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Autosomal recessive Parkinson disease 14(PARK14)

MedGen UID:
414488
Concept ID:
C2751842
Disease or Syndrome
Synonyms: DYSTONIA-PARKINSONISM, ADULT-ONSET; Parkinson disease 14
SNOMED CT: Adult-onset dystonia parkinsonism (720466001); Dystonia parkinsonism Paisan-Ruiz type (720466001); PLA2G6 (phospholipase A2 group VI) related dystonia parkinsonism (720466001)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): PLA2G6 (22q13.1)
 
Monarch Initiative: MONDO:0013060
OMIM®: 612953
Orphanet: ORPHA199351

Definition

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.

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.

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.

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. [from MedlinePlus Genetics]

Clinical features

From HPO
Nocturia
MedGen UID:
14440
Concept ID:
C0028734
Disease or Syndrome
Abnormally increased production of urine during the night leading to an unusually frequent need to urinate.
Ankle clonus
MedGen UID:
68672
Concept ID:
C0238651
Finding
Clonus is an involuntary tendon reflex that causes repeated flexion and extension of the foot. Ankle clonus is tested by rapidly flexing the foot upward.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Aggressive behavior can denote verbal aggression, physical aggression against objects, physical aggression against people, and may also include aggression towards oneself.
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequent feelings of being down, miserable, and/or hopeless; difficulty recovering from such moods; pessimism about the future; pervasive shame; feeling of inferior self-worth; thoughts of suicide and suicidal behavior.
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.
Dyskinesia
MedGen UID:
8514
Concept ID:
C0013384
Disease or Syndrome
A movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements.
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.
Hemiparesis
MedGen UID:
6783
Concept ID:
C0018989
Finding
Loss of strength in the arm, leg, and sometimes face on one side of the body. Hemiplegia refers to a complete loss of strength, whereas hemiparesis refers to an incomplete loss of strength.
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.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
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).
Clumsiness
MedGen UID:
66690
Concept ID:
C0233844
Sign or Symptom
Lack of physical coordination resulting in an abnormal tendency to drop items or bump into objects.
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.
Mental deterioration
MedGen UID:
66713
Concept ID:
C0234985
Mental or Behavioral Dysfunction
Loss of previously present mental abilities, generally in adults.
Hand tremor
MedGen UID:
68689
Concept ID:
C0239842
Finding
An unintentional, oscillating to-and-fro muscle movement affecting the hand.
Personality changes
MedGen UID:
66817
Concept ID:
C0240735
Mental or Behavioral Dysfunction
An abnormal shift in patterns of thinking, acting, or feeling.
Global brain atrophy
MedGen UID:
66840
Concept ID:
C0241816
Pathologic Function
Unlocalized atrophy of the brain with decreased total brain matter volume and increased ventricular size.
Parkinsonism
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.
Frontotemporal dementia
MedGen UID:
83266
Concept ID:
C0338451
Disease or Syndrome
Frontotemporal dementia (FTD) refers to a clinical manifestation of the pathologic finding of frontotemporal lobar degeneration (FTLD). FTD, the most common subtype of FTLD, is a behavioral variant characterized by changes in social and personal conduct with loss of volition, executive dysfunction, loss of abstract thought, and decreased speech output. A second clinical subtype of FTLD is 'semantic dementia,' characterized by specific loss of comprehension of language and impaired facial and object recognition. A third clinical subtype of FTLD is 'primary progressive aphasia' (PPA), characterized by a reduction in speech production, speech errors, and word retrieval difficulties resulting in mutism and an inability to communicate. All subtypes have relative preservation of memory, at least in the early stages. FTLD is often associated with parkinsonism or motor neuron disease (MND) resembling amyotrophic lateral sclerosis (ALS; 105400) (reviews by Tolnay and Probst, 2002 and Mackenzie and Rademakers, 2007). Mackenzie et al. (2009, 2010) provided a classification of FTLD subtypes according to the neuropathologic findings (see PATHOGENESIS below). Clinical Variability of Tauopathies Tauopathies comprise