Hereditary Spastic Paraplegia malady

NINDS: Hereditary spastic paraplegia (HSP), also called familial spastic paraparesis (FSP), refers to a group of inherited disorders that are characterized by progressive weakness and spasticity (stiffness) of the legs. Early in the disease course, there may be mild gait difficulties and stiffness. These symptoms typically slowly progress so that eventually individuals with HSP may require the assistance of a cane, walker, or wheelchair. Though the primary features of "pure" HSP are progressive lower limb spasticity and weakness, complicated forms may be accompanied by other symptoms. These additional impaired vision due to cataracts and problems with the optic nerve and retina of the eye, ataxia (lack of muscle coordination), epilepsy, cognitive impairment, peripheral neuropathy, and deafness. The diagnosis of HSP is primarily by neurological examination and testing to rule out other disorders. Brain MRI abnormalities, such as a thin corpus callosum, may be seen in some of the complicated forms of HSP. ³¹

MalaCards: Hereditary Spastic Paraplegia, also known as familial spastic paraplegia, is related to spastic paraparesis and corpus callosum. An important gene associated with Hereditary Spastic Paraplegia is AFG3L2 (AFG3 ATPase family gene 3-like 2 (S. cerevisiae)). The compounds amp-pnp and 8-azido-atp have been mentioned in the context of this disorder. Affiliated tissues include brain, retina and spinal cord, and related mouse phenotype behavior/neurological.

Disease Ontology: A paraplegia that is characterized by progressive stiffness and contraction (spasticity) in the lower limbs.⁶

NIH Rare Diseases: Hereditary spastic paraplegia is a group of hereditary, degenerative, neurological disorders that primarily affect the upper motor neurons. Upper motor neurons in the brain and spinal cord deliver signals to the lower motor neurons which in turn, carry messages to the muscles. In hereditary spastic paraplegia, upper motor neurons slowly degenerate so the muscles do not receive the correct messages causing progressive spasticity (increased muscle tone/stiffness) and weakness of the legs leading to difficulty walking.  As degeneration continues, symptoms worsen. ³⁰

Genetics Home Reference: Spastic paraplegia type 7 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 7 can occur in either the pure or complex form.¹⁷

Wikipedia: Hereditary Spastic Paraplegia (HSP), also called Familial Spastic Paraplegias or Strumpell-Lorrain...⁴⁴ more...

OMIM: 607259

GeneReviews summary for hsp

GeneReviews summary for spg7

Aliases & Descriptions:

hereditary spastic paraplegia 6 15 30 17 31 familial spastic paraplegia 6 15 16 spastic paraplegia 7 15 30 16 autosomal recessive hereditary spastic paraplegia 17 43 hereditary spastic paraplegia paraplegin type 30 16 hereditary spastic paraplegia (disorder) 6 16 spastic paraplegia, hereditary 17 43 hereditary spastic paraparesis 15 16 strumpell-lorrain syndrome 15 16 spg7 30 16 hsp 30 16 spastic paraplegia hereditary autosomal recessive 32

spastic paraplegia 7, autosomal recessive 43 spastic paraplegia hereditary 32 familial spastic paraparesis 30 spastic paraplegia type 7 17 spastic paraplegia-7 33 spastic paraplegia 43 paraplegin type 15 hsmn v 6 spg 7 16 hsp7 16 fsp 30

Diseases related to hereditary spastic paraplegia by text searches and GeneDecks gene sharing:

(show top 50)    (show all 444)

