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Hereditary spastic paraplegia 4(SPG4; FSP2)

MedGen UID:
401097
Concept ID:
C1866855
Disease or Syndrome
Synonyms: Familial spastic paraplegia autosomal dominant 2; Spastic Paraplegia 4; Spastic paraplegia 4, autosomal dominant
SNOMED CT: Autosomal dominant spastic paraplegia type 4 (723820001)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): SPAST (2p22.3)
 
Monarch Initiative: MONDO:0008438
OMIM®: 182601
Orphanet: ORPHA100985

Disease characteristics

Excerpted from the GeneReview: Spastic Paraplegia 4
Spastic paraplegia 4 (SPG4; also known as SPAST-HSP) is characterized by insidiously progressive bilateral lower-limb gait spasticity. More than 50% of affected individuals have some weakness in the legs and impaired vibration sense at the ankles. Sphincter disturbances are very common. Onset is insidious, mostly in young adulthood, although symptoms may start as early as age one year and as late as age 76 years. Intrafamilial variation is considerable. [from GeneReviews]
Authors:
Livia Parodi  |  Siri Lynne Rydning  |  Chantal Tallaksen, et. al.   view full author information

Additional descriptions

From OMIM
The hereditary spastic paraplegias (SPG, HSP) are a group of clinically and genetically diverse inherited disorders characterized predominantly by progressive lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and whether the primary symptoms occur in isolation ('uncomplicated') or with other neurologic abnormalities ('complicated'). Pure SPG4 is the most common form of autosomal dominant hereditary SPG, comprising up to 45% of cases (Svenson et al., 2001; Crippa et al., 2006). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).  http://www.omim.org/entry/182601
From MedlinePlus Genetics
Like all hereditary spastic paraplegias, spastic paraplegia type 4 involves spasticity of the leg muscles and muscle weakness. People with this condition can also experience exaggerated reflexes (hyperreflexia), ankle spasms, high-arched feet (pes cavus), and reduced bladder control. Spastic paraplegia type 4 generally affects nerve and muscle function in the lower half of the body only.

Spastic paraplegia type 4 (also known as SPG4) is the most common of a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by progressive muscle stiffness (spasticity) in the legs and difficulty walking. Hereditary spastic paraplegias are divided into two types: pure and complex. The pure types generally involve only spasticity of the lower limbs and walking difficulties. The complex types involve more widespread problems with the nervous system; 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). In complex forms, there can also be features outside of the nervous system. Spastic paraplegia type 4 is usually a pure hereditary spastic paraplegia, although a few complex cases have been reported.  https://medlineplus.gov/genetics/condition/spastic-paraplegia-type-4

