Multisystemic smooth muscle dysfunction syndrome is a rare autosomal dominant ACTA2-related smooth muscle disorder, classically caused by heterozygous pathogenic variants altering ACTA2 arginine 179. It affects vascular and nonvascular smooth muscle-dependent organs, producing congenital mydriasis, patent ductus arteriosus or aortopulmonary window, thoracic aortic aneurysm or dissection, moyamoya-like cerebrovascular arteriopathy, pulmonary arterial hypertension, hypotonic bladder, and gastrointestinal hypoperistalsis.
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name: Multisystemic smooth muscle dysfunction syndrome
creation_date: "2026-05-05T20:46:40Z"
updated_date: "2026-05-05T22:45:00Z"
category: Mendelian
description: >-
Multisystemic smooth muscle dysfunction syndrome is a rare autosomal dominant
ACTA2-related smooth muscle disorder, classically caused by heterozygous
pathogenic variants altering ACTA2 arginine 179. It affects vascular and
nonvascular smooth muscle-dependent organs, producing congenital mydriasis,
patent ductus arteriosus or aortopulmonary window, thoracic aortic aneurysm or
dissection, moyamoya-like cerebrovascular arteriopathy, pulmonary arterial
hypertension, hypotonic bladder, and gastrointestinal hypoperistalsis.
disease_term:
preferred_term: multisystemic smooth muscle dysfunction syndrome
term:
id: MONDO:0013452
label: multisystemic smooth muscle dysfunction syndrome
synonyms:
- MSMDS
- SMDS
- Smooth muscle dysfunction syndrome
- ACTA2-related multisystemic smooth muscle dysfunction syndrome
parents:
- Vascular Disease
- Mendelian Disease
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Classic SMDS is caused by heterozygous ACTA2 Arg179 alterations and is
autosomal dominant, although most reported classic cases arise de novo.
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It is caused by heterozygous mutations of the ACTA2 altering arginine 179,
most commonly p.Arg179His. With a single exception, all cases are due to de
novo mutations.
explanation: >-
This cohort paper directly supports heterozygous ACTA2 Arg179 variants and
frequent de novo occurrence.
genetic:
- name: ACTA2
association: Causal gene
gene_term:
preferred_term: ACTA2
term:
id: hgnc:130
label: ACTA2
notes: >-
ACTA2 encodes smooth muscle alpha-actin. Pathogenic variants that alter
arginine 179 cause the classic severe multisystemic smooth muscle dysfunction
phenotype, while other ACTA2 variants can overlap with parts of the syndrome.
evidence:
- reference: DOI:10.1002/ajmg.a.62775
reference_title: >-
Expanding ACTA2 genotypes with corresponding phenotypes overlapping with
smooth muscle dysfunction syndrome
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ACTA2 variants altering arginine 179 predispose to a more severe,
multisystemic disease termed smooth muscle dysfunction syndrome (SMDS; OMIM
613834).
explanation: >-
This directly supports ACTA2 Arg179 variants as causal for classic SMDS.
- reference: CGGV:assertion_2f4fb1fe-4b82-481d-a81d-398eea46acc5-2025-01-24T170000.000Z
reference_title: "ACTA2 / multisystemic smooth muscle dysfunction syndrome (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "ACTA2 | HGNC:130 | multisystemic smooth muscle dysfunction syndrome | MONDO:0013452 | AD | Definitive"
explanation: ClinGen classifies the ACTA2-multisystemic smooth muscle dysfunction syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
pathophysiology:
- name: Smooth muscle contractile apparatus dysfunction
description: >-
ACTA2 pathogenic variants disrupt smooth muscle alpha-actin function in the
contractile apparatus of vascular and visceral smooth muscle cells, impairing
organ systems that depend on smooth muscle contraction and vessel-wall
integrity.
genes:
- preferred_term: ACTA2
term:
id: hgnc:130
label: ACTA2
cell_types:
- preferred_term: smooth muscle cell
term:
id: CL:0000192
label: smooth muscle cell
biological_processes:
- preferred_term: muscle contraction
term:
id: GO:0006936
label: muscle contraction
modifier: DECREASED
evidence:
- reference: DOI:10.1186/s13023-019-1186-2
reference_title: >-
European reference network for rare vascular diseases (VASCERN) consensus
statement for the screening and management of patients with pathogenic
ACTA2 variants
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TheACTA2gene encodes for smooth muscle specific α-actin, a critical
component of the contractile apparatus of the vascular smooth muscle cell.
explanation: >-
This establishes ACTA2's contractile-apparatus role in vascular smooth
muscle cells.
downstream:
- target: Aortic aneurysm and dissection
description: Smooth muscle dysfunction weakens the thoracic aorta and predisposes to aneurysm repair or dissection.
causal_link_type: DIRECT
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Twelve (36%) patients had thoracic aortic aneurysm repair or dissection
at median age of 14 years and aortic disease was fully penetrant by the
age of 25 years.
explanation: >-
This directly supports early aortic disease as a major consequence.