id	Related Disease	Score	Top Affiliating Genes
1	spastic paraparesis	35.7	SPG7, SPAST, SPG11, HSPD1, FA2H, L1CAM
2	corpus callosum	34.1	SPG20, SPAST, SPG21, SPG46, SPG11, TUBA1A
3	spastic paraplegia 3a	33.6	SPAST, ATL1
4	spastic paraplegia 17	32.6	SNX15, SPAST, SPG38, CAPN1, ARL2, ATL1
5	axonal neuropathy	32.3	PLP1, ATL1, SACS, ZFYVE26, KIF5A
6	spastic paraplegia 3	32.1	ATL3, ATL1, ATL2
7	spastic ataxia	30.5	AFG3L2, GJC2, SACS
8	motor neuron disease	29.7	GALC, SLC1A2, SPG7, SPG20, SPAST, CDK5
9	neuropathy	29.4	TUBA1A, SPAST, SPG20, PLP1, DNAH8, AFG3L2
10	spinocerebellar ataxia type 28	29.1	AFG3L2, SPG7
11	dementia	28.9	SLC1A2, DNAH8, PLP1, SPAST, SPG21, MAPK8
12	optic atrophy	28.9	PLP1, SPG7, SPG11, CCDC50, ATXN3, ZFYVE26
13	spastic paraplegia	28.7	SNX7, SNX15, SPG23, SPG7, SPG20, SPG19
14	spasticity	28.7	PI4K2A, REEP1, SPG7, SPG20, SPG19, SPG27
15	hereditary ataxia	28.4	ATXN3, SPG7, AFG3L2
16	paraplegia	28.0	SPG19, SPG27, SPAST, SPG24, SPG37, SPG43
17	multiple sclerosis	27.6	SPG20, SPG7, PLP1, NIPA1, DNAH8, SLC1A2
18	neurodegeneration	26.8	SLC1A2, DNAH8, PLP1, SPAST, CAPN1, HSPD1
19	leukodystrophy	25.4	GALC, PLP1, GJC2, HSPD1, FA2H
20	neurodegenerative disease	24.7	PLP1, DNAH8, SLC1A2, RTN1, GALC, SPG7
21	neuronitis	24.3	SPG20, SPAST, SPG11, CYP7B1, TUBA1A, GJC2
22	autosomal recessive congenital ichthyosis	13.4	NIPA1, NIPA2, NIPAL4
23	congenital ichthyosiform erythroderma	13.3	NIPA1, NIPA2, NIPAL1, NIPAL4
24	ichthyosis	13.0	NIPAL4, NIPAL1, NIPA2, NIPA1, CAPN1
25	nystagmus	12.7	SACS, HSPD1, GJC2, PLP1
26	toxic encephalopathy	12.1	SLC1A2, DNAH8, TUBA1A, MAPK8, CDK5
27	carcinoma	10.3
28	spastic paraplegia type 4	9.9
29	troyer syndrome	9.9
30	spastic paraplegia type 11	9.6
31	breast cancer	9.3
32	spg11-related hereditary spastic paraplegia with thin corpus callosum	9.2
33	spastic paraplegia 8	9.2
34	spastic paraplegia 5a	9.0
35	arthritis	8.9
36	leukemia	8.9
37	spastic paraplegia 10	8.8
38	spastic paraplegia 31	8.8
39	prostatitis	8.8
40	spastic paraplegia 1	8.6
41	spastic paraplegia 13	8.6
42	spastic paraplegia 23	8.6
43	spastic paraplegia 39	8.6
44	spastic paraplegia 44	8.6
45	spastic paraplegia 20	8.5
46	prostate cancer	8.5
47	ischemia	8.4
48	masa syndrome	8.4
49	spastic paraplegia 25	8.4
50	spastic paraplegia 33	8.4

Clinical features from OMIM: 607259

Approved drugs:

Drug clinical trials:

Genetic tests related to hereditary spastic paraplegia:

id	Genetic test	Affiliating Genes
1	Hereditary Spastic Paraplegia clinical/research	SPG7

MalaCards organs/tissues related to hereditary spastic paraplegia:

²²

MGI Mouse Phenotypes related to hereditary spastic paraplegia:

²⁵

id	Description	MGI Source Accession	Score	Top Affiliating Genes
1	behavior/neurological phenotype	MP:0005386	7.6	PI4K2A, AFG3L2, SLC1A2, PLP1, SPG7, SPG20

Articles related to hereditary spastic paraplegia:

(show top 50)    (show all 171)