a clinically variable group of neurodegenerative diseases characterized neuropathologically by accumulation of abnormal MAPT-positive inclusions in nerve and/or glial cells. In addition to frontotemporal dementia, semantic dementia, and PPA, different clinical syndromes with overlapping features have been described, leading to confusion in the terminology (Tolnay and Probst, 2002). Other terms used historically include parkinsonism and dementia with pallidopontonigral degeneration (PPND) (Wszolek et al., 1992); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) (Lynch et al., 1994); frontotemporal dementia with parkinsonism (FLDEM) (Yamaoka et al., 1996); and multiple system tauopathy with presenile dementia (MSTD) (Spillantini et al., 1997). These disorders are characterized by variable degrees of frontal lobe dementia, parkinsonism, motor neuron disease, and amyotrophy. Other neurodegenerative associated with mutations in the MAPT gene include Pick disease (172700) and progressive supranuclear palsy (PSP; 601104), Inherited neurodegenerative tauopathies linked to chromosome 17 and caused by mutation in the MAPT gene have also been collectively termed 'FTDP17' (Lee et al., 2001). Kertesz (2003) suggested the term 'Pick complex' to represent the overlapping syndromes of FTD, primary progressive aphasia (PPA), corticobasal degeneration (CBD), PSP, and FTD with motor neuron disease. He noted that frontotemporal dementia may also be referred to as 'clinical Pick disease' and that the term 'Pick disease' should be restricted to the pathologic finding of Pick bodies. Genetic Heterogeneity of Frontotemporal Lobar Degeneration Mutations in several different genes can cause frontotemporal dementia and frontotemporal lobar degeneration, with or without motor neuron disease. See FTLD with TDP43 inclusions (607485), caused by mutation in the GRN gene (138945) on chromosome 17q21; FTLALS7 (600795), caused by mutation in the CHMP2B gene (609512) on chromosome 3p11; inclusion body myopathy with Paget disease and FTD (IBMPFD; 167320), caused by mutation in the VCP gene (601023) on chromosome 9p13; ALS6 (608030), caused by mutation in the FUS gene (137070) on 16p11; ALS10 (612069), caused by mutation in the TARDBP gene (605078) on 1p36; and FTDALS1 (105550), caused by mutation in the C9ORF72 gene (614260) on 9p21. In 1 family with FTD, a mutation was identified in the presenilin-1 gene (PSEN1; 104311) on chromosome 14, which is usually associated with a familial form of early-onset Alzheimer disease (AD3; 607822).
Eyelid myoclonus
MedGen UID:
148288
Concept ID:
C0751349
Disease or Syndrome
Marked, involuntary jerking of the eyelids.
Pill-rolling tremor
MedGen UID:
199684
Concept ID:
C0751564
Sign or Symptom
A type of resting tremor characterized by simultaneous rubbing movements of thumb and index fingers against each other.
Axial dystonia
MedGen UID:
373027
Concept ID:
C1836149
Finding
A type of dystonia that affects the midline muscles, i.e., the chest, abdominal, and back muscles.
Loss of ambulation
MedGen UID:
332305
Concept ID:
C1836843
Finding
Inability to walk in a person who previous had the ability to walk.
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.
Upper limb postural tremor
MedGen UID:
357212
Concept ID:
C1867138
Finding
A type of tremors that is triggered by holding an arm in a fixed position.
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.
Frontotemporal cerebral atrophy
MedGen UID:
867226
Concept ID:
C4021584
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the frontotemporal cerebrum.
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.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Facial tics
MedGen UID:
124458
Concept ID:
C0278151
Finding
Sudden, repetitive, nonrhythmic motor movements (spasms), involving the eyes and muscles of the face.
Hypomimic face
MedGen UID:
208827
Concept ID:
C0813217
Finding
A reduced degree of motion of the muscles beneath the skin of the face, often associated with reduced facial crease formation.
Eyelid apraxia
MedGen UID:
222979
Concept ID:
C1142448
Finding
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.
Vertical supranuclear gaze palsy
MedGen UID:
334385
Concept ID:
C1843369
Disease or Syndrome
A supranuclear gaze palsy is an inability to look in a vertical 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.
Hypometric upward saccades
MedGen UID:
1645369
Concept ID:
C4703563
Finding
Saccadic undershoot of upward saccadic eye movements, i.e., an upward saccadic eye movement that has less than the magnitude that would be required to gain fixation of the object.