- target: Congenital mydriasis
description: Ocular smooth muscle dysfunction produces fixed or non-reactive pupils from birth.
causal_link_type: DIRECT
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All patients had congenital mydriasis and related pupillary abnormalities
at birth and presented in infancy with a patent ductus arteriosus or
aortopulmonary window.
explanation: >-
This directly supports congenital mydriasis as a fully penetrant early
manifestation in the cohort.
- target: Patent ductus arteriosus or aortopulmonary window
description: Cardiovascular smooth muscle dysfunction is associated with persistent ductal cardiac lesions in infancy.
causal_link_type: DIRECT
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All patients had congenital mydriasis and related pupillary
abnormalities at birth and presented in infancy with a patent ductus
arteriosus or aortopulmonary window.
explanation: >-
This directly supports ductal cardiac lesions as fully penetrant infant
manifestations in the cohort.
- name: ACTA2-related cerebrovascular arteriopathy
description: >-
ACTA2 Arg179 variants cause a distinctive cerebral arteriopathy with
proximal carotid dilation, terminal internal carotid occlusive disease,
abnormally straight intracranial arteries, absent basal moyamoya collaterals,
and white-matter injury.
cell_types:
- preferred_term: smooth muscle cell
term:
id: CL:0000192
label: smooth muscle cell
biological_processes:
- preferred_term: blood vessel remodeling
term:
id: GO:0001974
label: blood vessel remodeling
modifier: ABNORMAL
evidence:
- reference: PMID:22831780
reference_title: >-
A novel distinctive cerebrovascular phenotype is associated with
heterozygous Arg179 ACTA2 mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Distinctive cerebrovascular features were dilatation of proximal internal
carotid artery, occlusive disease of terminal internal carotid artery, an
abnormally straight course of intracranial arteries, and absent basal
'moyamoya' collaterals.
explanation: >-
This directly supports the distinctive ACTA2 Arg179 cerebrovascular
phenotype.
phenotypes:
- name: Congenital mydriasis
category: Ophthalmologic
diagnostic: true
description: >-
Fixed dilated pupils or related pupillary abnormalities are present from
birth and are a major diagnostic clue.
phenotype_term:
preferred_term: Congenital mydriasis
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All patients had pupillary abnormalities described in the medical records
as fixed or non-reactive pupils (congenital mydriasis), iris hypoplasia,
and/or aniridia or partial aniridia.
explanation: >-
This directly supports congenital mydriasis or related pupillary
abnormalities as a core phenotype.
- name: Patent ductus arteriosus or aortopulmonary window
category: Cardiovascular
diagnostic: true
description: >-
Persistent ductal cardiac lesions present in infancy and may be large or
associated with pulmonary arterial hypertension.
phenotype_term:
preferred_term: Patent ductus arteriosus
term:
id: HP:0001643
label: Patent ductus arteriosus
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All patients had a patent ductus arteriosus (91%) or an aortopulmonary
window (APW; 9%) diagnosed during infancy.
explanation: >-
This supports ductal cardiovascular lesions as an early highly penetrant
feature.
- name: Thoracic aortic aneurysm or dissection
category: Cardiovascular
diagnostic: true
description: >-
Early thoracic aortic dilation, aneurysm repair, and dissection are central
life-threatening manifestations.
phenotype_term:
preferred_term: Aortic dissection
term:
id: HP:0002647
label: Aortic dissection
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Twelve patients (36%) had had an aortic event, defined as an elective
aortic aneurysm repair or dissection, at median age of 14 years.
explanation: >-
This cohort directly supports early aneurysm repair or dissection risk.