id	Title	Authors	Year	Affiliating Genes
1	Mutations in the ER-shaping protein reticulon 2 cause the axon- degenerative disorder hereditary spastic paraplegia type 12. (22232211)	Montenegro G.... Zuchner S.	2012	SPAST, RTN2
2	Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin (SPAST) muta tions is found more often in males. (21546041)	Proukakis C.... Houlden H.	2011	SPAST
3	A new locus (SPG47) maps to 1p13.2-1p12 in an Arabic family with complicated autosomal recessive hereditary spastic paraplegia and t hin corpus callosum. (21440262)	Blumkin L.... Leshinsky-Silver E.	2011	SPG11
4	A novel mutation in KIF5A gene causing hereditary spastic paraplegia with axonal neuropathy. (21107874)	Musumeci O.... Toscano A.	2011	KIF5A
5	A genome-scale DNA repair RNAi screen identifies SPG4 8 as a novel gene associated with hereditary spastic paraplegia. (20613862)	SA8abicki M.... Buchholz F.	2010	ZFYVE26, SPG11, AP5Z1
6	A novel splicing mutation (c.870+3A>G) in SPG4 in a Korean family with hereditary spastic paraplegia. (19939411)	Lim J.S.... Lee K.W.	2010	SPAST
7	The prevalence of hereditary spastic paraplegia and the occurrence of SPG4 mutations in Estonia. (19039240)	Braschinsky M.... Haldre S.	2009	SPAST
8	Direct evidence for axonal transport defects in a nov el mouse model of mutant spastin-induced hereditary spastic paraplegia (HSP) an d human HSP patients. (19453301)	Kasher P.R.... Grierson A.J.	2009	SPAST
9	Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. (18853458)	Goizet C.... Brice A.	2009	KIF5A
10	Frequency and phenotype of SPG11 and SPG15 in complic ated hereditary spastic paraplegia. (19917823)	SchA1le R.... Bauer P.	2009	ZFYVE26, SPG11
11	Hereditary spastic paraplegias. (19494379)	Lau K.K.... Chan Y.W.	2009	SPAST, ATL1
12	SPG11 mutations cause Kjellin syndrome, a hereditary spastic paraplegia with thin corpus callosum and central retinal degeneration. (19194956)	OrlAcn H.... Dahl N.	2009	SPG11
13	Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia. (18701882)	Shoukier M.... Mannan A.U.	2009	SPAST
14	Screening of hereditary spastic paraplegia patients for alterations at NIPA1 mutational hotspots. (18191948)	Beetz C.... Deufel T.	2008	NIPA1
15	Compound heterozygosity in the SPG4 gene causes hereditary spastic paraplegia. (18190593)	Pantakani D.V.... Mannan A.U.	2008	SPAST
16	Two novel mutations in the SPG11 gene causing hereditary spastic paraplegia associated with thin corpus callosum. (18361476)	Zhang S.S.... Yang Y.	2008	SPG11
17	New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP). (19034539)	Hewamadduma C.... Shaw P.	2008	REEP1
18	Structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin. (18202664)	Roll-Mecak A.... Vale R.D.	2008	SPAST, KATNB1
19	Autosomal dominant hereditary spastic paraplegia: novel mutations in the REEP1 gene (SPG31). (18644145)	Schlang K.J.... Stemmler S.	2008	SPAST, REEP1, ATL1
20	Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. (17160902)	Valdmanis P.N.... Rouleau G.A.	2007	KIAA0196
21	A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation. (17646629)	Warnecke T.... Young P.	2007	SPG7
22	Seven novel mutations and four exon deletions in a collection of Norwegian patients with SPG4 hereditary spastic paraplegia. (17594340)	Erichsen A.K.... Tallaksen C.M.	2007	SPAST
23	NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg2+ transporter. (17166836)	Goytain A.... Quamme G.A.	2007	NIPA1
24	Possible anticipation in hereditary spastic paraplegia type 4 (SPG4). (17598599)	Reddy P.L.... Grewal R.P.	2007	SPAST
