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Kufor-Rakeb syndrome(KRS)

MedGen UID:
338281
Concept ID:
C1847640
Disease or Syndrome
Synonyms: KRS; Pallidopyramidal degeneration with supranuclear upgaze paresis, and dementia; Park 9; PARKINSON DISEASE 9, AUTOSOMAL RECESSIVE, JUVENILE-ONSET
SNOMED CT: Kufor Rakeb syndrome (723992000); PARK9 - Parkinson disease 9 (723992000); Parkinson disease 9 (723992000)
 
Gene (location): ATP13A2 (1p36.13)
 
Monarch Initiative: MONDO:0011706
OMIM®: 606693
Orphanet: ORPHA306674

Definition

Kufor-Rakeb syndrome is a rare autosomal recessive form of juvenile-onset atypical Parkinson disease (PARK9) associated with supranuclear gaze palsy, spasticity, and dementia. Some patients have neuroradiologic evidence of iron deposition in the basal ganglia, indicating that the pathogenesis of PARK9 can be considered among the syndromes of neurodegeneration with brain iron accumulation (NBIA; see 234200) (summary by Bruggemann et al., 2010). For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease (PD), see 168600. Biallelic mutation in the ATP13A2 gene also causes autosomal recessive spastic paraplegia-78 (SPG78; 617225), an adult-onset neurodegenerative disorder with overlapping features. Patients with SPG78 have later onset and prominent spasticity, but rarely parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (summary by Estrada-Cuzcano et al., 2017). [from OMIM]

Clinical features

From HPO
Fatigue
MedGen UID:
41971
Concept ID:
C0015672
Sign or Symptom
A subjective feeling of tiredness characterized by a lack of energy and motivation.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
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).
Anosmia
MedGen UID:
1950
Concept ID:
C0003126
Finding
An inability to perceive odors. This is a general term describing inability to smell arising in any part of the process of smelling from absorption of odorants into the nasal mucous overlying the olfactory epithelium, diffusion to the cilia, binding to olfactory receptor sites, generation of action potentials in olfactory neurons, and perception of a smell.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
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.
Hallucinations
MedGen UID:
6709
Concept ID:
C0018524
Mental or Behavioral Dysfunction
Perceptions in a conscious and awake state that, in the absence of external stimuli, have qualities of real perception. These perceptions are vivid, substantial, and located in external objective space.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
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.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
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.
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Torticollis
MedGen UID:
11859
Concept ID:
C0040485
Sign or Symptom
Torticollis is a twisted neck as a result of shortening of sternocleidomastoid muscle. This short and fibrotic muscle pulls the head laterally and rotates the chin and face to the opposite end. Facial asymmetry may be a manifestation (summary by Engin et al., 1997).
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Akinesia
MedGen UID:
43218
Concept ID:
C0085623
Finding
Inability to initiate changes in activity or movement and to perform ordinary volitional movements rapidly and easily.
Hypokinesia
MedGen UID:
39223
Concept ID:
C0086439
Finding
Abnormally diminished motor activity. In contrast to paralysis, hypokinesia is not characterized by a lack of motor strength, but rather by a poverty of movement. The typical habitual movements (e.g., folding the arms, crossing the legs) are reduced in frequency.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Paraparesis
MedGen UID:
113150
Concept ID:
C0221166
Sign or Symptom
Weakness or partial paralysis in the lower limbs.
Bradykinesia
MedGen UID:
115925
Concept ID:
C0233565
Sign or Symptom
Bradykinesia literally means slow movement, and is used clinically to denote a slowness in the execution of movement (in contrast to hypokinesia, which is used to refer to slowness in the initiation of movement).
Anarthria
MedGen UID:
68604
Concept ID:
C0234517
Disease or Syndrome
A defect in the motor ability that enables speech.
Parkinsonian disorder
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Psychotic episodes
MedGen UID:
90930
Concept ID:
C0338614
Mental or Behavioral Dysfunction
Periods of time during which an individual experiences significant disturbances in their thoughts, perceptions, emotions, and behavior, resulting in a loss of touch with reality. These episodes are hallmark features of psychotic disorders such as schizophrenia, schizoaffective disorder, and certain forms of bipolar disorder.
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.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
Palmomental reflex
MedGen UID:
155866
Concept ID:
C0751470
Finding
A type of primitive reflex characterized by an involuntary contraction of the mentalis muscle of the chin caused by stimulation of the thenar eminence of the palm.
Postural instability
MedGen UID:
334529
Concept ID:
C1843921
Finding
A tendency to fall or the inability to keep oneself from falling; imbalance. The retropulsion test is widely regarded as the gold standard to evaluate postural instability, Use of the retropulsion test includes a rapid balance perturbation in the backward direction, and the number of balance correcting steps (or total absence thereof) is used to rate the degree of postural instability. Healthy subjects correct such perturbations with either one or two large steps, or without taking any steps, hinging rapidly at the hips while swinging the arms forward as a counterweight. In patients with balance impairment, balance correcting steps are often too small, forcing patients to take more than two steps. Taking three or more steps is generally considered to be abnormal, and taking more than five steps is regarded as being clearly abnormal. Markedly affected patients continue to step backward without ever regaining their balance and must be caught by the examiner (this would be called true retropulsion). Even more severely affected patients fail to correct entirely, and fall backward like a pushed toy soldier, without taking any corrective steps.
Parkinsonism with favorable response to dopaminergic medication
MedGen UID:
375989
Concept ID:
C1846868
Disease or Syndrome
Parkinsonism is a clinical syndrome that is a feature of a number of different diseases, including Parkinson disease itself, other neurodegenerative diseases such as progressive supranuclear palsy, and as a side-effect of some neuroleptic medications. Some but not all individuals with Parkinsonism show responsiveness to dopaminergic medication defined as a substantial reduction of amelioration of the component signs of Parkinsonism (including mainly tremor, bradykinesia, rigidity, and postural instability) upon administration of dopaminergic medication.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Hyposmia
MedGen UID:
473584
Concept ID:
C2364082
Finding
A decreased sensitivity to odorants (that is, a decreased ability to perceive odors).
Brisk reflexes
MedGen UID:
382164
Concept ID:
C2673700
Finding
Tendon reflexes that are noticeably more active than usual (conventionally denoted 3+ on clinical examination). Brisk reflexes may or may not indicate a neurological lesion. They are distinguished from hyperreflexia by the fact that hyerreflexia is characterized by hyperactive repeating (clonic) reflexes, which are considered to be always abnormal.
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.
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Leg muscle stiffness
MedGen UID:
870176
Concept ID:
C4024610
Sign or Symptom
Mask-like facies
MedGen UID:
140860
Concept ID:
C0424448
Finding
A lack of facial expression often with staring eyes and a slightly open mouth.
Slow saccadic eye movements
MedGen UID:
232942
Concept ID:
C1321329
Finding
An abnormally slow velocity of the saccadic eye movements.
Supranuclear gaze palsy
MedGen UID:
314030
Concept ID:
C1720037
Disease or Syndrome
A supranuclear gaze palsy is an inability to look in a particular direction as a result of cerebral impairment. There is a loss of the voluntary aspect of eye movements, but, as the brainstem is still intact, all the reflex conjugate eye movements are normal.