- name: Cerebrovascular arteriopathy and ischemic stroke
category: Neurologic
description: >-
Affected individuals have moyamoya-like steno-occlusive arteriopathy,
periventricular white-matter changes, and ischemic stroke risk.
phenotype_term:
preferred_term: Ischemic stroke
term:
id: HP:0002140
label: Ischemic stroke
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients had cerebrovascular disease characterized by small vessel disease
(hyperintense periventricular white matter lesions; 95%), intracranial
artery stenosis (77%), ischemic strokes (27%), and seizures (18%).
explanation: >-
This directly supports the cerebrovascular disease spectrum and stroke
risk.
- name: Pulmonary arterial hypertension
category: Cardiopulmonary
description: >-
Pulmonary arterial hypertension occurs as part of the smooth muscle-dependent
cardiopulmonary phenotype.
phenotype_term:
preferred_term: Pulmonary arterial hypertension
term:
id: HP:0002092
label: Pulmonary arterial hypertension
evidence:
- reference: DOI:10.1002/ajmg.a.62775
reference_title: >-
Expanding ACTA2 genotypes with corresponding phenotypes overlapping with
smooth muscle dysfunction syndrome
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Vascular complications of SMDS include patent ductus arteriosus (PDA) or
aortopulmonary window, early-onset thoracic aortic disease (TAD),
moyamoya-like cerebrovascular disease, and primary pulmonary hypertension.
explanation: >-
This directly supports pulmonary hypertension as part of the SMDS vascular
phenotype.
- name: Hypotonic bladder
category: Genitourinary
description: >-
Hypotonic bladder is a cardinal nonvascular smooth muscle manifestation of
SMDS.
phenotype_term:
preferred_term: Hypotonic bladder
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our findings confirm the cardinal features of SMDS are PDA or APW,
thoracic aortic aneurysm and dissection, thoracoabdominal aortic aneurysm,
peripheral artery aneurysms, cerebrovascular disease, retinal vessel
tortuosity, congenital mydriasis, pulmonary artery hypertension, chronic
lung disease, hypotonic bladder, undescended testes, atonic gravid uterus,
gut malrotation, hypoperistalsis, and gall bladder sludge or
cholelithiasis.
explanation: >-
This identifies hypotonic bladder among the cardinal features of SMDS.
- name: Intestinal hypoperistalsis
category: Gastrointestinal
description: >-
Gut hypoperistalsis and malrotation reflect visceral smooth muscle
dysfunction in SMDS.
phenotype_term:
preferred_term: Intestinal hypoperistalsis
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Smooth muscle dysfunction syndrome (SMDS, MIM# 613834) presents with a
recognizable pattern of complications, including congenital mydriasis,
patent ductus arteriosus (PDA), pulmonary arterial hypertension, aortic and
other arterial aneurysms, moyamoya-like cerebrovascular disease,
intestinal hypoperistalsis and malrotation, and hypotonic bladder1.
explanation: >-
This directly supports intestinal hypoperistalsis and malrotation as
nonvascular smooth muscle-dependent manifestations.
- name: Seizures
category: Neurologic
description: >-
Seizures occur in a subset of patients with SMDS-associated cerebrovascular
disease and structural brain abnormalities.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients had cerebrovascular disease characterized by small vessel disease
(hyperintense periventricular white matter lesions; 95%), intracranial
artery stenosis (77%), ischemic strokes (27%), and seizures (18%).
explanation: >-
This cohort directly quantifies seizures among cerebrovascular features.
- name: Periventricular white matter hyperintensities
category: Neurologic
description: >-
Brain MRI commonly shows T2-weighted hyperintense periventricular white
matter changes.
phenotype_term:
preferred_term: Hyperintensity of cerebral white matter on MRI
term:
id: HP:0030890
label: Hyperintensity of cerebral white matter on MRI
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The majority of patients (95%) had T2-weighted hyperintense
periventricular white matter changes on brain MRI.
explanation: >-
This supports the common MRI white-matter phenotype in SMDS.
biochemical: []
environmental: []
treatments:
- name: Lifelong multidisciplinary surveillance and organ-directed management
description: >-
Management is surveillance- and organ-directed, including genetic diagnosis,
aortic and cerebrovascular imaging, ophthalmologic evaluation, pulmonary and
cardiac care, and timely surgical or medical treatment of complications.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ACTA2 Arg179 alterations cause a chronic condition presenting in infancy
and requiring life-long surveillance and treatment.
explanation: >-
This directly supports lifelong surveillance and treatment as the central
management framework.