25	Isoform-specific increase of spastin stability by N-terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia. (17916079)	Schickel J.... Beetz C.	2007	SPAST
26	A SPG3A mutation with a novel foot phenotype of hereditary spastic paraplegia in a Chinese Han family. (17531128)	Li X.H.... Wang Y.M.	2007	ATL1
27	A novel mutation in the HSPD1 gene in a patient with hereditary spastic paraplegia. (17420924)	Hansen J.... Bross P.	2007	HSPD1
28	Translating m-AAA protease function in mitochondria to hereditary spastic paraplegia. (16647881)	Rugarli E.I.... Langer T.	2006	SPG7
29	The hereditary spastic paraplegia protein spartin localises to mitochondria. (16945107)	Lu J.... Byrne P.C.	2006	TUBA1A, SPG20
30	Spastin gene mutations in Bulgarian patients with hereditary spastic paraplegia. (17100993)	Ivanova N.... Mitev V.	2006	SPAST
31	Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia. (16534102)	Elleuch N.... Brice A.	2006	SPG7
32	Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. (16826527)	Zuechner S.... Pericak-Vance M.A.	2006	REEP1
33	Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance. (16815977)	Evans K.J.... Lauring B.P.	2006	SPAST, ATL1
34	Spastin related hereditary spastic paraplegia with dysplastic corpus callosum. (16009377)	Alber B.... Meyer T.	2005	SPAST
35	A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia. (14985266)	Wilkinson P.A.... Warner T.T.	2004	SPG7
36	Three novel mutations of the spastin gene in Chinese patients with hereditary spastic paraplegia. (14732620)	Tang B.... Jiang H.	2004	SPAST
37	Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation. (15667412)	Nielsen J.E.... Sorensen S.A.	2004	SPAST
38	Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus. (14695538)	Sauter S.M.... Neesen J.	2004	ATL1
39	Novel mutation in the SPG3A gene in an African American family with an early onset of hereditary spastic paraplegia. (15477516)	Hedera P.... Haines J.L.	2004	ATL1
40	Prenatal diagnosis of autosomal dominant hereditary spastic paraplegia (SPG4) using direct mutation detection. (15164410)	Nielsen J.E.... Hasholt L.	2004	SPAST
41	A clinical, genetic and candidate gene study of Silver syndrome, a complicated form of hereditary spastic paraplegia. (15372247)	Warner T.T.... Crosby A.H.	2004	CAPN1, ARL2, SNX15
42	Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin. (14506257)	Zhu P.-P.... Blackstone C.	2003	ATL2, ATL1, ATL3
43	Spastin gene mutation in Chinese patients with hereditary spastic paraplegia (12778437)	Zhao G.H.... Xia J.H.	2003	SPAST
44	Spastin gene mutation in Japanese with hereditary spastic paraplegia. (12161613)	Yabe I.... Satoh T.	2002	SPAST
45	Mutation analysis of the spastin gene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia. (12124993)	Sauter S.M.... Neesen J.	2002	SPAST
46	Recent advances in hereditary spastic paraplegia. (11470961)	Tallaksen C.M.... Brice A.	2001	SPG7, SACS
47	Intrafamilial variability in hereditary spastic paraplegia associated with an SPG4 gene mutation. (10980739)	Santorelli F.M.... Casali C.	2000	SPAST
48	A locus for autosomal dominant 'pure' hereditary spastic paraplegia maps to chromosome 19q13. (10677333)	Reid E.... Rubinsztein D.C.	2000	RTN2
49	Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q. (9973294)	Hedera P.... Fink J.K.	1999	KIAA0196
50	A new locus for autosomal dominant 'pure' hereditary spastic paraplegia mapping to chromosome 12q13, and evidence for further genetic heterogeneity. (10441583)	Reid E.... Rubinsztein D.C.	1999	KIF5A

