MCID: SPS133
MIFTS: 40

Spastic Paraplegia 2, X-Linked

Categories: Genetic diseases, Rare diseases, Neuronal diseases, Eye diseases

Aliases & Classifications for Spastic Paraplegia 2, X-Linked

MalaCards integrated aliases for Spastic Paraplegia 2, X-Linked:

Name: Spastic Paraplegia 2, X-Linked 57 75 13 73
Spastic Paraplegia 2 53 25 75 29 6
Spg2 57 12 53 59 75
Spastic Paraplegia Type 2 12 25 59
Sppx2 57 53 75
Hereditary X-Linked Recessive Spastic Paraplegia 25 73
Hereditary Spastic Paraplegia 2 12 15
X Linked Recessive Hereditary Spastic Paraplegia 25
Spastic Paraplegia Type 2, X-Linked 76
X-Linked Spastic Paraplegia Type 2 59
X-Linked Spastic Paraplegia 2 12
Paraplegia, Spastic, Type 2 40
Spastic Paraparesis Type 2 59
Spastic Gait Type 2 59

Characteristics:

Orphanet epidemiological data:

59
spastic paraplegia type 2
Inheritance: X-linked recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Childhood; Age of death: adult;

OMIM:

57
Miscellaneous:
highly variable phenotype
onset in childhood
pelizaeus-merzbacher disease (pmd, ) is an allelic disorder

Inheritance:
x-linked recessive


HPO:

32
spastic paraplegia 2, x-linked:
Onset and clinical course phenotypic variability juvenile onset
Inheritance x-linked recessive inheritance


Classifications:



Summaries for Spastic Paraplegia 2, X-Linked

NIH Rare Diseases : 53 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 99015Disease definitionSpastic paraplegia type 2 (SPG2) is an X-linked leukodystrophy characterized primarily by spastic gait and autonomic dysfunction. When additional central nervous system (CNS) signs, such as intellectual deficit, ataxia, or extrapyramidal signs, are present, the syndrome is referred to as complicated SPG.EpidemiologyThe prevalence and incidence of SPG2 have not been reported, but as part of the Pelizaeus-Merzbacher (PMD; see this term) spectrum, SPG2 roughly accounts for about 20 % of cases. There have been approximately 20 cases published on SPG2. SPG2 affects males but some female heterozygotes presenting in adulthood with a milder phenotype have also been reported.Clinical descriptionSPG2 spans a continuum of phenotypes that goes from pure to complicated SPG2. Pure SPG2 manifests as early as infancy or early childhood (EtiologySPG2 is due to missense substitutions affecting the PLP1 gene. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20). SPG2 is allelic to Pelizaeus-Merzbacher disease (PMD; see this term) that is also due to PLP1 mutations.Diagnostic methodsDiagnosis is based on clinical, electrophysiologic, and neuroradiological findings. White matter N-acetyl aspartate levels are reduced. Brain magnetic resonance imaging (MRI) reveals patchy or diffuse hypomyelination on T2-weighted images. Patients with pure SPG2 can have very subtle T2 hyperintensity. Other MR techniques, including MR spectroscopy and diffusion tensor imaging are useful in the diagnosis of the disease. Molecular genetic testing of PLP1 confirms the diagnosis.Differential diagnosisDifferential diagnosis includes other forms of hereditary spastic paraplegia (see this tem). Complicated SPG2 is not clearly distinguishable from mild Pelizaeus-Merzbacher disease (PMD) and null syndrome (see these terms).Antenatal diagnosisPrenatal genetic testing is possible when a family's underlying PLP1 mutation has been identified.Genetic counselingTransmission is X-linked recessive.Management and treatmentA son born to a female carrier has a 50% risk of inheriting the mutation and developing the disease, while a daughter has a 50% risk of being a carrier. All daughters of an affected male will be carriers but none of his sons will be affected. Management is multidisciplinary and involves neurologists, physical therapists, and orthopedic doctors. Treatment may include antiepileptic drugs for seizures, and physical therapy with antispasticity drugs (baclofen, diazepam, tizanidine, botulinum toxin, dantrolene) for spasticity. Regular surveillance is necessary.PrognosisPure SPG2 patients show a normal life expectancy. In complicated SPG2 cases, patients deteriorate neurologically leading to a shorter life expectancy (between the fourth and seventh decade) typically from aspiration pneumonia, pulmonary embolism and other complications of generalized weakness.Visit the Orphanet disease page for more resources.

