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Hereditary spastic paraplegia 56(SPG56)

MedGen UID:
761343
•Concept ID:
C3539507
•
Disease or Syndrome
Synonyms: Spastic Paraplegia 56; Spastic paraplegia 56, autosomal recessive; SPASTIC PARAPLEGIA 56, AUTOSOMAL RECESSIVE, WITH OR WITHOUT PSEUDOXANTHOMA ELASTICUM
SNOMED CT: Autosomal recessive spastic paraplegia type 56 (783764008)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
•Concept ID:
C0441748
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (Orphanet)
 
Gene (location): CYP2U1 (4q25)
 
Monarch Initiative: MONDO:0014015
OMIM®: 615030
Orphanet: ORPHA320411

Definition

Spastic paraplegia-56 with or without pseudoxanthoma elasticum (SPG56) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive lower-limb spasticity resulting in walking difficulties. Upper limbs are often also affected, and some patients may have a subclinical axonal neuropathy (summary by Tesson et al., 2012). Some patients also have pseudoxanthoma elasticum (Legrand et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800. [from OMIM]

Clinical features

From HPO
Dystonic disorder
MedGen UID:
3940
•Concept ID:
C0013421
•
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
See: Feature record | Search on this feature
Babinski sign
MedGen UID:
19708
•Concept ID:
C0034935
•
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
See: Feature record | Search on this feature
Spastic paraplegia
MedGen UID:
20882
•Concept ID:
C0037772
•
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
See: Feature record | Search on this feature
Unsteady gait
MedGen UID:
68544
•Concept ID:
C0231686
•
Finding
A shaky or wobbly manner of walking.
See: Feature record | Search on this feature
Delayed ability to walk
MedGen UID:
66034
•Concept ID:
C0241726
•
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
See: Feature record | Search on this feature
Cognitive impairment
MedGen UID:
90932
•Concept ID:
C0338656
•
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
See: Feature record | Search on this feature
Hypoplasia of the corpus callosum
MedGen UID:
138005
•Concept ID:
C0344482
•
Congenital Abnormality
Underdevelopment of the corpus callosum.
See: Feature record | Search on this feature
Tip-toe gait
MedGen UID:
98104
•Concept ID:
C0427144
•
Finding
An abnormal gait pattern characterized by the failure of the heel to contact the floor at the onset of stance during gait.
See: Feature record | Search on this feature
Abnormal cerebral white matter morphology
MedGen UID:
181756
•Concept ID:
C0948163
•
Pathologic Function
An abnormality of the cerebral white matter.
See: Feature record | Search on this feature
Peripheral axonal neuropathy
MedGen UID:
266071
•Concept ID:
C1263857
•
Disease or Syndrome
An abnormality characterized by disruption of the normal functioning of peripheral axons.
See: Feature record | Search on this feature
Lower limb hyperreflexia
MedGen UID:
322973
•Concept ID:
C1836696
•
Finding
See: Feature record | Search on this feature
Hyperreflexia in upper limbs
MedGen UID:
375112
•Concept ID:
C1843175
•
Finding
See: Feature record | Search on this feature
Motor delay
MedGen UID:
381392
•Concept ID:
C1854301
•
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
See: Feature record | Search on this feature
Intellectual disability
MedGen UID:
811461
•Concept ID:
C3714756
•
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
See: Feature record | Search on this feature
Basal ganglia calcification
MedGen UID:
234651
•Concept ID:
C1389280
•
Pathologic Function
The presence of calcium deposition affecting one or more structures of the basal ganglia.
See: Feature record | Search on this feature
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHereditary spastic paraplegia 56
Follow this link to review classifications for Hereditary spastic paraplegia 56 in Orphanet.

