U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Hereditary spastic paraplegia 51(SPG51; CPSQ4, FORMERLY)

MedGen UID:
462406
Concept ID:
C3151056
Disease or Syndrome
Synonyms: Cerebral palsy, spastic quadriplegic, 4; Spastic paraplegia 51, autosomal recessive
 
Gene (location): AP4E1 (15q21.2)
 
Monarch Initiative: MONDO:0013401
OMIM®: 613744

Disease characteristics

Excerpted from the GeneReview: AP-4-Associated Hereditary Spastic Paraplegia
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe. [from GeneReviews]
Authors:
Darius Ebrahimi-Fakhari  |  Robert Behne  |  Alexandra K Davies, et. al.   view full author information

Additional description

From OMIM
Spastic paraplegia-51 (SPG51) is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity. Affected individuals also have global developmental delay with impaired intellectual development and poor or absent speech (summary by Moreno-De-Luca et al., 2011). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).  http://www.omim.org/entry/613744

Clinical features

From HPO
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Overweight
MedGen UID:
105424
Concept ID:
C0497406
Finding
Increased body weight with a body mass index of 25-29.9 kg per square meter.
Prominent antihelix
MedGen UID:
335147
Concept ID:
C1845272
Finding
The presence of an abnormally prominent antihelix.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
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.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Excessive shyness
MedGen UID:
20741
Concept ID:
C0037020
Social Behavior
Atypically high degree of awkwardness or apprehension experienced when approaching or being approached by others.
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
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.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Decreased muscle mass
MedGen UID:
373256
Concept ID:
C1837108
Finding
Facial hypotonia
MedGen UID:
336889
Concept ID:
C1845251
Finding
Reduced muscle tone of a muscle that is innervated by the facial nerve (the seventh cranial nerve).
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Drooling
MedGen UID:
8484
Concept ID:
C0013132
Finding
Habitual flow of saliva out of the mouth.
Wide mouth
MedGen UID:
44238
Concept ID:
C0024433
Congenital Abnormality
Distance between the oral commissures more than 2 SD above the mean. Alternatively, an apparently increased width of the oral aperture (subjective).
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Narrow face
MedGen UID:
373334
Concept ID:
C1837463
Finding
Bizygomatic (upper face) and bigonial (lower face) width are both more than 2 standard deviations below the mean (objective); or, an apparent reduction in the width of the upper and lower face (subjective).
Narrow forehead
MedGen UID:
326956
Concept ID:
C1839758
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
Long nose
MedGen UID:
326583
Concept ID:
C1839798
Finding
Distance from nasion to subnasale more than two standard deviations above the mean, or alternatively, an apparently increased length from the nasal root to the nasal base.
Pointed chin
MedGen UID:
336193
Concept ID:
C1844505
Finding
A marked tapering of the lower face to the chin.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Short philtrum
MedGen UID:
350006
Concept ID:
C1861324
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD below the mean. Alternatively, an apparently decreased distance between nasal base and midline upper lip vermilion border.
Amblyopia
MedGen UID:
8009
Concept ID:
C0002418
Disease or Syndrome
Reduced visual acuity that is uncorrectable by lenses in the absence of detectable anatomic defects in the eye or visual pathways.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

Professional guidelines

PubMed

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
Zhou YX, Qiao WH, Gu WH, Xie H, Tang BS, Zhou LS, Yang BX, Takiyama Y, Tsuji S, He HY, Deng CX, Goldfarb LG, Wang GX
Arch Neurol 2001 May;58(5):789-94. doi: 10.1001/archneur.58.5.789. PMID: 11346374