MalaCards based summary : Spastic Paraplegia 2, X-Linked, also known as spastic paraplegia 2, is related to pelizaeus-merzbacher disease and paraplegia, and has symptoms including ataxia and cerebellar signs. An important gene associated with Spastic Paraplegia 2, X-Linked is PLP1 (Proteolipid Protein 1). Affiliated tissues include brain, spinal cord and testes, and related phenotypes are nystagmus and intellectual disability

Disease Ontology : 12 A hereditary spastic paraplegia that has material basis in mutation in the PLP1 gene on chromosome Xq22.2.

Genetics Home Reference : 25 Spastic paraplegia type 2 is part of a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by progressive muscle stiffness (spasticity) and the development of paralysis of the lower limbs (paraplegia). Hereditary spastic paraplegias are divided into two types: pure and complex. The pure types involve the lower limbs. The complex types involve the lower limbs and can also affect the upper limbs to a lesser degree; the structure or functioning of the brain; and the nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound (the peripheral nervous system). Spastic paraplegia type 2 can occur in either the pure or complex form.

OMIM : 57 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. (312920)

UniProtKB/Swiss-Prot : 75 Spastic paraplegia 2, X-linked: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG2 is characterized by spastic gait and hyperreflexia. In some patients, complicating features include nystagmus, dysarthria, sensory disturbance, mental retardation, optic atrophy.

Wikipedia : 76 Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive... more...

Related Diseases for Spastic Paraplegia 2, X-Linked

Diseases in the Spastic Paraplegia 2, X-Linked family:

Spastic Paraplegia 16, X-Linked Spastic Paraplegia 34, X-Linked

Diseases related to Spastic Paraplegia 2, X-Linked via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 36)
# Related Disease Score Top Affiliating Genes
1 pelizaeus-merzbacher disease 32.7 GJC2 PLP1
2 paraplegia 25.5 AP5Z1 ATL1 ERLIN2 PLP1 REEP1 RTN2
3 pelizaeus-merzbacher-like disease 10.4 GJC2 PLP1
4 leukodystrophy, hypomyelinating, 4 10.3 GJC2 PLP1
5 hypomyelinating leukoencephalopathy 10.3 GJC2 PLP1
6 leukodystrophy, hypomyelinating, 2 10.3 GJC2 PLP1
7 hereditary spastic paraplegia 51 10.2 AP5Z1 RTN2
8 spastic paraplegia 52, autosomal recessive 10.2 AP5Z1 RTN2
9 spastic paraplegia 50, autosomal recessive 10.2 AP5Z1 RTN2
10 cerebral degeneration 10.2 GJC2 PLP1
11 spastic paraplegia 28, autosomal recessive 10.1 AP5Z1 RTN2
12 spastic paraplegia 54, autosomal recessive 10.1 AP5Z1 RTN2
13 hypomyelinating leukodystrophy 10.1 GJC2 PLP1
14 spastic paraplegia 48, autosomal recessive 10.0 AP5Z1 ERLIN2
15 spasticity 10.0
16 spastic paraplegia 35, autosomal recessive 9.9 AP5Z1 ERLIN2
17 leukodystrophy 9.7 GJC2 PLP1
18 cerebral palsy 9.4 ATL1 PLP1
19 spastic paraplegia 18, autosomal recessive 9.4 AP5Z1 ERLIN2 REEP1
20 spastic paraplegia 47, autosomal recessive 9.4 AP5Z1 ERLIN2 REEP1
21 spastic paraplegia 39, autosomal recessive 9.4 AP5Z1 ERLIN2 REEP1
22 spastic paraplegia 30, autosomal recessive 9.4 AP5Z1 ERLIN2 REEP1
23 spastic paraplegia 42, autosomal dominant 9.4 AP5Z1 ERLIN2 REEP1
24 spastic paraplegia 44, autosomal recessive 9.2 AP5Z1 ERLIN2 GJC2 ZFYVE27
25 spastic paraplegia 61, autosomal recessive 9.1 ATL1 REEP1 RTN2
26 spastic paraplegia 33, autosomal dominant 9.0 AP5Z1 REEP1 RTN2 ZFYVE27
27 masa syndrome 9.0 AP5Z1 ATL1 REEP1
28 spastic paraplegia 13, autosomal dominant 8.7 AP5Z1 ATL1 ERLIN2 GJC2
29 spastic paraplegia 3, autosomal dominant 8.6 ATL1 REEP1 RTN2 ZFYVE27
30 spastic paraplegia 6, autosomal dominant 8.4 AP5Z1 ATL1 ERLIN2 REEP1
31 spastic paraplegia 8, autosomal dominant 8.4 AP5Z1 ATL1 ERLIN2 REEP1
32 spastic paraplegia 31, autosomal dominant 8.1 AP5Z1 ATL1 REEP1 RTN2 ZFYVE27
33 spastic paraplegia 10, autosomal dominant 8.1 AP5Z1 ATL1 REEP1 RTN2 ZFYVE27
34 spastic paraplegia 4, autosomal dominant 8.0 ATL1 ERLIN2 REEP1 RTN2 ZFYVE27
35 spastic paraplegia 12, autosomal dominant 7.4 AP5Z1 ATL1 ERLIN2 REEP1 RTN2 ZFYVE27
36 hereditary spastic paraplegia 6.6 AP5Z1 ATL1 ERLIN2 GJC2 PLP1 REEP1