- reference: DOI:10.1186/s13023-019-1186-2
reference_title: >-
European reference network for rare vascular diseases (VASCERN) consensus
statement for the screening and management of patients with pathogenic
ACTA2 variants
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This consensus statement summarizes our recommendations on diagnosis,
monitoring, treatment, pregnancy, genetic counselling and testing in
patients withACTA2-related vasculopathy.
explanation: >-
This supports structured management and surveillance for ACTA2-related
vasculopathy.
- name: Aortic imaging surveillance
description: >-
The entire aorta should be imaged at diagnosis and followed longitudinally,
with cardiac MRI/MRA or echocardiography used when appropriate.
treatment_term:
preferred_term: magnetic resonance imaging procedure
term:
id: MAXO:0000424
label: magnetic resonance imaging procedure
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Follow-up imaging should be performed by echocardiography (if the root and
ascending aorta are adequately visualized) or cardiac MRI/MRA with
cardiac-gated sequences for the aortic root.
explanation: >-
This directly supports longitudinal aortic imaging surveillance.
- name: Elective aortic repair when indicated
description: >-
Elective repair is considered for high-risk thoracic or thoracoabdominal
aortic disease at lower diameters than many nonsyndromic aortopathies,
balancing cerebrovascular, pulmonary, and cardiac comorbidities.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
evidence:
- reference: PMID:29300374
reference_title: >-
Clinical history and management recommendations of the smooth muscle
dysfunction syndrome due to ACTA2 arginine 179 alterations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Given the poor outcomes, i.e. aortic rupture and sudden death, in SMDS
patients who had a thoracic aortic aneurysm greater than 45 mm or a
descending aortic dissection, elective open or endovascular aortic repair
should be considered in these situations when possible.
explanation: >-
This supports elective open or endovascular aortic repair in selected
high-risk SMDS aortic disease.
clinical_trials:
- name: NCT06280482
phase: PHASE_I
status: RECRUITING
description: >-
Phase 1 interventional trial testing oral nicotinamide riboside in SMDS,
with aortic metabolism, NAD+/NR levels, aortic measurements, safety, and
tolerability as study outcomes.
target_phenotypes:
- preferred_term: Ischemic stroke
term:
id: HP:0002140
label: Ischemic stroke
- preferred_term: Aortic aneurysm and dissection
evidence:
- reference: clinicaltrials:NCT06280482
reference_title: >-
Nicotinamide Riboside (NR) to Treat Moyamoya-like Cerebrovascular Disease
in Smooth Muscle Dysfunction Syndrome (SMDS)
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The purpose of this study is to determine whether SMDS patients treated
with NR at the proposed dose exhibit decreased glucose uptake in the
aorta, to determine if NR treatment results in measurable changes of blood
NAD+ and NR levels, to determine if aortic measurements are stable after
treatment with NR and to evaluate the safety and tolerability of NR in
SMDS patients.
explanation: >-
This ClinicalTrials.gov summary supports NCT06280482 as an
SMDS-specific interventional trial.
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Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on Multisystemic smooth muscle dysfunction syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
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Multisystemic smooth muscle dysfunction syndrome (MSMDS; also called smooth muscle dysfunction syndrome, SMDS) is an ultrarare, typically de novo, autosomal-dominant smooth muscle disorder classically caused by heterozygous missense substitution of ACTA2 arginine 179 (ACTA2 p.Arg179*) and characterized by congenital mydriasis plus early congenital heart disease (patent ductus arteriosus/aortopulmonary window), early-onset aortic disease, and a distinctive cerebral arteriopathy with small-vessel white-matter injury and large-artery stenosis/occlusion. Quantitative natural-history data from a 33-patient cohort demonstrate very high burdens of brain MRI abnormalities (e.g., 95% white-matter lesions) and early aortic events (36% by a median age of 14; 100% penetrance of aortic disease by age 25), underpinning recommendations for aggressive, multidisciplinary surveillance. (regalado2018clinicalhistoryand pages 1-2)
