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Multiple system atrophy 1, susceptibility to(MSA1)

MedGen UID:
811503
Concept ID:
C3714927
Finding
Synonym: MSA1, SUSCEPTIBILITY TO
 
Gene (location): COQ2 (4q21.23)
 
Monarch Initiative: MONDO:0020715
OMIM®: 146500

Definition

Multiple system atrophy (MSA) is a distinct clinicopathologic entity that manifests as a progressive adult-onset neurodegenerative disorder causing parkinsonism, cerebellar ataxia, and autonomic, urogenital, and pyramidal dysfunction in various combinations. Two main subtypes are recognized: 'subtype C,' characterized predominantly by cerebellar ataxia, and 'subtype P,' characterized predominantly by parkinsonism. MSA is characterized pathologically by the degeneration of striatonigral and olivopontocerebellar structures and glial cytoplasmic inclusions (GCIs) that consist of abnormally phosphorylated alpha-synuclein (SNCA; 163890) or tau (MAPT; 157140) (Gilman et al., 1998; Gilman et al., 2008; Scholz et al., 2009). 'Subtype C' of MSA has been reported to be more prevalent than 'subtype P' in the Japanese population (65-67% vs 33-35%), whereas 'subtype P' has been reported to be more prevalent than 'subtype C' in Europe (63% vs 34%) and North America (60% vs 13%, with 27% of cases unclassified) (summary by The Multiple-System Atrophy Research Collaboration, 2013). MSA is similar clinically and pathologically to Parkinson disease (PD; 168600) and Lewy body dementia (127750). See also PARK1 (168601), which is specifically caused by mutation in the SNCA gene. Pure autonomic failure manifests as orthostatic hypotension and other autonomic abnormalities without other neurologic involvement. Although there is some phenotypic overlap, the relationship of pure autonomic failure to MSA is unclear (Vanderhaeghen et al., 1970; Schatz, 1996). [from OMIM]

Additional description

From MedlinePlus Genetics
Multiple system atrophy is a progressive brain disorder that affects movement and balance and disrupts the function of the autonomic nervous system. The autonomic nervous system controls body functions that are mostly involuntary, such as regulation of blood pressure. The most frequent autonomic symptoms associated with multiple system atrophy are a sudden drop in blood pressure upon standing (orthostatic hypotension), urinary difficulties, and erectile dysfunction in men.

Researchers have described two major types of multiple system atrophy, which are distinguished by their major signs and symptoms at the time of diagnosis. In one type, known as MSA-P, a group of movement abnormalities called parkinsonism are predominant. These abnormalities include unusually slow movement (bradykinesia), muscle rigidity, tremors, and an inability to hold the body upright and balanced (postural instability). The other type of multiple system atrophy, known as MSA-C, is characterized by cerebellar ataxia, which causes problems with coordination and balance. This form of the condition can also include speech difficulties (dysarthria) and problems controlling eye movement.

Multiple system atrophy usually occurs in older adults; on average, signs and symptoms appear around age 55. The condition worsens with time, and affected individuals survive an average of 10 years after the signs and symptoms first appear.  https://medlineplus.gov/genetics/condition/multiple-system-atrophy

Clinical features

From HPO
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.
Impotence
MedGen UID:
1720680
Concept ID:
CN208474
Finding
Inability to develop or maintain an erection of the penis.
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.
Abnormal autonomic nervous system physiology
MedGen UID:
8511
Concept ID:
C0013363
Disease or Syndrome
A functional abnormality of the autonomic nervous system.
Orthostatic hypotension
MedGen UID:
43803
Concept ID:
C0020651
Disease or Syndrome
A form of hypotension characterized by a sudden fall in blood pressure that occurs when a person assumes a standing position.
Neurodegeneration
MedGen UID:
17999
Concept ID:
C0027746
Cell or Molecular Dysfunction
Progressive loss of neural cells and tissue.
Olivopontocerebellar atrophy
MedGen UID:
10435
Concept ID:
C0028968
Disease or Syndrome
Neuronal degeneration in the cerebellum, pontine nuclei, and inferior olivary nucleus.
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.
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).
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.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
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.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Anhidrosis
MedGen UID:
1550
Concept ID:
C0003028
Disease or Syndrome
Inability to sweat.
Hypohidrosis
MedGen UID:
43796
Concept ID:
C0020620
Disease or Syndrome
Abnormally diminished capacity to sweat.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Iris atrophy
MedGen UID:
96095
Concept ID:
C0423319
Disease or Syndrome
Loss of iris tissue (atrophy)
Gaze-evoked nystagmus
MedGen UID:
1808161
Concept ID:
C5574666
Disease or Syndrome
Nystagmus made apparent by looking to the right or to the left.