Graphical network of the top 20 diseases related to Spastic Paraplegia 2, X-Linked:



Diseases related to Spastic Paraplegia 2, X-Linked

Symptoms & Phenotypes for Spastic Paraplegia 2, X-Linked

Symptoms via clinical synopsis from OMIM:

57
Head And Neck Eyes:
nystagmus
optic atrophy

Skeletal Feet:
pes cavus

Muscle Soft Tissue:
atrophy

Neurologic Central Nervous System:
ataxia
dysarthria
hyperreflexia
dysmetria
lower limb spasticity
more
Skeletal Limbs:
joint contractures


Clinical features from OMIM:

312920

Human phenotypes related to Spastic Paraplegia 2, X-Linked:

59 32 (show all 27)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 nystagmus 59 32 occasional (7.5%) Occasional (29-5%) HP:0000639
2 intellectual disability 59 32 frequent (33%) Frequent (79-30%) HP:0001249
3 ataxia 59 32 occasional (7.5%) Occasional (29-5%) HP:0001251
4 dysarthria 59 32 occasional (7.5%) Occasional (29-5%) HP:0001260
5 muscle weakness 59 32 hallmark (90%) Very frequent (99-80%) HP:0001324
6 hyperreflexia 59 32 hallmark (90%) Very frequent (99-80%) HP:0001347
7 bowel incontinence 59 32 frequent (33%) Frequent (79-30%) HP:0002607
8 recurrent respiratory infections 59 32 occasional (7.5%) Occasional (29-5%) HP:0002205
9 optic atrophy 59 32 frequent (33%) Frequent (79-30%) HP:0000648
10 pulmonary embolism 59 32 occasional (7.5%) Occasional (29-5%) HP:0002204
11 sensory neuropathy 59 32 occasional (7.5%) Occasional (29-5%) HP:0000763
12 limitation of joint mobility 59 32 occasional (7.5%) Occasional (29-5%) HP:0001376
13 babinski sign 59 32 hallmark (90%) Very frequent (99-80%) HP:0003487
14 abnormality of extrapyramidal motor function 59 32 frequent (33%) Frequent (79-30%) HP:0002071
15 spastic gait 59 32 hallmark (90%) Very frequent (99-80%) HP:0002064
16 spastic/hyperactive bladder 59 32 frequent (33%) Frequent (79-30%) HP:0005340
17 spasticity 59 Very frequent (99-80%)
18 flexion contracture 32 HP:0001371
19 skeletal muscle atrophy 32 HP:0003202
20 dysmetria 32 HP:0001310
21 pes cavus 32 HP:0001761
22 spastic paraplegia 32 HP:0001258
23 lower limb spasticity 32 HP:0002061
24 degeneration of the lateral corticospinal tracts 32 HP:0002314
25 lower limb muscle weakness 32 HP:0007340
26 spinocerebellar tract degeneration 32 HP:0002503
27 spastic paraparesis 32 HP:0002313

UMLS symptoms related to Spastic Paraplegia 2, X-Linked:


ataxia, cerebellar signs

Drugs & Therapeutics for Spastic Paraplegia 2, X-Linked

Search Clinical Trials , NIH Clinical Center for Spastic Paraplegia 2, X-Linked

Genetic Tests for Spastic Paraplegia 2, X-Linked

Genetic tests related to Spastic Paraplegia 2, X-Linked:

# Genetic test Affiliating Genes
1 Spastic Paraplegia 2 29 PLP1

Anatomical Context for Spastic Paraplegia 2, X-Linked

MalaCards organs/tissues related to Spastic Paraplegia 2, X-Linked:

41
Brain, Spinal Cord, Testes, Eye, Skeletal Muscle

Publications for Spastic Paraplegia 2, X-Linked

Articles related to Spastic Paraplegia 2, X-Linked:

# Title Authors Year
1
Brain magnetic resonance imaging findings and auditory brainstem response in a child with spastic paraplegia 2 due to a PLP1 splice site mutation. ( 24685771 )
2014
2
A case of complicated spastic paraplegia 2 due to a point mutation in the proteolipid protein 1 gene. ( 15450775 )
2004

Variations for Spastic Paraplegia 2, X-Linked

UniProtKB/Swiss-Prot genetic disease variations for Spastic Paraplegia 2, X-Linked:

75
# Symbol AA change Variation ID SNP ID
1 PLP1 p.His140Tyr VAR_004551 rs132630287
2 PLP1 p.Ile187Thr VAR_004556 rs132630288
3 PLP1 p.Phe237Ser VAR_004563 rs132630291
4 PLP1 p.His130Tyr VAR_015024 rs878853076
5 PLP1 p.His148Tyr VAR_015025
6 PLP1 p.Ser170Phe VAR_015029 rs132630294
7 PLP1 p.Ser226Pro VAR_015046
8 PLP1 p.Arg137Trp VAR_046910 rs132630295
9 PLP1 p.Pro216Leu VAR_046914
10 PLP1 p.Ala30Pro VAR_070667

ClinVar genetic disease variations for Spastic Paraplegia 2, X-Linked:

6
(show all 33)
# Gene Variation Type Significance SNP ID Assembly Location
1 PLP1 NM_001128834.2(PLP1): c.418C> T (p.His140Tyr) single nucleotide variant Pathogenic rs132630287 GRCh37 Chromosome X, 103041620: 103041620
2 PLP1 NM_001128834.2(PLP1): c.418C> T (p.His140Tyr) single nucleotide variant Pathogenic rs132630287 GRCh38 Chromosome X, 103786691: 103786691
3 PLP1 NM_001128834.2(PLP1): c.560T> C (p.Ile187Thr) single nucleotide variant Pathogenic rs132630288 GRCh37 Chromosome X, 103042833: 103042833
4 PLP1 NM_001128834.2(PLP1): c.560T> C (p.Ile187Thr) single nucleotide variant Pathogenic rs132630288 GRCh38 Chromosome X, 103787904: 103787904
5 PLP1 NM_001128834.2(PLP1): c.710T> C (p.Phe237Ser) single nucleotide variant Pathogenic rs132630291 GRCh37 Chromosome X, 103044275: 103044275
6 PLP1 NM_001128834.2(PLP1): c.710T> C (p.Phe237Ser) single nucleotide variant Pathogenic rs132630291 GRCh38 Chromosome X, 103789346: 103789346
7 PLP1 NM_001128834.2(PLP1): c.509C> T (p.Ser170Phe) single nucleotide variant Pathogenic rs132630294 GRCh37 Chromosome X, 103042782: 103042782
8 PLP1 NM_001128834.2(PLP1): c.509C> T (p.Ser170Phe) single nucleotide variant Pathogenic rs132630294 GRCh38 Chromosome X, 103787853: 103787853
9 PLP1 NM_001128834.2(PLP1): c.409C> T (p.Arg137Trp) single nucleotide variant Pathogenic rs132630295 GRCh37 Chromosome X, 103041611: 103041611
10 PLP1 NM_001128834.2(PLP1): c.409C> T (p.Arg137Trp) single nucleotide variant Pathogenic rs132630295 GRCh38 Chromosome X, 103786682: 103786682
11 PLP1 NM_000533.4(PLP1): c.-31C> T single nucleotide variant Benign/Likely benign rs2233695 GRCh37 Chromosome X, 103031893: 103031893
12 PLP1 NM_000533.4(PLP1): c.-31C> T single nucleotide variant Benign/Likely benign rs2233695 GRCh38 Chromosome X, 103776965: 103776965
13 PLP1 NM_000533.4(PLP1): c.2T> C (p.Met1Thr) single nucleotide variant Pathogenic rs864622194 GRCh37 Chromosome X, 103031925: 103031925
14 PLP1 NM_000533.4(PLP1): c.2T> C (p.Met1Thr) single nucleotide variant Pathogenic rs864622194 GRCh38 Chromosome X, 103776997: 103776997
15 PLP1 NC_000023.10: g.(?_103031918)_(103045531_?)dup duplication Pathogenic GRCh37 Chromosome X, 103031918: 103045531
16 PLP1 NM_000533.4(PLP1): c.140T> C (p.Ile47Thr) single nucleotide variant Likely pathogenic rs1060500909 GRCh37 Chromosome X, 103040646: 103040646
17 PLP1 NM_000533.4(PLP1): c.140T> C (p.Ile47Thr) single nucleotide variant Likely pathogenic rs1060500909 GRCh38 Chromosome X, 103785717: 103785717
18 PLP1 NC_000023.10: g.(?_103031754)_(103047548_?)dup duplication Pathogenic GRCh37 Chromosome X, 103031754: 103047548
19 PLP1 NM_000533.4(PLP1): c.701A> T (p.Gln234Leu) single nucleotide variant Uncertain significance rs1060500908 GRCh38 Chromosome X, 103789337: 103789337
20 PLP1 NM_000533.4(PLP1): c.701A> T (p.Gln234Leu) single nucleotide variant Uncertain significance rs1060500908 GRCh37 Chromosome X, 103044266: 103044266
21 PLP1 NM_001128834.2(PLP1): c.365A> G (p.Lys122Arg) single nucleotide variant Likely pathogenic rs1135401759 GRCh37 Chromosome X, 103041567: 103041567
22 PLP1 NM_001128834.2(PLP1): c.365A> G (p.Lys122Arg) single nucleotide variant Likely pathogenic rs1135401759 GRCh38 Chromosome X, 103786638: 103786638
23 PLP1 NM_000533.4(PLP1): c.380G> C (p.Arg127Thr) single nucleotide variant Uncertain significance GRCh37 Chromosome X, 103041582: 103041582
24 PLP1 NM_000533.4(PLP1): c.380G> C (p.Arg127Thr) single nucleotide variant Uncertain significance GRCh38 Chromosome X, 103786653: 103786653
25 PLP1 NM_000533.4(PLP1): c.689C> G (p.Thr230Arg) single nucleotide variant Uncertain significance GRCh38 Chromosome X, 103788503: 103788503
26 PLP1 NM_000533.4(PLP1): c.689C> G (p.Thr230Arg) single nucleotide variant Uncertain significance GRCh37 Chromosome X, 103043432: 103043432
27 PLP1 NM_001128834.2(PLP1): c.817C> T (p.Arg273Ter) single nucleotide variant Pathogenic GRCh37 Chromosome X, 103045509: 103045509
28 PLP1 NM_001128834.2(PLP1): c.817C> T (p.Arg273Ter) single nucleotide variant Pathogenic GRCh38 Chromosome X, 103790581: 103790581
29 PLP1 NC_000023.10: g.(?_103031893)_(103045546_?)dup duplication Pathogenic GRCh37 Chromosome X, 103031893: 103045546
30 PLP1 NM_001128834.2(PLP1): c.415_418delTGTCinsAGT (p.Cys139Serfs) indel Pathogenic GRCh37 Chromosome X, 103041617: 103041620
31 PLP1 NM_001128834.2(PLP1): c.415_418delTGTCinsAGT (p.Cys139Serfs) indel Pathogenic GRCh38 Chromosome X, 103786688: 103786691
32 PLP1 NM_000533.4(PLP1): c.485T> C (p.Val162Ala) single nucleotide variant Uncertain significance GRCh38 Chromosome X, 103787829: 103787829
33 PLP1 NM_000533.4(PLP1): c.485T> C (p.Val162Ala) single nucleotide variant Uncertain significance GRCh37 Chromosome X, 103042758: 103042758

Expression for Spastic Paraplegia 2, X-Linked

Search GEO for disease gene expression data for Spastic Paraplegia 2, X-Linked.

Pathways for Spastic Paraplegia 2, X-Linked

GO Terms for Spastic Paraplegia 2, X-Linked

Cellular components related to Spastic Paraplegia 2, X-Linked according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 integral component of membrane GO:0016021 9.8 ATL1 ERLIN2 GJC2 PLP1 REEP1 RTN2
2 endoplasmic reticulum GO:0005783 9.55 ATL1 ERLIN2 REEP1 RTN2 ZFYVE27
3 endoplasmic reticulum membrane GO:0005789 9.35 ATL1 ERLIN2 REEP1 RTN2 ZFYVE27
4 integral component of endoplasmic reticulum membrane GO:0030176 9.32 RTN2 ZFYVE27
5 endoplasmic reticulum tubular network GO:0071782 8.8 ATL1 REEP1 ZFYVE27

Sources for Spastic Paraplegia 2, X-Linked

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