Recent clinical studies

Etiology

Ortega Suero G, Abenza Abildúa MJ, Serrano Munuera C, Rouco Axpe I, Arpa Gutiérrez FJ, Adarmes Gómez AD, Rodríguez de Rivera FJ, Quintans Castro B, Posada Rodríguez I, Vadillo Bermejo A, Domingo Santos Á, Blanco Vicente E, Infante Ceberio I, Pardo Fernández J, Costa Arpín E, Painous Martí C, Muñoz García JE, Mir Rivera P, Montón Álvarez F, Bataller Alberola L, Gascón Bayarri J, Casasnovas Pons C, Vélez Santamaría V, López de Munain A, Fernández-Eulate G, Gazulla Abío J, Sanz Gallego I, Rojas Bartolomé L, Ayo Martín Ó, Segura Martín T, González Mingot C, Baraldés Rovira M, Sivera Mascaró R, Cubo Delgado E, Echavarría Íñiguez A, Vázquez Sánchez F, Bártulos Iglesias M, Casadevall Codina MT, Martínez Fernández EM, Labandeira Guerra C, Alemany Perna B, Carvajal Hernández A, Fernández Moreno C, Palacín Larroy M, Caballol Pons N, Ávila Rivera A, Navacerrada Barrero FJ, Lobato Rodríguez R, Sobrido Gómez MJ
Neurologia (Engl Ed) 2023 Jul-Aug;38(6):379-386. Epub 2023 Apr 28 doi: 10.1016/j.nrleng.2023.04.003. PMID: 37120112
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
Teinert J, Behne R, Wimmer M, Ebrahimi-Fakhari D
J Inherit Metab Dis 2020 Jan;43(1):51-62. Epub 2019 Apr 8 doi: 10.1002/jimd.12084. PMID: 30854657
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320
Ormerod IE, Harding AE, Miller DH, Johnson G, MacManus D, du Boulay EP, Kendall BE, Moseley IF, McDonald WI
J Neurol Neurosurg Psychiatry 1994 Jan;57(1):51-7. doi: 10.1136/jnnp.57.1.51. PMID: 8301305Free PMC Article

Diagnosis

Ortega Suero G, Abenza Abildúa MJ, Serrano Munuera C, Rouco Axpe I, Arpa Gutiérrez FJ, Adarmes Gómez AD, Rodríguez de Rivera FJ, Quintans Castro B, Posada Rodríguez I, Vadillo Bermejo A, Domingo Santos Á, Blanco Vicente E, Infante Ceberio I, Pardo Fernández J, Costa Arpín E, Painous Martí C, Muñoz García JE, Mir Rivera P, Montón Álvarez F, Bataller Alberola L, Gascón Bayarri J, Casasnovas Pons C, Vélez Santamaría V, López de Munain A, Fernández-Eulate G, Gazulla Abío J, Sanz Gallego I, Rojas Bartolomé L, Ayo Martín Ó, Segura Martín T, González Mingot C, Baraldés Rovira M, Sivera Mascaró R, Cubo Delgado E, Echavarría Íñiguez A, Vázquez Sánchez F, Bártulos Iglesias M, Casadevall Codina MT, Martínez Fernández EM, Labandeira Guerra C, Alemany Perna B, Carvajal Hernández A, Fernández Moreno C, Palacín Larroy M, Caballol Pons N, Ávila Rivera A, Navacerrada Barrero FJ, Lobato Rodríguez R, Sobrido Gómez MJ
Neurologia (Engl Ed) 2023 Jul-Aug;38(6):379-386. Epub 2023 Apr 28 doi: 10.1016/j.nrleng.2023.04.003. PMID: 37120112
Du J
J Clin Neurosci 2021 Mar;85:67-71. Epub 2021 Jan 15 doi: 10.1016/j.jocn.2020.11.036. PMID: 33581793
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
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320
Ormerod IE, Harding AE, Miller DH, Johnson G, MacManus D, du Boulay EP, Kendall BE, Moseley IF, McDonald WI
J Neurol Neurosurg Psychiatry 1994 Jan;57(1):51-7. doi: 10.1136/jnnp.57.1.51. PMID: 8301305Free PMC Article

