy, S. R., Geraghty, M. T., Hodes, M. E. A male child with the rumpshaker mutation, X-linked spastic paraplegia/Pelizaeus-Merzbacher disease and lysinuria. J. Inherit. Metab. Dis. 20: 811-816, 1997. [PubMed: 9427151] [Full Text: https://doi.org/10.1023/a:1005328019832]
Nixon, C. W., Connelly, M. E. Hind-leg paralysis: a new sex-linked mutation in the Syrian hamster. J. Hered. 59: 276-278, 1968. [PubMed: 5713627] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a107718]
Saugier-Veber, P., Munnich, A., Bonneau, D., Rozet, J.-M., Le Merrer, M., Gil, R., Boespflug-Tanguy, O. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nature Genet. 6: 257-262, 1994. [PubMed: 8012387] [Full Text: https://doi.org/10.1038/ng0394-257]
Schneider, A., Montague, P., Griffiths, I., Fanarraga, M., Kennedy, P., Brophy, P., Nave, K.-A. Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene. Nature 358: 758-761, 1992. [PubMed: 1380672] [Full Text: https://doi.org/10.1038/358758a0]
Thurmon, T. F., Walker, B. A., Scott, C. I., Jr., Abbott, M. H. Two kindreds with a sex-linked recessive form of spastic paraplegia. Birth Defects Orig. Art. Ser. VII(1): 219-221, 1971. [PubMed: 5173365]
Whelan, D. T., Scriver, C. R. Hyperdibasicaminoaciduria: an inherited disorder of amino acid transport. Pediat. Res. 2: 525-534, 1968. [PubMed: 5727921] [Full Text: https://doi.org/10.1203/00006450-196811000-00011]