A major recent development is that an MSMDS phenotype can also be produced by a de novo noncoding MIR145 (miR-145-5p seed) variant, functionally converging on loss of smooth muscle contractile/cytoskeletal programs. (cardenas2023aseedsequence pages 1-3)
MSMDS is a multisystem disorder of smooth muscle-dependent organs, classically due to heterozygous ACTA2 Arg179 substitutions. It features ocular (congenital mydriasis), cardiovascular (PDA/AP window, thoracic aortic aneurysm/dissection), cerebrovascular disease (moyamoya-like/steno-occlusive arteriopathy plus small-vessel white matter lesions), pulmonary arterial hypertension, and additional smooth muscle organ dysfunction (e.g., bladder hypotonia, gut hypoperistalsis). (kaw2022expandingacta2genotypes pages 1-2, regalado2018clinicalhistoryand pages 1-2)
Evidence in this report is derived from: - Aggregated cohort natural history and management recommendations (human clinical; multicenter series). (regalado2018clinicalhistoryand pages 1-2, regalado2018clinicalhistoryand pages 8-9) - Case reports/literature reviews (human clinical). (yang2021acta2mutationis pages 5-6, li2025casereportmultisystemic pages 2-4, logeswaran2017twopatientswith pages 3-4) - Consensus management guidance for ACTA2 vasculopathy (expert consensus). (laar2019europeanreferencenetwork pages 2-4, laar2019europeanreferencenetwork pages 4-6, laar2019europeanreferencenetwork pages 6-7) - Mechanistic cellular/genomic studies (iPSC/SMC models; human tissue single-cell; mouse models). (kwartler2023nuclearsmoothmuscle pages 7-11, kwartler2023nuclearsmoothmuscle pages 42-46, milewicz2023augmentingmitochondrialrespiration pages 6-9) - ClinicalTrials.gov trial registry entries (real-world implementation and translational research). (NCT06280482 chunk 1)
Primary genetic cause (classic MSMDS/SMDS): heterozygous missense variants in ACTA2 that alter arginine 179 (e.g., p.Arg179His) affecting smooth muscle α-actin. (regalado2018clinicalhistoryand pages 1-2, yang2021acta2mutationis pages 5-6)
Expanded genetic cause (2023): a de novo MIR145 seed-sequence variant (miR-145-5p) was reported to cause an MSMDS phenotype, expanding the locus beyond ACTA2 while converging on smooth muscle contractile/cytoskeletal regulation. (cardenas2023aseedsequence pages 1-3)
Environmental risk factors: none established in the retrieved sources; MSMDS is largely monogenic in classic cases. (regalado2018clinicalhistoryand pages 1-2, cardenas2023aseedsequence pages 1-3)
No protective genetic or environmental factors were identified in the retrieved sources.
Not established in the retrieved sources.
A high-quality 33-patient natural-history study provides cohort-level frequencies for major findings and outcomes. (regalado2018clinicalhistoryand pages 1-2)
Key quantitative features are summarized in the artifact table below.
| Category | Finding | Quantitative detail | Notes | Citation |
|---|---|---|---|---|
| Disease concept | Multisystemic/smooth muscle dysfunction syndrome (MSMDS/SMDS) due to ACTA2 Arg179 alterations | Cohort n=33; median age 12 years in major natural-history series | Severe childhood-onset multisystem smooth-muscle disorder | (regalado2018clinicalhistoryand pages 1-2) |
| Inheritance | Usually autosomal dominant, but most classic Arg179 cases are de novo heterozygous | “Most”/nearly all reported classic cases de novo | Family transmission and somatic mosaicism have also been reported for non-Arg179 overlap phenotypes | (kaw2022expandingacta2genotypes pages 1-2, regalado2018clinicalhistoryand pages 1-2) |
| Typical causal variants | ACTA2 Arg179 substitutions | Commonly p.Arg179His; also p.Arg179Cys, p.Arg179Leu, p.Arg179Ser, p.Arg179Gly | Arg179 substitutions define the classic severe syndrome; other ACTA2 missense variants can overlap with MSMDS | (kaw2022expandingacta2genotypes pages 1-2, yang2021acta2mutationis pages 5-6, regalado2018clinicalhistoryand pages 1-2) |
| Core ocular feature | Congenital mydriasis / fixed dilated pupils | 100% in 33-patient series; 37/37 in literature review | Often present at birth; strong diagnostic clue | (regalado2018clinicalhistoryand pages 1-2, yang2021acta2mutationis pages 5-6) |