Genes related to hereditary spastic paraplegia according to GeneCards:

(show top 50)    (show all 69)

id	Symbol	Description	Score	GeneCards Section Context
1	AFG3L2	AFG3 ATPase family gene 3-like 2 (S. cerevisiae)	11.1	Orthologs, Summaries, Publications
2	KIAA0196	KIAA0196	11.1	Summaries, Publications
3	ZFYVE27	zinc finger, FYVE domain containing 27	11.1	Summaries, Publications
4	SPG24	spastic paraplegia 24 (autosomal recessive)	11.0	Publications
5	SPG29	spastic paraplegia 29 (autosomal dominant)	11.0	Publications
6	SPG43	spastic paraplegia 43 (autosomal recessive)	11.0	Publications
7	SPG19	spastic paraplegia 19 (autosomal dominant)	11.0	Publications
8	SPG38	spastic paraplegia 38 (autosomal dominant, Silver syndrome)	11.0	Publications
9	SPG23	spastic paraplegia 23 (autosomal recessive)	11.0	Publications
10	SPG27	spastic paraplegia 27 (autosomal recessive)	11.0	Publications
11	SPG26	spastic paraplegia 26	11.0	Publications
12	SPG37	spastic paraplegia 37 (autosomal dominant)	11.0	Publications
13	SPG46	spastic paraplegia 46 (autosomal recessive)	11.0	Publications
14	SPG41	spastic paraplegia 41 (autosomal dominant)	11.0	Publications
15	SPAST	spastin	11.0	Publications
16	ATL1	atlastin GTPase 1	11.0	Publications
17	NIPA1	non imprinted in Prader-Willi/Angelman syndrome 1	11.0	Publications
18	KIF5A	kinesin family member 5A	11.0	Publications
19	CHMP1B	charged multivesicular body protein 1B	11.0	Publications
20	SPG20	spastic paraplegia 20 (Troyer syndrome)	11.0	Publications
21	SNX15	sorting nexin 15	11.0	Publications
22	SPG21	spastic paraplegia 21 (autosomal recessive, Mast syndrome)	11.0	Publications
23	SPG7	spastic paraplegia 7 (pure and complicated autosomal recessive)	11.0	Publications
24	SPG11	spastic paraplegia 11 (autosomal recessive)	11.0	Publications
25	GJC2	gap junction protein, gamma 2, 47kDa	11.0	Publications
26	BSCL2	Berardinelli-Seip congenital lipodystrophy 2 (seipin)	11.0	Publications
27	NIPAL4	NIPA-like domain containing 4	11.0	Orthologs
28	NIPAL1	NIPA-like domain containing 1	11.0	Orthologs
29	ARL2	ADP-ribosylation factor-like 2	11.0	Publications
30	CLPP	ClpP caseinolytic peptidase, ATP-dependent, proteolytic subunit homolog (E. coli)	11.0	Publications
31	KATNB1	katanin p80 (WD repeat containing) subunit B 1	11.0	Publications
32	TMED9	transmembrane emp24 protein transport domain containing 9	11.0	Publications
33	REEP1	receptor accessory protein 1	11.0	Publications
34	AFG3L1P	AFG3 ATPase family gene 3-like 1 (S. cerevisiae), pseudogene	11.0	Publications
35	ATL3	atlastin GTPase 3	11.0	Publications
36	ZFYVE26	zinc finger, FYVE domain containing 26	11.0	Publications
37	TUBA1A	tubulin, alpha 1a	11.0	Publications
38	PI4K2A	phosphatidylinositol 4-kinase type 2 alpha	11.0	Publications
39	HSPE1	heat shock 10kDa protein 1 (chaperonin 10)	11.0	Publications
40	MT-ATP6	mitochondrially encoded ATP synthase 6	11.0	Publications
41	ERLIN2	ER lipid raft associated 2	11.0	Publications
42	NIPA2	non imprinted in Prader-Willi/Angelman syndrome 2	11.0	Orthologs
43	L1CAM	L1 cell adhesion molecule	11.0	Publications
44	CCDC50	coiled-coil domain containing 50	11.0	UniProt Related
45	F12	coagulation factor XII (Hageman factor)	11.0	Publications
46	FA2H	fatty acid 2-hydroxylase	11.0	Publications
47	PLP1	proteolipid protein 1	11.0	Publications
48	SNX7	sorting nexin 7	11.0	Publications
49	SACS	spastic ataxia of Charlevoix-Saguenay (sacsin)	11.0	Publications
50	HSPD1	heat shock 60kDa protein 1 (chaperonin)	11.0	Publications

Compounds related to hereditary spastic paraplegia according to GeneDecks:

id	Compound	Score	Top Affiliating Genes
1	amp-pnp32	9.8	HSPE1, HSPD1, DNAH8
2	8-azido-atp32	9.7	DNAH8, HSPD1, HSPE1
3	alsterpaullone32 9 9	11.6	CDK5, CDK1
4	vinblastine32 9 9	10.9	CDK1, MAPK8, MAP2K4, TUBA1A, DNAH8

Cellular components related to hereditary spastic paraplegia according to GeneDecks:

id	Name	GO ID	Score	Top Affiliating Genes
1	axon	GO:030424	9.7	KIF13B, ZFYVE27, SACS, ATL1, CDK5
2	endoplasmic reticulum	GO:005783	8.8	RTN2, SPAST, TMED9, ERLIN2, ATL3, ATL1
3	AP-type membrane coat adaptor complex	GO:030119	8.4	AP5B1, AP5S1, AP5Z1

Biological processes related to hereditary spastic paraplegia according to GeneDecks:

id	Name	GO ID	Score	Top Affiliating Genes
1	magnesium ion transport	GO:015693	10.2	NIPAL4, NIPAL1, NIPA2, NIPA1
2	endoplasmic reticulum organization	GO:007029	10.0	ATL3, ATL1, ATL2
3	protein homooligomerization	GO:051260	9.4	SPAST, LONP1, ATL3, ATL1, ATL2
4	MyD88-dependent toll-like receptor signaling pathway	GO:002755	9.3	CDK1, MAPK8, MAP2K4, HSPD1
5	endosomal transport	GO:016197	7.9	VPS37A, AP5B1, AP5S1, AP5Z1
6	cell death	GO:008219	6.5	AFG3L2, ERLIN2, CYP7B1, SPG11, SPG21, SPAST

Molecular functions related to hereditary spastic paraplegia according to GeneDecks:

id	Name	GO ID	Score	Top Affiliating Genes
1	ATP binding	GO:005524	7.4	LONP1, HSPE1, HSPD1, SPAST, SPG7, DNAH8
2	protein binding	GO:005515	3.1	AFG3L2, MAP2K4, CCDC50, LONP1, F12, HSPE1