Clinical features

From HPO
Low back pain
MedGen UID:
7389
Concept ID:
C0024031
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the lower back.
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Loss of the ability to control the urinary bladder leading to involuntary urination.
Urinary urgency
MedGen UID:
39315
Concept ID:
C0085606
Finding
Urge incontinence is the strong, sudden need to urinate.
Urinary bladder sphincter dysfunction
MedGen UID:
334804
Concept ID:
C1843663
Finding
Abnormal function of a sphincter of the urinary bladder.
Lower limb muscle weakness
MedGen UID:
324478
Concept ID:
C1836296
Finding
Weakness of the muscles of the legs.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
Impulse control disorder
MedGen UID:
5769
Concept ID:
C0021122
Mental or Behavioral Dysfunction
Reduced ability to control, or a failure to resist a temptation, urge, or impulse. Examples include disregard for social conventions, general impulsivity, and poor risk assessment.
Paraplegia
MedGen UID:
45323
Concept ID:
C0030486
Disease or Syndrome
Severe or complete weakness of both lower extremities with sparing of the upper extremities.
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.
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Agitation
MedGen UID:
88447
Concept ID:
C0085631
Sign or Symptom
A state of extreme restlessness and excessive motor activity is associated with mental distress or a feeling of inner tension.
Apathy
MedGen UID:
39083
Concept ID:
C0085632
Mental or Behavioral Dysfunction
Apathy is a quantitative reduction of motivation and the initiation and persistence of goal-directed behavior, where the accompanying emotions, thoughts, and social interactions are also suppressed.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Spastic gait
MedGen UID:
115907
Concept ID:
C0231687
Finding
Spasticity is manifested by increased stretch reflex which is intensified with movement velocity. This results in excessive and inappropriate muscle activation which can contribute to muscle hypertonia. Spastic gait is characterized by manifestations such as muscle hypertonia, stiff knee, and circumduction of the leg.
Memory impairment
MedGen UID:
68579
Concept ID:
C0233794
Mental or Behavioral Dysfunction
An impairment of memory as manifested by a reduced ability to remember things such as dates and names, and increased forgetfulness.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Lower limb spasticity
MedGen UID:
220865
Concept ID:
C1271100
Finding
Spasticity (velocity-dependent increase in tonic stretch reflexes with increased muscle tone and hyperexcitable tendon reflexes) in the muscles of the lower limbs, hips, and pelvis
Degeneration of the lateral corticospinal tracts
MedGen UID:
375921
Concept ID:
C1846566
Finding
Deterioration of the tissues of the lateral corticospinal tracts.
Impaired vibration sensation in the lower limbs
MedGen UID:
338617
Concept ID:
C1849134
Finding
A decrease in the ability to perceive vibration in the legs.
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.
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHereditary spastic paraplegia 4
Follow this link to review classifications for Hereditary spastic paraplegia 4 in Orphanet.

Professional guidelines

PubMed

van de Pol LA, Burgert N, van Schie PEM, Slot KM, Gouw AA, Buizer AI
Childs Nerv Syst 2024 Mar;40(3):855-861. Epub 2023 Oct 3 doi: 10.1007/s00381-023-06159-w. PMID: 37783799Free PMC Article
Byrne DJ, Garcia-Pardo ME, Cole NB, Batnasan B, Heneghan S, Sohail A, Blackstone C, O'Sullivan NC
Acta Neuropathol Commun 2022 Mar 28;10(1):40. doi: 10.1186/s40478-022-01343-6. PMID: 35346366Free PMC Article
Méreaux JL, Firanescu C, Coarelli G, Kvarnung M, Rodrigues R, Pegoraro E, Tazir M, Taithe F, Valter R, Huin V, Lidström K, Banneau G, Morais S, Parodi L, Coutelier M, Papin M, Svenningsson P, Azulay JP, Alonso I, Nilsson D, Brice A, Le Guern E, Press R, Vazza G, Loureiro JL, Goizet C, Durr A, Paucar M, Stevanin G
Neurogenetics 2021 Mar;22(1):71-79. Epub 2021 Jan 23 doi: 10.1007/s10048-020-00633-2. PMID: 33486633Free PMC Article

Recent clinical studies

Etiology

Xing W, Wang XY, Liao XX, Liao WH, Shen L
Magn Reson Imaging 2014 Dec;32(10):1330-4. Epub 2014 Aug 28 doi: 10.1016/j.mri.2014.08.022. PMID: 25172988
Sauter S, Miterski B, Klimpe S, Bönsch D, Schöls L, Visbeck A, Papke T, Hopf HC, Engel W, Deufel T, Epplen JT, Neesen J
Hum Mutat 2002 Aug;20(2):127-32. doi: 10.1002/humu.10105. PMID: 12124993

Diagnosis

Chen X, Li X, Tan Y, Yang D, Lu L, Deng Y, Xu R
Neurosci Lett 2023 Aug 24;812:137399. Epub 2023 Jul 19 doi: 10.1016/j.neulet.2023.137399. PMID: 37473796
Xing W, Wang XY, Liao XX, Liao WH, Shen L
Magn Reson Imaging 2014 Dec;32(10):1330-4. Epub 2014 Aug 28 doi: 10.1016/j.mri.2014.08.022. PMID: 25172988
Chinnery PF, Howell N, Andrews RM, Turnbull DM
J Med Genet 1999 Jun;36(6):425-36. PMID: 10874629Free PMC Article

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