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Autosomal recessive early-onset Parkinson disease 6(PARK6)

MedGen UID:
342982
Concept ID:
C1853833
Disease or Syndrome
Synonyms: PARK6; PARKINSON DISEASE 6, EARLY-ONSET; PARKINSON DISEASE 6, MODIFIER OF; PINK1 Type of Young-Onset Parkinson Disease; PINK1-Related Parkinson Disease
 
Gene (location): PINK1 (1p36.12)
 
Monarch Initiative: MONDO:0011613
OMIM®: 605909

Definition

PINK1 type of young-onset Parkinson disease is characterized by early onset (mean age 33 years) of tremor, bradykinesia, and rigidity that are often indistinguishable from other causes of Parkinson disease. Lower-limb dystonia may be a presenting sign. Postural instability, hyperreflexia, abnormal behavior, and psychiatric manifestations have been described. The disease is usually slowly progressive. Individuals have a marked and sustained response to oral administration of levodopa (L-dopa), frequently associated with L-dopa-induced fluctuations and dyskinesias. [from GeneReviews]

Additional description

From MedlinePlus Genetics
Parkinson's disease can also affect emotions and thinking ability (cognition). Some affected individuals develop psychiatric conditions such as depression and visual hallucinations. People with Parkinson's disease also have an increased risk of developing dementia, which is a decline in intellectual functions including judgment and memory.

Often the first symptom of Parkinson's disease is trembling or shaking (tremor) of a limb, especially when the body is at rest. Typically, the tremor begins on one side of the body, usually in one hand. Tremors can also affect the arms, legs, feet, and face. Other characteristic symptoms of Parkinson's disease include rigidity or stiffness of the limbs and torso, slow movement (bradykinesia) or an inability to move (akinesia), and impaired balance and coordination (postural instability). These symptoms worsen slowly over time.

Generally, Parkinson's disease that begins after age 50 is called late-onset disease. The condition is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 are sometimes referred to as juvenile-onset Parkinson's disease.

Parkinson's disease is a progressive disorder of the nervous system. The disorder affects several regions of the brain, especially an area called the substantia nigra that controls balance and movement.  https://medlineplus.gov/genetics/condition/parkinsons-disease

Clinical features

From HPO
Urinary urgency
MedGen UID:
39315
Concept ID:
C0085606
Finding
Urge incontinence is the strong, sudden need to urinate.
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.
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.
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.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
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).
Resting tremor
MedGen UID:
66697
Concept ID:
C0234379
Sign or Symptom
A resting tremor occurs when muscles are at rest and becomes less noticeable or disappears when the affected muscles are moved. Resting tremors are often slow and coarse.
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.
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.
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.
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.

Recent clinical studies

Etiology

Bakhit Y, Tesson C, Ibrahim MO, Eltom K, Eltazi I, Elsayed LEO, Lesage S, Seidi O, Corvol JC, Wüllner U; Sudanese Parkinson's Disease Study Group
Ann Clin Transl Neurol 2023 Jun;10(6):983-989. Epub 2023 May 3 doi: 10.1002/acn3.51781. PMID: 37139542Free PMC Article
Chen YP, Yu SH, Zhang GH, Hou YB, Gu XJ, Ou RW, Shen Y, Song W, Chen XP, Zhao B, Cao B, Zhang LY, Sun MM, Liu FF, Wei QQ, Liu KC, Lin JY, Yang TM, Yang J, Wu Y, Jiang Z, Liu J, Cheng YF, Xiao Y, Su WM, Feng F, Cai YY, Li SR, Hu T, Yuan XQ, Zhou QQ, Shao N, Ma S, Shang HF
Eur J Neurol 2022 Nov;29(11):3218-3228. Epub 2022 Aug 4 doi: 10.1111/ene.15509. PMID: 35861376
Hattori N, Shimura H, Kubo S, Wang M, Shimizu N, Tanaka K, Mizuno Y
J Neural Transm Suppl 2000;(60):101-16. doi: 10.1007/978-3-7091-6301-6_6. PMID: 11205133
Hattori N, Shimura H, Kubo S, Kitada T, Wang M, Asakawa S, Minashima S, Shimizu N, Suzuki T, Tanaka K, Mizuno Y
Neuropathology 2000 Sep;20 Suppl:S85-90. doi: 10.1046/j.1440-1789.2000.00312.x. PMID: 11037196
Lücking CB, Dürr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denèfle P, Wood NW, Agid Y, Brice A; French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson's Disease
N Engl J Med 2000 May 25;342(21):1560-7. doi: 10.1056/NEJM200005253422103. PMID: 10824074

Diagnosis

Bakhit Y, Tesson C, Ibrahim MO, Eltom K, Eltazi I, Elsayed LEO, Lesage S, Seidi O, Corvol JC, Wüllner U; Sudanese Parkinson's Disease Study Group
Ann Clin Transl Neurol 2023 Jun;10(6):983-989. Epub 2023 May 3 doi: 10.1002/acn3.51781. PMID: 37139542Free PMC Article
Sarasola LI, Del Torrent CL, Pérez-Arévalo A, Argerich J, Casajuana-Martín N, Chevigné A, Fernández-Dueñas V, Ferré S, Pardo L, Ciruela F
Biomed Pharmacother 2022 Dec;156:113896. Epub 2022 Oct 21 doi: 10.1016/j.biopha.2022.113896. PMID: 36279718
Fang YQ, Mao F, Zhu MJ, Li XH
Medicine (Baltimore) 2019 Feb;98(5):e14228. doi: 10.1097/MD.0000000000014228. PMID: 30702579Free PMC Article
Schormair B, Kemlink D, Mollenhauer B, Fiala O, Machetanz G, Roth J, Berutti R, Strom TM, Haslinger B, Trenkwalder C, Zahorakova D, Martasek P, Ruzicka E, Winkelmann J
Clin Genet 2018 Mar;93(3):603-612. Epub 2018 Jan 24 doi: 10.1111/cge.13124. PMID: 28862745
Lücking CB, Dürr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denèfle P, Wood NW, Agid Y, Brice A; French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson's Disease
N Engl J Med 2000 May 25;342(21):1560-7. doi: 10.1056/NEJM200005253422103. PMID: 10824074