| Congenital heart disease | Patent ductus arteriosus (PDA) or aortopulmonary window | PDA in 35/37 (94.6%) in review; infancy presentation typical in cohort | Hemodynamically important PDA/AP window is a hallmark neonatal feature | (yang2021acta2mutationis pages 5-6, regalado2018clinicalhistoryand pages 1-2) |
| Cerebral small-vessel disease | Periventricular white-matter lesions | 95% | MRI hallmark of ACTA2 Arg179 syndrome | (regalado2018clinicalhistoryand pages 1-2) |
| Cerebrovascular large-artery disease | Intracranial artery stenosis | 77% | Moyamoya-like arteriopathy/arterial straightening-stenosis pattern | (regalado2018clinicalhistoryand pages 1-2) |
| Ischemic complications | Ischemic stroke | 27% in 33-patient cohort; seizures in 4/37 (10.8%) in literature review | Neurologic morbidity begins in childhood in many patients | (regalado2018clinicalhistoryand pages 1-2, yang2021acta2mutationis pages 5-6) |
| Seizures | Epileptic seizures | 18% in 33-patient cohort | Likely secondary to cerebrovascular and white-matter injury | (regalado2018clinicalhistoryand pages 1-2, yang2021acta2mutationis pages 5-6) |
| Aortic disease | Thoracic aortic aneurysm repair or dissection (“aortic event”) | 12/33 (36%) at median age 14 years | Aortic disease reached full penetrance by age 25 years in the cohort | (regalado2018clinicalhistoryand pages 1-2) |
| Peripheral vasculopathy | Axillary artery aneurysm with thromboembolism | 3/33 (9%) | Illustrates systemic arterial involvement beyond the aorta/cerebral circulation | (regalado2018clinicalhistoryand pages 1-2) |
| Mortality | Deaths from aortic, pulmonary, stroke, or unknown causes | 9/33; age at death 0.5–32 years | Confirms high early-life morbidity and mortality | (regalado2018clinicalhistoryand pages 1-2) |
| Other smooth-muscle organ involvement | Pulmonary hypertension, hypotonic bladder, gut hypoperistalsis/megacystis/hydronephrosis | Common but variably reported | Multisystem involvement reflects generalized smooth-muscle dysfunction | (kaw2022expandingacta2genotypes pages 1-2, regalado2018clinicalhistoryand pages 1-2) |
| Epidemiology | Reported global cases | ~90 cases reported by Apr 2024; 85 with genotype described | Ultra-rare disorder; published cases concentrated in Europe/USA | (li2025casereportmultisystemic pages 2-4) |
| Sex distribution | Female share among reported cases | 66.7% | Based on compiled case reports, not population-based registry data | (li2025casereportmultisystemic pages 2-4) |
| 2023–2024 development | Key finding | Quantitative / study detail | Why it matters | Citation |
|---|---|---|---|---|
| 2023: MIR145 noncoding cause | De novo MIR145 seed-sequence variant (NR_029686.1:n.18C>A) caused an MSMDS phenotype | Variant absent from gnomAD; CADD 20.9 | First reported monogenic vascular disease causing MSMDS from a noncoding-gene mutation; links miR-145 to actin-cytoskeleton/SMC contractile program | (cardenas2023aseedsequence pages 1-3) |
| 2023: mechanistic insight | Mutant/knockdown miR-145 reduced transgelin, calponin, and α-SMA and disrupted stress-fiber induction | RNA-seq enriched for actin-cytoskeleton regulation | Supports a shared downstream contractile-cytoskeletal mechanism with ACTA2-related disease | (cardenas2023aseedsequence pages 1-3) |
| 2024: WES in moyamoya syndrome | WES identified MSMDS among genetic causes of moyamoya syndrome and highlighted modifier architecture | 13 patients with diverse genetic disorders; 2 had MSMDS | Reinforces value of exome sequencing in unexplained moyamoya-like disease and suggests modifier genes may shape cerebrovascular severity | (laar2019europeanreferencenetwork pages 1-2) |
| 2024–ongoing clinical translation | Nicotinamide riboside (NR) trial for moyamoya-like cerebrovascular disease in SMDS | NCT06280482; Phase 1; recruiting; target enrollment 15 | First interventional trial directly targeting a mechanistic pathway emerging from ACTA2 smooth-muscle metabolism studies | (laar2019europeanreferencenetwork pages 1-2) |
Table: This table compiles the main quantitative clinical features of ACTA2 Arg179-related MSMDS/SMDS and highlights notable 2023–2024 developments, including the MIR145 discovery, WES evidence in moyamoya syndrome, and the ongoing nicotinamide riboside trial.