Therapy

Varghaei P, Yoon G, Estiar MA, Veyron S, Leveille E, Dupré N, Trempe JF, Rouleau GA, Gan-Or Z
Clin Genet 2021 Jul;100(1):51-58. Epub 2021 Mar 18 doi: 10.1111/cge.13955. PMID: 33713342
van Lith BJH, den Boer J, van de Warrenburg BPC, Weerdesteyn V, Geurts AC
J Rehabil Med 2019 Jun 18;51(6):434-441. doi: 10.2340/16501977-2556. PMID: 30968942

Prognosis

Zhang X, Xiang F, Li D, Yang F, Yu S, Wang X
BMC Neurol 2024 Jan 2;24(1):15. doi: 10.1186/s12883-023-03480-4. PMID: 38166857Free PMC Article
Durand CM, Angelini C, Michaud V, Delleci C, Coupry I, Goizet C, Trimouille A
BMC Neurol 2022 Feb 12;22(1):53. doi: 10.1186/s12883-022-02553-0. PMID: 35151251Free PMC Article
Varghaei P, Yoon G, Estiar MA, Veyron S, Leveille E, Dupré N, Trempe JF, Rouleau GA, Gan-Or Z
Clin Genet 2021 Jul;100(1):51-58. Epub 2021 Mar 18 doi: 10.1111/cge.13955. PMID: 33713342
Jia X, Madireddy L, Caillier S, Santaniello A, Esposito F, Comi G, Stuve O, Zhou Y, Taylor B, Kilpatrick T, Martinelli-Boneschi F, Cree BAC, Oksenberg JR, Hauser SL, Baranzini SE
Ann Neurol 2018 Jul;84(1):51-63. Epub 2018 Jul 3 doi: 10.1002/ana.25263. PMID: 29908077Free PMC Article
Banfi S, Bassi MT, Andolfi G, Marchitiello A, Zanotta S, Ballabio A, Casari G, Franco B
Genomics 1999 Jul 1;59(1):51-8. doi: 10.1006/geno.1999.5818. PMID: 10395799

Clinical prediction guides

Varghaei P, Yoon G, Estiar MA, Veyron S, Leveille E, Dupré N, Trempe JF, Rouleau GA, Gan-Or Z
Clin Genet 2021 Jul;100(1):51-58. Epub 2021 Mar 18 doi: 10.1111/cge.13955. PMID: 33713342
Du J
J Clin Neurosci 2021 Mar;85:67-71. Epub 2021 Jan 15 doi: 10.1016/j.jocn.2020.11.036. PMID: 33581793
Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, Chelban V, Manole A, Hamed SA, Haridy NA, Federoff M, Preza E, Hughes D, Pittman A, Jaunmuktane Z, Brandner S, Xiromerisiou G, Wiethoff S, Schottlaender L, Proukakis C, Morris H, Warner T, Bhatia KP, Korlipara LV, Singleton AB, Hardy J, Wood NW, Lewis PA, Houlden H
Brain 2016 Jul;139(Pt 7):1904-18. Epub 2016 May 23 doi: 10.1093/brain/aww111. PMID: 27217339Free PMC Article
Racis L, Storti E, Pugliatti M, Agnetti V, Tessa A, Santorelli FM
BMC Med Genet 2014 Apr 1;15:39. doi: 10.1186/1471-2350-15-39. PMID: 24690193Free PMC Article
Zhao J, Matthies DS, Botzolakis EJ, Macdonald RL, Blakely RD, Hedera P
J Neurosci 2008 Dec 17;28(51):13938-51. doi: 10.1523/JNEUROSCI.4668-08.2008. PMID: 19091982Free PMC Article

Recent systematic reviews

Du J
J Clin Neurosci 2021 Mar;85:67-71. Epub 2021 Jan 15 doi: 10.1016/j.jocn.2020.11.036. PMID: 33581793
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Consumer resources

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...