Professional guidelines

PubMed

Bu S, Pang H, Li X, Zhao M, Wang J, Liu Y, Yu H
BMC Med Imaging 2023 Dec 8;23(1):204. doi: 10.1186/s12880-023-01169-1. PMID: 38066432Free PMC Article
Mongelli A, Sarro L, Rizzo E, Nanetti L, Meucci N, Pezzoli G, Goldwurm S, Taroni F, Mariotti C, Gellera C
Neurosci Lett 2018 Jun 21;678:37-42. Epub 2018 Apr 30 doi: 10.1016/j.neulet.2018.04.044. PMID: 29715545

Recent clinical studies

Etiology

Bougea A
Int J Mol Sci 2023 Mar 9;24(6) doi: 10.3390/ijms24065281. PMID: 36982356Free PMC Article
Porto KJ, Hirano M, Mitsui J, Chikada A, Matsukawa T, Ishiura H; Japan Multiple System Atrophy Registry Consortium, Toda T, Kusunoki S, Tsuji S
J Neurol Sci 2021 Oct 15;429:117623. Epub 2021 Aug 24 doi: 10.1016/j.jns.2021.117623. PMID: 34455210
Wernick AI, Walton RL, Koga S, Soto-Beasley AI, Heckman MG, Gan-Or Z, Ren Y, Rademakers R, Uitti RJ, Wszolek ZK, Cheshire WP, Dickson DW, Ross OA
Parkinsonism Relat Disord 2020 Aug;77:64-69. Epub 2020 Jun 22 doi: 10.1016/j.parkreldis.2020.06.007. PMID: 32623306
Labbé C, Heckman MG, Lorenzo-Betancor O, Murray ME, Ogaki K, Soto-Ortolaza AI, Walton RL, Fujioka S, Koga S, Uitti RJ, van Gerpen JA, Petersen RC, Graff-Radford NR, Younkin SG, Boeve BF, Cheshire WP Jr, Low PA, Sandroni P, Coon EA, Singer W, Wszolek ZK, Dickson DW, Ross OA
Parkinsonism Relat Disord 2016 Sep;30:40-5. Epub 2016 Jun 16 doi: 10.1016/j.parkreldis.2016.06.010. PMID: 27374978Free PMC Article
Mennuni S, Rubattu S, Pierelli G, Tocci G, Fofi C, Volpe M
J Hum Hypertens 2014 Feb;28(2):74-9. Epub 2013 Jun 27 doi: 10.1038/jhh.2013.55. PMID: 23803592

Diagnosis

Linard M, Ravier A, Mougué L, Grgurina I, Boutillier AL, Foubert-Samier A, Blanc F, Helmer C
Mov Disord 2022 Mar;37(3):464-477. Epub 2022 Jan 18 doi: 10.1002/mds.28925. PMID: 35040520
Wernick AI, Walton RL, Koga S, Soto-Beasley AI, Heckman MG, Gan-Or Z, Ren Y, Rademakers R, Uitti RJ, Wszolek ZK, Cheshire WP, Dickson DW, Ross OA
Parkinsonism Relat Disord 2020 Aug;77:64-69. Epub 2020 Jun 22 doi: 10.1016/j.parkreldis.2020.06.007. PMID: 32623306
Katzeff JS, Phan K, Purushothuman S, Halliday GM, Kim WS
Acta Neuropathol Commun 2019 Jul 24;7(1):117. doi: 10.1186/s40478-019-0769-4. PMID: 31340844Free PMC Article
Jordan J, Kaufmann H
Clin Auton Res 2015 Feb;25(1):1-2. doi: 10.1007/s10286-015-0283-0. PMID: 25840762
Mennuni S, Rubattu S, Pierelli G, Tocci G, Fofi C, Volpe M
J Hum Hypertens 2014 Feb;28(2):74-9. Epub 2013 Jun 27 doi: 10.1038/jhh.2013.55. PMID: 23803592

Therapy

Lim SJ, Suh CH, Shim WH, Kim SJ
Eur Radiol 2022 Jan;32(1):308-318. Epub 2021 Jul 16 doi: 10.1007/s00330-021-08174-4. PMID: 34272590
Hu X, Sun X, Hu F, Liu F, Ruan W, Wu T, An R, Lan X
Eur J Nucl Med Mol Imaging 2021 Oct;48(11):3469-3481. Epub 2021 Apr 7 doi: 10.1007/s00259-021-05325-z. PMID: 33829415
Lee J, Lee AL, Park JH, Moon JE, Park JM, Kim SJ, Chang KH
PLoS One 2020;15(4):e0231010. Epub 2020 Apr 2 doi: 10.1371/journal.pone.0231010. PMID: 32240236Free PMC Article
Jordan J, Kaufmann H
Clin Auton Res 2015 Feb;25(1):1-2. doi: 10.1007/s10286-015-0283-0. PMID: 25840762
Mennuni S, Rubattu S, Pierelli G, Tocci G, Fofi C, Volpe M
J Hum Hypertens 2014 Feb;28(2):74-9. Epub 2013 Jun 27 doi: 10.1038/jhh.2013.55. PMID: 23803592