Below are commonly reported phenotypes with suggested HPO terms and typical temporal patterns:
Ocular - Congenital mydriasis / fixed dilated pupils (present at birth; highly penetrant). HPO: HP:0007726 (Mydriasis); also consider iris anomalies. (regalado2018clinicalhistoryand pages 1-2, yang2021acta2mutationis pages 5-6)
Cardiovascular / great vessels - Patent ductus arteriosus (often infancy). HPO: HP:0001643 (Patent ductus arteriosus). (regalado2018clinicalhistoryand pages 1-2, yang2021acta2mutationis pages 5-6) - Aortopulmonary window (reported in cohort abstract; infancy presentation). HPO: HP:0004940 (Aortopulmonary window). (regalado2018clinicalhistoryand pages 1-2) - Thoracic aortic aneurysm and/or dissection; early aortic events. HPO: HP:0002647 (Aortic aneurysm); HP:0002648 (Aortic dissection). (regalado2018clinicalhistoryand pages 1-2, regalado2018clinicalhistoryand pages 8-9)
Cerebrovascular / neurologic - White matter lesions/leukoencephalopathy on MRI (very common in Arg179 cohort). HPO: HP:0006975 (White matter abnormalities). (regalado2018clinicalhistoryand pages 1-2) - Intracranial artery stenosis / moyamoya-like arteriopathy; distinctive “straight” arteries and absent basal collaterals. HPO: HP:0002638 (Cerebral artery stenosis); HP:0002138 (Moyamoya disease) (note: phenotype overlaps but is distinguishable). (munot2012anoveldistinctive pages 1-2, munot2012anoveldistinctive pages 4-4) - Ischemic stroke. HPO: HP:0001297 (Stroke). (regalado2018clinicalhistoryand pages 1-2) - Seizures. HPO: HP:0001250 (Seizures). (regalado2018clinicalhistoryand pages 1-2, yang2021acta2mutationis pages 5-6)
Pulmonary - Pulmonary arterial hypertension. HPO: HP:0002092 (Pulmonary hypertension). (kaw2022expandingacta2genotypes pages 1-2, yang2021acta2mutationis pages 5-6) - Interstitial lung disease (rare; ~13.3% in a 2024 compilation) with infantile presentation described. HPO: HP:0006530 (Interstitial lung disease). (li2025casereportmultisystemic pages 2-4)
Gastrointestinal / genitourinary smooth muscle dysfunction - Hypotonic bladder / megacystis / hydronephrosis. HPO: HP:0000017 (Hydronephrosis); HP:0000028 (Cryptorchidism) may be relevant for male reproductive issues noted in counseling. (kaw2022expandingacta2genotypes pages 1-2, regalado2018clinicalhistoryand pages 8-9) - Gut hypoperistalsis/dysmotility. HPO: HP:0002579 (Intestinal pseudo-obstruction) and/or HP:0002028 (Abdominal pain) depending on clinical manifestation. (kaw2022expandingacta2genotypes pages 1-2, regalado2018clinicalhistoryand pages 1-2)
Direct standardized QoL metrics (e.g., EQ-5D, SF-36) were not present in retrieved sources. However, the multisystem nature and early cerebrovascular/aortic morbidity (strokes, seizures, aneurysm repair) imply substantial functional impact and need for multidisciplinary support. (regalado2018clinicalhistoryand pages 1-2, regalado2018clinicalhistoryand pages 8-9)
ACTA2 - c.536G>A (p.Arg179His; “R179H”): recurrent; common in literature review; associated with broad MSMDS phenotype including seizures. (yang2021acta2mutationis pages 5-6) - Other Arg179 substitutions (e.g., Arg179Cys/Leu/Ser/Gly) are described as causal for the severe syndrome or classic features. (yang2021acta2mutationis pages 5-6, kaw2022expandingacta2genotypes pages 1-2)
MIR145 - NR_029686.1:n.18C>A (seed sequence nucleotide 3; de novo; absent from gnomAD; CADD 20.9). (cardenas2023aseedsequence pages 1-3)
Variant classification (ACMG/ClinVar), allele frequencies (beyond “absent from gnomAD” for MIR145), and HGNC IDs were not fully extractable from the retrieved texts and are therefore flagged as not retrieved.