Professional guidelines

PubMed

Functional and Clinical Outcomes of Combined Simultaneous Bilateral Anterior Distal Femoral Plate Hemiepiphysiodesis and Hamstrings Release in Management of Knee Flexion Contractures in Children With Neuromuscular Disorders.
Zaghloul A, Manoukian D, Barrett MC, Geronta I, Maizen C
J Pediatr Orthop 2021 Oct 1;41(9):559-565. doi: 10.1097/BPO.0000000000001942. PMID: 34387232

Recent clinical studies

Etiology

Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56.
Legrand A, Pujol C, Durand CM, Mesnil A, Rubera I, Duranton C, Zuily S, Sousa AB, Renaud M, Boucher JL, Pietrancosta N, Adham S, Orssaud C, Marelli C, Casali C, Ziccardi L, Villain N, Ewenczyk C, Durr A, Mignot C, Stevanin G, Billon C, Hureaux M, Jeunemaitre X, Goizet C, Albuisson J
J Intern Med 2021 May;289(5):709-725. Epub 2021 Mar 31 doi: 10.1111/joim.13193. PMID: 33107650
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.
Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D'Amore A, Eberhardt K, Brechmann B, Ziegler M, Jensen DM, Nagabhyrava P, Geisel G, Carmody E, Shamshad U, Dies KA, Yuskaitis CJ, Salussolia CL, Ebrahimi-Fakhari D, Pearson TS, Saffari A, Ziegler A, Kölker S, Volkmann J, Wiesener A, Bearden DR, Lakhani S, Segal D, Udwadia-Hegde A, Martinuzzi A, Hirst J, Perlman S, Takiyama Y, Xiromerisiou G, Vill K, Walker WO, Shukla A, Dubey Gupta R, Dahl N, Aksoy A, Verhelst H, Delgado MR, Kremlikova Pourova R, Sadek AA, Elkhateeb NM, Blumkin L, Brea-Fernández AJ, Dacruz-Álvarez D, Smol T, Ghoumid J, Miguel D, Heine C, Schlump JU, Langen H, Baets J, Bulk S, Darvish H, Bakhtiari S, Kruer MC, Lim-Melia E, Aydinli N, Alanay Y, El-Rashidy O, Nampoothiri S, Patel C, Beetz C, Bauer P, Yoon G, Guillot M, Miller SP, Bourinaris T, Houlden H, Robelin L, Anheim M, Alamri AS, Mahmoud AAH, Inaloo S, Habibzadeh P, Faghihi MA, Jansen AC, Brock S, Roubertie A, Darras BT, Agrawal PB, Santorelli FM, Gleeson J, Zaki MS, Sheikh SI, Bennett JT, Sahin M
Brain 2020 Oct 1;143(10):2929-2944. doi: 10.1093/brain/awz307. PMID: 32979048Free PMC Article
Hereditary and idiopathic spastic paraparesis: preliminary findings of a single center experience.
Cui F, Sun L, Qiao J, Xiong J, Zhao Y, Li J, Li M, Chen S, Huang X
Neurol Res 2018 Dec;40(12):1088-1093. doi: 10.1080/01616412.2018.1522412. PMID: 30352018
Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial.
Schöls L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, Jägle C, Fraidakis MJ, Martinuzzi A, Saute JA, Scarlato M, Antenora A, Stendel C, Höflinger P, Lourenco CM, Abreu L, Smets K, Paucar M, Deconinck T, Bis DM, Wiethoff S, Bauer P, Arnoldi A, Marques W, Jardim LB, Hauser S, Criscuolo C, Filla A, Züchner S, Bassi MT, Klopstock T, De Jonghe P, Björkhem I, Schüle R
Brain 2017 Dec 1;140(12):3112-3127. doi: 10.1093/brain/awx273. PMID: 29126212Free PMC Article
The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies.
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

