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Spastic paraplegia 52, autosomal recessive(SPG52)

MedGen UID:
481373
Concept ID:
C3279743
Disease or Syndrome
Synonyms: Cerebral palsy, spastic quadriplegic, 6; SPG52
 
Gene (location): AP4S1 (14q12)
 
Monarch Initiative: MONDO:0013552
OMIM®: 614067

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 quadriplegia-52 (SPG52) is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (summary by Abou Jamra et al., 2011). Some patients may have seizures (Hardies et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).  http://www.omim.org/entry/614067

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).
Cerebral palsy
MedGen UID:
854
Concept ID:
C0007789
Disease or Syndrome
Cerebral palsy describes a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication, and behavior, by epilepsy, and by secondary musculoskeletal problems.
Febrile seizure (within the age range of 3 months to 6 years)
MedGen UID:
3232
Concept ID:
C0009952
Disease or Syndrome
A febrile seizure is any type of seizure (most often a generalized tonic-clonic seizure) occurring with fever (at least 38 degrees Celsius) but in the absence of central nervous system infection, severe metabolic disturbance or other alternative precipitant in children between the ages of 3 months and 6 years.
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.
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.
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.
Focal-onset seizure
MedGen UID:
199670
Concept ID:
C0751495
Disease or Syndrome
A focal-onset seizure is a type of seizure originating within networks limited to one hemisphere. They may be discretely localized or more widely distributed, and may originate in subcortical structures.
Loss of ambulation
MedGen UID:
332305
Concept ID:
C1836843
Finding
Inability to walk in a person who previous had the ability to walk.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
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.
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).
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
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.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Prominent nose
MedGen UID:
98423
Concept ID:
C0426415
Finding
Distance between subnasale and pronasale more than two standard deviations above the mean, or alternatively, an apparently increased anterior protrusion of the nasal tip.
Thick vermilion border
MedGen UID:
332232
Concept ID:
C1836543
Finding
Increased width of the skin of vermilion border region of upper lip.
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.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).

Recent clinical studies

Etiology

D'Amore A, Tessa A, Naef V, Bassi MT, Citterio A, Romaniello R, Fichi G, Galatolo D, Mero S, Battini R, Bertocci G, Baldacci J, Sicca F, Gemignani F, Ricca I, Rubegni A, Hirst J, Marchese M, Sahin M, Ebrahimi-Fakhari D, Santorelli FM
Ann Clin Transl Neurol 2020 Apr;7(4):584-589. Epub 2020 Mar 25 doi: 10.1002/acn3.51018. PMID: 32216065Free PMC Article
Lu X, Cen Z, Xie F, Ouyang Z, Zhang B, Zhao G, Luo W
J Neurol Sci 2014 Dec 15;347(1-2):368-71. Epub 2014 Oct 16 doi: 10.1016/j.jns.2014.10.017. PMID: 25454648
Racis L, Tessa A, Di Fabio R, Storti E, Agnetti V, Casali C, Santorelli FM, Pugliatti M
J Neurol 2014 Jan;261(1):52-9. Epub 2013 Oct 20 doi: 10.1007/s00415-013-7151-4. PMID: 24141732
Settasatian C, Whitmore SA, Crawford J, Bilton RL, Cleton-Jansen AM, Sutherland GR, Callen DF
Hum Genet 1999 Jul-Aug;105(1-2):139-44. doi: 10.1007/s004399900087. PMID: 10480368
Pearce DA
Hum Genet 1999 Jun;104(6):443-8. doi: 10.1007/s004390050985. PMID: 10453730