Recent clinical studies

Etiology

Jellinger KA
J Neural Transm (Vienna) 2022 Jun;129(5-6):521-543. Epub 2021 Aug 7 doi: 10.1007/s00702-021-02392-2. PMID: 34363531
van Veen S, Martin S, Van den Haute C, Benoy V, Lyons J, Vanhoutte R, Kahler JP, Decuypere JP, Gelders G, Lambie E, Zielich J, Swinnen JV, Annaert W, Agostinis P, Ghesquière B, Verhelst S, Baekelandt V, Eggermont J, Vangheluwe P
Nature 2020 Feb;578(7795):419-424. Epub 2020 Jan 29 doi: 10.1038/s41586-020-1968-7. PMID: 31996848
Salomão RP, Pedroso JL, Gama MT, Dutra LA, Maciel RH, Godeiro-Junior C, Chien HF, Teive HA, Cardoso F, Barsottini OG
Arq Neuropsiquiatr 2016 Jul;74(7):587-96. doi: 10.1590/0004-282X20160080. PMID: 27487380
McNeill A
Curr Drug Targets 2012 Aug;13(9):1204-6. doi: 10.2174/138945012802002401. PMID: 22515743
Radi E, Formichi P, Di Maio G, Battisti C, Federico A
J Cell Mol Med 2012 Aug;16(8):1916-23. doi: 10.1111/j.1582-4934.2011.01488.x. PMID: 22117566Free PMC Article

Diagnosis

Jellinger KA
J Neural Transm (Vienna) 2022 Jun;129(5-6):521-543. Epub 2021 Aug 7 doi: 10.1007/s00702-021-02392-2. PMID: 34363531
Salomão RP, Pedroso JL, Gama MT, Dutra LA, Maciel RH, Godeiro-Junior C, Chien HF, Teive HA, Cardoso F, Barsottini OG
Arq Neuropsiquiatr 2016 Jul;74(7):587-96. doi: 10.1590/0004-282X20160080. PMID: 27487380
Sharma S, Moon CS, Khogali A, Haidous A, Chabenne A, Ojo C, Jelebinkov M, Kurdi Y, Ebadi M
Neurochem Int 2013 Sep;63(3):201-29. Epub 2013 Jun 19 doi: 10.1016/j.neuint.2013.06.005. PMID: 23791710
Vilariño-Güell C, Soto AI, Lincoln SJ, Ben Yahmed S, Kefi M, Heckman MG, Hulihan MM, Chai H, Diehl NN, Amouri R, Rajput A, Mash DC, Dickson DW, Middleton LT, Gibson RA, Hentati F, Farrer MJ
Hum Mutat 2009 Mar;30(3):406-10. doi: 10.1002/humu.20877. PMID: 19085912Free PMC Article
Klein C, Lohmann-Hedrich K
Curr Opin Neurol 2007 Aug;20(4):453-64. doi: 10.1097/WCO.0b013e3281e6692b. PMID: 17620882