Diagnosis

Retinal ganglion cell and microvascular density loss in hereditary spastic paraplegia.
Turski GN, Turski CA, Grobe-Einsler M, Kobeleva X, Turski JS, Holz FG, Finger RP, Klockgether T
Restor Neurol Neurosci 2023;41(5-6):229-239. doi: 10.3233/RNN-231380. PMID: 38217556Free PMC Article
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.
Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D'Amore A, Eberhardt K, Brechmann B, Ziegler M, Jensen DM, Nagabhyrava P, Geisel G, Carmody E, Shamshad U, Dies KA, Yuskaitis CJ, Salussolia CL, Ebrahimi-Fakhari D, Pearson TS, Saffari A, Ziegler A, Kölker S, Volkmann J, Wiesener A, Bearden DR, Lakhani S, Segal D, Udwadia-Hegde A, Martinuzzi A, Hirst J, Perlman S, Takiyama Y, Xiromerisiou G, Vill K, Walker WO, Shukla A, Dubey Gupta R, Dahl N, Aksoy A, Verhelst H, Delgado MR, Kremlikova Pourova R, Sadek AA, Elkhateeb NM, Blumkin L, Brea-Fernández AJ, Dacruz-Álvarez D, Smol T, Ghoumid J, Miguel D, Heine C, Schlump JU, Langen H, Baets J, Bulk S, Darvish H, Bakhtiari S, Kruer MC, Lim-Melia E, Aydinli N, Alanay Y, El-Rashidy O, Nampoothiri S, Patel C, Beetz C, Bauer P, Yoon G, Guillot M, Miller SP, Bourinaris T, Houlden H, Robelin L, Anheim M, Alamri AS, Mahmoud AAH, Inaloo S, Habibzadeh P, Faghihi MA, Jansen AC, Brock S, Roubertie A, Darras BT, Agrawal PB, Santorelli FM, Gleeson J, Zaki MS, Sheikh SI, Bennett JT, Sahin M
Brain 2020 Oct 1;143(10):2929-2944. doi: 10.1093/brain/awz307. PMID: 32979048Free PMC Article
Hereditary and idiopathic spastic paraparesis: preliminary findings of a single center experience.
Cui F, Sun L, Qiao J, Xiong J, Zhao Y, Li J, Li M, Chen S, Huang X
Neurol Res 2018 Dec;40(12):1088-1093. doi: 10.1080/01616412.2018.1522412. PMID: 30352018
Targeted next-generation sequencing improves diagnosis of hereditary spastic paraplegia in Chinese patients.
Lu C, Li LX, Dong HL, Wei Q, Liu ZJ, Ni W, Gitler AD, Wu ZY
J Mol Med (Berl) 2018 Jul;96(7):701-712. Epub 2018 Jun 11 doi: 10.1007/s00109-018-1655-4. PMID: 29934652
The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies.
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

Therapy

Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial.
Schöls L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, Jägle C, Fraidakis MJ, Martinuzzi A, Saute JA, Scarlato M, Antenora A, Stendel C, Höflinger P, Lourenco CM, Abreu L, Smets K, Paucar M, Deconinck T, Bis DM, Wiethoff S, Bauer P, Arnoldi A, Marques W, Jardim LB, Hauser S, Criscuolo C, Filla A, Züchner S, Bassi MT, Klopstock T, De Jonghe P, Björkhem I, Schüle R
Brain 2017 Dec 1;140(12):3112-3127. doi: 10.1093/brain/awx273. PMID: 29126212Free PMC Article
Effect of intrathecal baclofen on sleep and respiratory function in patients with spasticity.
Bensmail D, Quera Salva MA, Roche N, Benyahia S, Bohic M, Denys P, Bussel B, Lofaso F
Neurology 2006 Oct 24;67(8):1432-6. doi: 10.1212/01.wnl.0000239827.38036.23. PMID: 17060570