Professional guidelines

PubMed

Stirnemann J, Vigan M, Hamroun D, Heraoui D, Rossi-Semerano L, Berger MG, Rose C, Camou F, de Roux-Serratrice C, Grosbois B, Kaminsky P, Robert A, Caillaud C, Froissart R, Levade T, Masseau A, Mignot C, Sedel F, Dobbelaere D, Vanier MT, Valayanopoulos V, Fain O, Fantin B, de Villemeur TB, Mentré F, Belmatoug N
Orphanet J Rare Dis 2012 Oct 9;7:77. doi: 10.1186/1750-1172-7-77. PMID: 23046562Free PMC Article

Recent clinical studies

Etiology

Bakhit Y, Ibrahim MO, Tesson C, Elhassan AA, Ahmed MA, Alebeed MA, Elrasheed SM, Omar MA, Abubaker R, Eltom K, Shaheen MT, Ibrahim YA, Almak ME, Ali HA, Abugrain AA, Almahal MA, MohamedSharif AA, Tahir MY, Malik SM, Eldirdiri Abdelrahman H, Khidir RJ, Mohamed MT, Abdalla A, Elsayed LEO, Lesage S, Corvol JC, Seidi O, Wüllner U
Parkinsonism Relat Disord 2023 Jun;111:105401. Epub 2023 Apr 25 doi: 10.1016/j.parkreldis.2023.105401. PMID: 37150071
Emekli I, Tepgeç F, Samancı B, Toksoy G, Hasanoğulları Kına G, Tüfekçioğlu Z, Başaran S, Bilgiç B, Gürvit IH, Emre M, Uyguner ZO, Hanagasi HA
Parkinsonism Relat Disord 2021 Dec;93:35-39. Epub 2021 Nov 3 doi: 10.1016/j.parkreldis.2021.10.024. PMID: 34781237
Gopurappilly R
Adv Exp Med Biol 2021;1347:115-133. doi: 10.1007/5584_2021_643. PMID: 33990932Free PMC Article
Zhao Y, Qin L, Pan H, Liu Z, Jiang L, He Y, Zeng Q, Zhou X, Zhou X, Zhou Y, Fang Z, Wang Z, Xiang Y, Yang H, Wang Y, Zhang K, Zhang R, He R, Zhou X, Zhou Z, Yang N, Liang D, Chen J, Zhang X, Zhou Y, Liu H, Deng P, Xu K, Xu K, Zhou C, Zhong J, Xu Q, Sun Q, Li B, Zhao G, Wang T, Chen L, Shang H, Liu W, Chan P, Xue Z, Wang Q, Guo L, Wang X, Xu C, Zhang Z, Chen T, Lei L, Zhang H, Wang C, Tan J, Yan X, Shen L, Jiang H, Zhang Z, Hu Z, Xia K, Yue Z, Li J, Guo J, Tang B
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Tanner CM, Chen B, Wang WZ, Peng ML, Liu ZL, Liang XL, Kao LC, Gilley DW, Schoenberg BS
Can J Neurol Sci 1987 Aug;14(3 Suppl):419-23. doi: 10.1017/s0317167100037835. PMID: 3315147

Diagnosis

Zhao Y, Qin L, Pan H, Liu Z, Jiang L, He Y, Zeng Q, Zhou X, Zhou X, Zhou Y, Fang Z, Wang Z, Xiang Y, Yang H, Wang Y, Zhang K, Zhang R, He R, Zhou X, Zhou Z, Yang N, Liang D, Chen J, Zhang X, Zhou Y, Liu H, Deng P, Xu K, Xu K, Zhou C, Zhong J, Xu Q, Sun Q, Li B, Zhao G, Wang T, Chen L, Shang H, Liu W, Chan P, Xue Z, Wang Q, Guo L, Wang X, Xu C, Zhang Z, Chen T, Lei L, Zhang H, Wang C, Tan J, Yan X, Shen L, Jiang H, Zhang Z, Hu Z, Xia K, Yue Z, Li J, Guo J, Tang B
Brain 2020 Jul 1;143(7):2220-2234. doi: 10.1093/brain/awaa167. PMID: 32613234
Ahfeldt T, Ordureau A, Bell C, Sarrafha L, Sun C, Piccinotti S, Grass T, Parfitt GM, Paulo JA, Yanagawa F, Uozumi T, Kiyota Y, Harper JW, Rubin LL
Stem Cell Reports 2020 Jan 14;14(1):75-90. Epub 2020 Jan 2 doi: 10.1016/j.stemcr.2019.12.005. PMID: 31902706Free PMC Article
Stirnemann J, Vigan M, Hamroun D, Heraoui D, Rossi-Semerano L, Berger MG, Rose C, Camou F, de Roux-Serratrice C, Grosbois B, Kaminsky P, Robert A, Caillaud C, Froissart R, Levade T, Masseau A, Mignot C, Sedel F, Dobbelaere D, Vanier MT, Valayanopoulos V, Fain O, Fantin B, de Villemeur TB, Mentré F, Belmatoug N
Orphanet J Rare Dis 2012 Oct 9;7:77. doi: 10.1186/1750-1172-7-77. PMID: 23046562Free PMC Article
Mizuno Y, Hattori N, Mori H, Suzuki T, Tanaka K
Curr Opin Neurol 2001 Aug;14(4):477-82. doi: 10.1097/00019052-200108000-00008. PMID: 11470964
Gouider-Khouja N, Belal S, Hamida MB, Hentati F
Neurology 2000 Apr 25;54(8):1603-9. doi: 10.1212/wnl.54.8.1603. PMID: 10762501