Prognosis

Faergeman SL, Evans H, Attfield KE, Desel C, Kuttikkatte SB, Sommerlund M, Jensen LT, Frokiaer J, Friese MA, Matthews PM, Luchtenborg C, Brügger B, Oturai AB, Dendrou CA, Fugger L
Cell Death Dis 2020 May 1;11(5):303. doi: 10.1038/s41419-020-2494-0. PMID: 32358523Free PMC Article
Lee J, Lee AL, Park JH, Moon JE, Park JM, Kim SJ, Chang KH
PLoS One 2020;15(4):e0231010. Epub 2020 Apr 2 doi: 10.1371/journal.pone.0231010. PMID: 32240236Free PMC Article
Kasai T, Tokuda T, Ohmichi T, Ishii R, Tatebe H, Nakagawa M, Mizuno T
PLoS One 2016;11(1):e0147574. Epub 2016 Jan 26 doi: 10.1371/journal.pone.0147574. PMID: 26812605Free PMC Article
Mennuni S, Rubattu S, Pierelli G, Tocci G, Fofi C, Volpe M
J Hum Hypertens 2014 Feb;28(2):74-9. Epub 2013 Jun 27 doi: 10.1038/jhh.2013.55. PMID: 23803592
von Lewinski F, Werner C, Jörn T, Mohr A, Sixel-Döring F, Trenkwalder C
J Neurol 2007 Sep;254(9):1184-8. Epub 2007 Mar 14 doi: 10.1007/s00415-006-0496-1. PMID: 17361340

Clinical prediction guides

Valentino RR, Heckman MG, Johnson PW, Soto-Beasley AI, Walton RL, Koga S, Uitti RJ, Wszolek ZK, Dickson DW, Ross OA
Parkinsonism Relat Disord 2020 Dec;81:200-204. Epub 2020 Oct 29 doi: 10.1016/j.parkreldis.2020.10.040. PMID: 33189969Free PMC Article
Kaji S, Maki T, Ueda J, Ishimoto T, Inoue Y, Yasuda K, Sawamura M, Hikawa R, Ayaki T, Yamakado H, Takahashi R
Acta Neuropathol Commun 2020 Jul 29;8(1):120. doi: 10.1186/s40478-020-00997-4. PMID: 32727582Free PMC Article
Wernick AI, Walton RL, Koga S, Soto-Beasley AI, Heckman MG, Gan-Or Z, Ren Y, Rademakers R, Uitti RJ, Wszolek ZK, Cheshire WP, Dickson DW, Ross OA
Parkinsonism Relat Disord 2020 Aug;77:64-69. Epub 2020 Jun 22 doi: 10.1016/j.parkreldis.2020.06.007. PMID: 32623306
Heckman MG, Schottlaender L, Soto-Ortolaza AI, Diehl NN, Rayaprolu S, Ogaki K, Fujioka S, Murray ME, Cheshire WP, Uitti RJ, Wszolek ZK, Farrer MJ, Sailer A, Singleton AB, Chinnery PF, Keogh MJ, Gentleman SM, Holton JL, Aoife K, Mann DM, Al-Sarraj S, Troakes C, Dickson DW, Houlden H, Ross OA
Neurology 2014 Dec 9;83(24):2256-61. Epub 2014 Nov 5 doi: 10.1212/WNL.0000000000001078. PMID: 25378673Free PMC Article
Ozawa T, Revesz T, Paviour D, Lees AJ, Quinn N, Tada M, Kakita A, Onodera O, Wakabayashi K, Takahashi H, Nishizawa M, Holton JL
J Parkinsons Dis 2012;2(1):7-18. doi: 10.3233/JPD-2012-11056. PMID: 23939403

Recent systematic reviews

Linard M, Ravier A, Mougué L, Grgurina I, Boutillier AL, Foubert-Samier A, Blanc F, Helmer C
Mov Disord 2022 Mar;37(3):464-477. Epub 2022 Jan 18 doi: 10.1002/mds.28925. PMID: 35040520
Lim SJ, Suh CH, Shim WH, Kim SJ
Eur Radiol 2022 Jan;32(1):308-318. Epub 2021 Jul 16 doi: 10.1007/s00330-021-08174-4. PMID: 34272590

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