Prognosis

Identification of novel compound heterozygous SPG7 mutations-related hereditary spastic paraplegia in a Chinese family: a case report.
Zhang X, Zhang L, Wu Y, Li G, Chen S, Xia Y, Li H
BMC Neurol 2018 Nov 29;18(1):196. doi: 10.1186/s12883-018-1199-9. PMID: 30497413Free PMC Article
Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study.
Zucchi E, Bedin R, Fasano A, Fini N, Gessani A, Vinceti M, Mandrioli J
Neurodegener Dis 2018;18(5-6):255-261. Epub 2018 Nov 14 doi: 10.1159/000493986. PMID: 30428468
Toe Walking: A Neurological Perspective After Referral From Pediatric Orthopaedic Surgeons.
Haynes KB, Wimberly RL, VanPelt JM, Jo CH, Riccio AI, Delgado MR
J Pediatr Orthop 2018 Mar;38(3):152-156. doi: 10.1097/BPO.0000000000001115. PMID: 29309384
CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56.
Durand CM, Dhers L, Tesson C, Tessa A, Fouillen L, Jacqueré S, Raymond L, Coupry I, Benard G, Darios F, El-Hachimi KH, Astrea G, Rivier F, Banneau G, Pujol C, Lacombe D, Durr A, Babin PJ, Santorelli FM, Pietrancosta N, Boucher JL, Mansuy D, Stevanin G, Goizet C
Hum Mutat 2018 Jan;39(1):140-151. Epub 2017 Nov 11 doi: 10.1002/humu.23359. PMID: 29034544
Clinical heterogeneity of autosomal recessive spastic paraplegias: analysis of 106 patients in 46 families.
Coutinho P, Barros J, Zemmouri R, Guimarães J, Alves C, Chorão R, Lourenço E, Ribeiro P, Loureiro JL, Santos JV, Hamri A, Paternotte C, Hazan J, Silva MC, Prud'homme JF, Grid D
Arch Neurol 1999 Aug;56(8):943-9. doi: 10.1001/archneur.56.8.943. PMID: 10448799

Clinical prediction guides

Retinal ganglion cell and microvascular density loss in hereditary spastic paraplegia.
Turski GN, Turski CA, Grobe-Einsler M, Kobeleva X, Turski JS, Holz FG, Finger RP, Klockgether T
Restor Neurol Neurosci 2023;41(5-6):229-239. doi: 10.3233/RNN-231380. PMID: 38217556Free PMC Article
Functional and Clinical Outcomes of Combined Simultaneous Bilateral Anterior Distal Femoral Plate Hemiepiphysiodesis and Hamstrings Release in Management of Knee Flexion Contractures in Children With Neuromuscular Disorders.
Zaghloul A, Manoukian D, Barrett MC, Geronta I, Maizen C
J Pediatr Orthop 2021 Oct 1;41(9):559-565. doi: 10.1097/BPO.0000000000001942. PMID: 34387232
Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study.
Zucchi E, Bedin R, Fasano A, Fini N, Gessani A, Vinceti M, Mandrioli J
Neurodegener Dis 2018;18(5-6):255-261. Epub 2018 Nov 14 doi: 10.1159/000493986. PMID: 30428468
Hereditary and idiopathic spastic paraparesis: preliminary findings of a single center experience.
Cui F, Sun L, Qiao J, Xiong J, Zhao Y, Li J, Li M, Chen S, Huang X
Neurol Res 2018 Dec;40(12):1088-1093. doi: 10.1080/01616412.2018.1522412. PMID: 30352018
CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56.
Durand CM, Dhers L, Tesson C, Tessa A, Fouillen L, Jacqueré S, Raymond L, Coupry I, Benard G, Darios F, El-Hachimi KH, Astrea G, Rivier F, Banneau G, Pujol C, Lacombe D, Durr A, Babin PJ, Santorelli FM, Pietrancosta N, Boucher JL, Mansuy D, Stevanin G, Goizet C
Hum Mutat 2018 Jan;39(1):140-151. Epub 2017 Nov 11 doi: 10.1002/humu.23359. PMID: 29034544

Recent systematic reviews

The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies.
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

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