Therapy

Reetz K, Dogan I, Costa AS, Dafotakis M, Fedosov K, Giunti P, Parkinson MH, Sweeney MG, Mariotti C, Panzeri M, Nanetti L, Arpa J, Sanz-Gallego I, Durr A, Charles P, Boesch S, Nachbauer W, Klopstock T, Karin I, Depondt C, vom Hagen JM, Schöls L, Giordano IA, Klockgether T, Bürk K, Pandolfo M, Schulz JB
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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
Tanner CM, Chen B, Wang WZ, Peng ML, Liu ZL, Liang XL, Kao LC, Gilley DW, Schoenberg BS
Can J Neurol Sci 1987 Aug;14(3 Suppl):419-23. doi: 10.1017/s0317167100037835. PMID: 3315147

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
Zech M, Kumar KR, Reining S, Reunert J, Tchan M, Riley LG, Drew AP, Adam RJ, Berutti R, Biskup S, Derive N, Bakhtiari S, Jin SC, Kruer MC, Bardakjian T, Gonzalez-Alegre P, Keller Sarmiento IJ, Mencacci NE, Lubbe SJ, Kurian MA, Clot F, Méneret A, de Sainte Agathe JM, Fung VSC, Vidailhet M, Baumann M, Marquardt T, Winkelmann J, Boesch S
Mov Disord 2022 Jan;37(1):137-147. Epub 2021 Oct 1 doi: 10.1002/mds.28804. PMID: 34596301
Cahan EM, Frick SL
Orphanet J Rare Dis 2019 Jun 19;14(1):148. doi: 10.1186/s13023-019-1131-4. PMID: 31217022Free PMC Article
Lai YC, Kondapalli C, Lehneck R, Procter JB, Dill BD, Woodroof HI, Gourlay R, Peggie M, Macartney TJ, Corti O, Corvol JC, Campbell DG, Itzen A, Trost M, Muqit MM
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Gouider-Khouja N, Belal S, Hamida MB, Hentati F
Neurology 2000 Apr 25;54(8):1603-9. doi: 10.1212/wnl.54.8.1603. PMID: 10762501

Clinical prediction guides

Samanci B, Bilgiç B, Gelişin Ö, Tepgeç F, Guven G, Tüfekçioğlu Z, Alaylıoğlu M, Hanagasi HA, Gürvit H, Guerreiro R, Hardy J, Emre M
Eur J Neurol 2021 Aug;28(8):2603-2613. Epub 2021 Jun 1 doi: 10.1111/ene.14908. PMID: 33969597
Ahfeldt T, Ordureau A, Bell C, Sarrafha L, Sun C, Piccinotti S, Grass T, Parfitt GM, Paulo JA, Yanagawa F, Uozumi T, Kiyota Y, Harper JW, Rubin LL
Stem Cell Reports 2020 Jan 14;14(1):75-90. Epub 2020 Jan 2 doi: 10.1016/j.stemcr.2019.12.005. PMID: 31902706Free PMC Article
Marshall RD, Collins A, Escolar ML, Jinnah HA, Klopstock T, Kruer MC, Videnovic A, Robichaux-Viehoever A, Burns C, Swett LL, Revicki DA, Bender RH, Lenderking WR
Orphanet J Rare Dis 2019 Jul 12;14(1):174. doi: 10.1186/s13023-019-1142-1. PMID: 31300018Free PMC Article
Imai Y, Takahashi R
Curr Opin Neurobiol 2004 Jun;14(3):384-9. doi: 10.1016/j.conb.2004.04.002. PMID: 15194120
Gouider-Khouja N, Belal S, Hamida MB, Hentati F
Neurology 2000 Apr 25;54(8):1603-9. doi: 10.1212/wnl.54.8.1603. PMID: 10762501

Recent systematic reviews

Fereshtehnejad SM, Saleh PA, Oliveira LM, Patel N, Bhowmick S, Saranza G, Kalia LV
Neurol Sci 2023 Mar;44(3):947-959. Epub 2022 Nov 28 doi: 10.1007/s10072-022-06516-8. PMID: 36441344Free PMC Article

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