Therapy

Biosa A, Sanchez-Martinez A, Filograna R, Terriente-Felix A, Alam SM, Beltramini M, Bubacco L, Bisaglia M, Whitworth AJ
Hum Mol Genet 2018 May 1;27(9):1618-1629. doi: 10.1093/hmg/ddy069. PMID: 29529199Free PMC Article
Halder T, Raj J, Sharma V, Das P
Neurosci Lett 2015 Sep 25;605:29-33. Epub 2015 Aug 14 doi: 10.1016/j.neulet.2015.08.021. PMID: 26282903
Khan NL, Graham E, Critchley P, Schrag AE, Wood NW, Lees AJ, Bhatia KP, Quinn N
Brain 2003 Jun;126(Pt 6):1279-92. doi: 10.1093/brain/awg142. PMID: 12764051
Valente EM, Brancati F, Ferraris A, Graham EA, Davis MB, Breteler MM, Gasser T, Bonifati V, Bentivoglio AR, De Michele G, Dürr A, Cortelli P, Wassilowsky D, Harhangi BS, Rawal N, Caputo V, Filla A, Meco G, Oostra BA, Brice A, Albanese A, Dallapiccola B, Wood NW; European Consortium on Genetic Susceptibility in Parkinson's Disease
Ann Neurol 2002 Jan;51(1):14-8. PMID: 11782979
Matsumine H, Yamamura Y, Kobayashi T, Nakamura S, Kuzuhara S, Mizuno Y
Neurology 1998 May;50(5):1340-5. doi: 10.1212/wnl.50.5.1340. PMID: 9595984

Prognosis

Cordts I, Semmler L, Prasuhn J, Seibt A, Herebian D, Navaratnarajah T, Park J, Deininger N, Laugwitz L, Göricke SL, Lingor P, Brüggemann N, Münchau A, Synofzik M, Timmann D, Mayr JA, Haack TB, Distelmaier F, Deschauer M
Mov Disord 2022 Oct;37(10):2147-2153. Epub 2022 Sep 1 doi: 10.1002/mds.29167. PMID: 36047608
Wei J, Takamatsu Y, Wada R, Fujita M, Ho G, Masliah E, Hashimoto M
Biomolecules 2021 Feb 15;11(2) doi: 10.3390/biom11020289. PMID: 33672048Free PMC Article
Smaili I, Tesson C, Regragui W, Bertrand H, Rahmani M, Bouslam N, Benomar A, Brice A, Lesage S, Bouhouche A
J Mol Neurosci 2021 Jan;71(1):142-152. Epub 2020 Jun 16 doi: 10.1007/s12031-020-01635-3. PMID: 32557143
Simón-Sánchez J, Kilarski LL, Nalls MA, Martinez M, Schulte C, Holmans P; International Parkinson's Disease Genomics Consortium; Wellcome Trust Case Control Consortium, Gasser T, Hardy J, Singleton AB, Wood NW, Brice A, Heutink P, Williams N, Morris HR
PLoS One 2012;7(3):e28787. Epub 2012 Mar 12 doi: 10.1371/journal.pone.0028787. PMID: 22427796Free PMC Article
Saito M, Maruyama M, Ikeuchi K, Kondo H, Ishikawa A, Yuasa T, Tsuji S
Brain Dev 2000 Sep;22 Suppl 1:S115-7. doi: 10.1016/s0387-7604(00)00137-6. PMID: 10984671

Clinical prediction guides

Wei J, Takamatsu Y, Wada R, Fujita M, Ho G, Masliah E, Hashimoto M
Biomolecules 2021 Feb 15;11(2) doi: 10.3390/biom11020289. PMID: 33672048Free PMC Article
Tan AH, Lohmann K, Tay YW, Lim JL, Ahmad-Annuar A, Ramli N, Chin YT, Mawardi AS, Azmi K, Aziz ZA, Puvanarajah SD, Bauer P, Klein C, Rolfs A, Lim SY
Parkinsonism Relat Disord 2020 Oct;79:34-39. Epub 2020 Aug 19 doi: 10.1016/j.parkreldis.2020.08.015. PMID: 32861104
Oliveira SA, Scott WK, Martin ER, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Ondo WG, Allen FH Jr, Scott BL, Goetz CG, Small GW, Mastaglia F, Stajich JM, Zhang F, Booze MW, Winn MP, Middleton LT, Haines JL, Pericak-Vance MA, Vance JM
Ann Neurol 2003 May;53(5):624-9. doi: 10.1002/ana.10524. PMID: 12730996
van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, Houwing-Duistermaat JJ, Snijders PJ, Testers L, Breedveld GJ, Horstink M, Sandkuijl LA, van Swieten JC, Oostra BA, Heutink P
Am J Hum Genet 2001 Sep;69(3):629-34. Epub 2001 Jul 2 doi: 10.1086/322996. PMID: 11462174Free PMC Article
Hattori N, Shimura H, Kubo S, Kitada T, Wang M, Asakawa S, Minashima S, Shimizu N, Suzuki T, Tanaka K, Mizuno Y
Neuropathology 2000 Sep;20 Suppl:S85-90. doi: 10.1046/j.1440-1789.2000.00312.x. PMID: 11037196

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