Diagnosis

Yahia A, Hamed AAA, Mohamed IN, Elseed MA, Salih MA, El-Sadig SM, Siddig HE, Nasreldien AEM, Abdullah MA, Elzubair M, Omer FY, Bakhiet AM, Abubaker R, Abozar F, Adil R, Emad S, Musallam MA, Eltazi IZM, Omer Z, Malik H, Mohamed MOE, Elhassan AA, Mohamed EOE, Ahmed AKMA, Ahmed EAA, Eltaraifee E, Hussein BK, Abd Allah ASI, Salah L, Nimir M, Tag Elseed OM, Elhassan TEA, Elbashier A, Alfadul ESA, Fadul M, Ali KF, Taha SOMA, Bushara EE, Amin M, Koko M, Ibrahim ME, Ahmed AE, Elsayed LEO, Stevanin G
Eur J Hum Genet 2024 Oct;32(10):1214-1226. Epub 2023 Apr 3 doi: 10.1038/s41431-023-01344-6. PMID: 37012327Free PMC Article
Haj Salem I, Beaudin M, Stumpf M, Estiar MA, Côté PO, Brunet F, Gamache PL, Rouleau GA, Mourabit-Amari K, Gan-Or Z, Dupré N
Can J Neurol Sci 2021 Sep;48(5):655-665. Epub 2021 Jan 5 doi: 10.1017/cjn.2020.277. PMID: 33397523
Racis L, Tessa A, Di Fabio R, Storti E, Agnetti V, Casali C, Santorelli FM, Pugliatti M
J Neurol 2014 Jan;261(1):52-9. Epub 2013 Oct 20 doi: 10.1007/s00415-013-7151-4. PMID: 24141732
Klebe S, Depienne C, Gerber S, Challe G, Anheim M, Charles P, Fedirko E, Lejeune E, Cottineau J, Brusco A, Dollfus H, Chinnery PF, Mancini C, Ferrer X, Sole G, Destée A, Mayer JM, Fontaine B, de Seze J, Clanet M, Ollagnon E, Busson P, Cazeneuve C, Stevanin G, Kaplan J, Rozet JM, Brice A, Durr A
Brain 2012 Oct;135(Pt 10):2980-93. doi: 10.1093/brain/aws240. PMID: 23065789Free PMC Article
Thiffault I, Rioux MF, Tetreault M, Jarry J, Loiselle L, Poirier J, Gros-Louis F, Mathieu J, Vanasse M, Rouleau GA, Bouchard JP, Lesage J, Brais B
Brain 2006 Sep;129(Pt 9):2332-40. Epub 2006 May 3 doi: 10.1093/brain/awl110. PMID: 16672289

Prognosis

Pearce DA
Hum Genet 1999 Jun;104(6):443-8. doi: 10.1007/s004390050985. PMID: 10453730

Clinical prediction guides

Goizet C, Boukhris A, Durr A, Beetz C, Truchetto J, Tesson C, Tsaousidou M, Forlani S, Guyant-Maréchal L, Fontaine B, Guimarães J, Isidor B, Chazouillères O, Wendum D, Grid D, Chevy F, Chinnery PF, Coutinho P, Azulay JP, Feki I, Mochel F, Wolf C, Mhiri C, Crosby A, Brice A, Stevanin G
Brain 2009 Jun;132(Pt 6):1589-600. Epub 2009 May 12 doi: 10.1093/brain/awp073. PMID: 19439420
Thiffault I, Rioux MF, Tetreault M, Jarry J, Loiselle L, Poirier J, Gros-Louis F, Mathieu J, Vanasse M, Rouleau GA, Bouchard JP, Lesage J, Brais B
Brain 2006 Sep;129(Pt 9):2332-40. Epub 2006 May 3 doi: 10.1093/brain/awl110. PMID: 16672289
Settasatian C, Whitmore SA, Crawford J, Bilton RL, Cleton-Jansen AM, Sutherland GR, Callen DF
Hum Genet 1999 Jul-Aug;105(1-2):139-44. doi: 10.1007/s004399900087. PMID: 10480368
Pearce DA
Hum Genet 1999 Jun;104(6):443-8. doi: 10.1007/s004390050985. PMID: 10453730
Sridharan R, Radhakrishnan K, Ashok PP, Mousa ME
Brain 1985 Dec;108 ( Pt 4):831-43. doi: 10.1093/brain/108.4.831. PMID: 4075075

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