Therapy

Colijn MA, Vrijsen S, Au PYB, Abou El Asrar R, Houdou M, Van den Haute C, Sarna J, Montgomery G, Vangheluwe P
Neurogenetics 2024 Oct;25(4):405-415. Epub 2024 Jul 18 doi: 10.1007/s10048-024-00767-7. PMID: 39023817Free PMC Article
McNeil-Gauthier AL, Brais B, Rouleau G, Anoja N, Ducharme S
Neurocase 2019 Jun-Aug;25(3-4):133-137. Epub 2019 Jun 24 doi: 10.1080/13554794.2019.1625928. PMID: 31232173
Paisán-Ruiz C, Guevara R, Federoff M, Hanagasi H, Sina F, Elahi E, Schneider SA, Schwingenschuh P, Bajaj N, Emre M, Singleton AB, Hardy J, Bhatia KP, Brandner S, Lees AJ, Houlden H
Mov Disord 2010 Sep 15;25(12):1791-800. doi: 10.1002/mds.23221. PMID: 20669327Free PMC Article
Najim al-Din AS, Wriekat A, Mubaidin A, Dasouki M, Hiari M
Acta Neurol Scand 1994 May;89(5):347-52. doi: 10.1111/j.1600-0404.1994.tb02645.x. PMID: 8085432

Prognosis

Gao K, Song Z, Liang H, Zheng W, Deng X, Yuan Y, Zhao Y, Deng H
Mol Biol Rep 2014;41(4):2307-11. Epub 2014 Jan 14 doi: 10.1007/s11033-014-3084-y. PMID: 24420862
Sharma S, Moon CS, Khogali A, Haidous A, Chabenne A, Ojo C, Jelebinkov M, Kurdi Y, Ebadi M
Neurochem Int 2013 Sep;63(3):201-29. Epub 2013 Jun 19 doi: 10.1016/j.neuint.2013.06.005. PMID: 23791710
Tan J, Zhang T, Jiang L, Chi J, Hu D, Pan Q, Wang D, Zhang Z
J Biol Chem 2011 Aug 26;286(34):29654-62. Epub 2011 Jul 1 doi: 10.1074/jbc.M111.233874. PMID: 21724849Free PMC Article
Farias FH, Zeng R, Johnson GS, Wininger FA, Taylor JF, Schnabel RD, McKay SD, Sanders DN, Lohi H, Seppälä EH, Wade CM, Lindblad-Toh K, O'Brien DP, Katz ML
Neurobiol Dis 2011 Jun;42(3):468-74. Epub 2011 Feb 26 doi: 10.1016/j.nbd.2011.02.009. PMID: 21362476
Paisán-Ruiz C, Guevara R, Federoff M, Hanagasi H, Sina F, Elahi E, Schneider SA, Schwingenschuh P, Bajaj N, Emre M, Singleton AB, Hardy J, Bhatia KP, Brandner S, Lees AJ, Houlden H
Mov Disord 2010 Sep 15;25(12):1791-800. doi: 10.1002/mds.23221. PMID: 20669327Free PMC Article

Clinical prediction guides

Marcos AL, Corradi GR, Mazzitelli LR, Casali CI, Fernández Tome MDC, Adamo HP, de Tezanos Pinto F
Biochim Biophys Acta Biomembr 2019 Oct 1;1861(10):182993. Epub 2019 May 24 doi: 10.1016/j.bbamem.2019.05.015. PMID: 31132336
Park JS, Koentjoro B, Davis RL, Sue CM
Parkinsonism Relat Disord 2016 Jun;27:67-73. Epub 2016 Mar 22 doi: 10.1016/j.parkreldis.2016.03.018. PMID: 27039055
Eiberg H, Hansen L, Korbo L, Nielsen IM, Svenstrup K, Bech S, Pinborg LH, Friberg L, Hjermind LE, Olsen OR, Nielsen JE
Clin Genet 2012 Sep;82(3):256-63. Epub 2011 Jul 18 doi: 10.1111/j.1399-0004.2011.01745.x. PMID: 21696388
Tan J, Zhang T, Jiang L, Chi J, Hu D, Pan Q, Wang D, Zhang Z
J Biol Chem 2011 Aug 26;286(34):29654-62. Epub 2011 Jul 1 doi: 10.1074/jbc.M111.233874. PMID: 21724849Free PMC Article
Hampshire DJ, Roberts E, Crow Y, Bond J, Mubaidin A, Wriekat AL, Al-Din A, Woods CG
J Med Genet 2001 Oct;38(10):680-2. doi: 10.1136/jmg.38.10.680. PMID: 11584046Free PMC Article

Recent systematic reviews

Ysselstein D, Shulman JM, Krainc D
Mov Disord 2019 May;34(5):614-624. Epub 2019 Feb 6 doi: 10.1002/mds.27631. PMID: 30726573Free PMC Article

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