Classic ACTA2 Arg179 MSMDS/SMDS is autosomal dominant with a high proportion of de novo events in reported cohorts. (regalado2018clinicalhistoryand pages 1-2)
A 2024 exome-sequencing study of moyamoya syndrome (secondary moyamoya) identified multiple primary diagnoses including MSMDS and discussed modifier architecture (e.g., RNF213/MRVI1 in other syndromes; potential enrichment of rare variants in other vascular genes), supporting a broader concept that cerebrovascular severity can be modified by additional rare variants. (laar2019europeanreferencenetwork pages 1-2)
ACTA2 Arg179 variants are associated with altered chromatin states in smooth muscle cells, including altered chromatin accessibility and increased H3K27me3 at smooth muscle loci in ACTA2 R179C SMCs. (kwartler2023nuclearsmoothmuscle pages 24-28)
No specific environmental, lifestyle, or infectious triggers have been established for MSMDS in the retrieved sources. Disease manifestations appear primarily driven by the causal genetic alteration and downstream smooth muscle dysfunction. (regalado2018clinicalhistoryand pages 1-2, cardenas2023aseedsequence pages 1-3)
Upstream trigger: ACTA2 Arg179 (or MIR145 seed) pathogenic variation → impaired smooth muscle cell (SMC) differentiation/contractile program and increased SMC plasticity. (kwartler2023nuclearsmoothmuscle pages 7-11, cardenas2023aseedsequence pages 1-3)
Intermediate cellular consequences: SMCs exhibit reduced expression of contractile proteins and increased proliferative/migratory behavior (“synthetic”/immature phenotype), leading to: - Occlusive lesions and steno-occlusive arteriopathy in cerebral vessels (moyamoya-like pattern). (munot2012anoveldistinctive pages 1-2, munot2012anoveldistinctive pages 7-8) - Aneurysm/dissection predisposition in elastic arteries including thoracic aorta (early aortic events). (regalado2018clinicalhistoryand pages 1-2) - Multiorgan smooth muscle dysfunction affecting iris sphincter, ductus arteriosus closure, pulmonary vascular tone, gut motility, and bladder function. (kaw2022expandingacta2genotypes pages 1-2, regalado2018clinicalhistoryand pages 1-2)
Clinical manifestations: congenital mydriasis and PDA in infancy; progressive vasculopathy (aortic aneurysm/dissection; cerebral stenosis and strokes), pulmonary hypertension, and visceral dysmotility. (regalado2018clinicalhistoryand pages 1-2, yang2021acta2mutationis pages 5-6)
(A) Nuclear ACTA2 function and chromatin remodeling (2023) A 2023 Nature Cardiovascular Research study provides a mechanism connecting ACTA2 Arg179 variants to impaired SMC differentiation via loss of nuclear αSMA interactions with chromatin remodelers and promoters of SMC contractile genes. Key statements in the text include: “the absence of nuclear αSMA in patients with ACTA2 R179 mutations leads to global defects in SMC differentiation” and evidence that nuclear αSMA co-occupies promoters (e.g., Cnn1, Myh11, Tagln) with INO80/BAF remodeling complexes. (kwartler2023nuclearsmoothmuscle pages 7-11)
(B) MIR145 seed-sequence variant as a convergent upstream regulator (2023) The 2023 JCI report shows a de novo MIR145 seed variant producing an MSMDS phenotype and functionally reducing cytoskeletal/contractile proteins (including α-SMA), with RNA-seq enrichment for “regulation of actin cytoskeleton,” strengthening the hypothesis that dysregulation of the actin cytoskeleton and SMC contractile differentiation is central and potentially targetable. (cardenas2023aseedsequence pages 1-3)
(C) Metabolic modulation (OXPHOS) and nicotinamide riboside (NR) translational path (2023–2024) A 2023 preclinical study reports that Acta2R179C/+ SMCs exhibit immature features and that NR (a NAD+ precursor) increases oxygen consumption and reduces glycolytic flux, increases differentiation markers, decreases migration, and attenuates strokes and moyamoya-like occlusive lesions after carotid injury in mutant mice. (milewicz2023augmentingmitochondrialrespiration pages 6-9)
This preclinical work has translated into a 2024 Phase 1 trial (NCT06280482) in patients with ACTA2 arginine-179 SMDS to evaluate safety/tolerability and multiple physiologic endpoints (e.g., cerebral oxygenation/perfusion, cognition, autonomic symptoms) during 60 days of oral NR. (NCT06280482 chunk 1)
GO biological process (examples): - Smooth muscle cell differentiation; regulation of actin cytoskeleton organization; cell migration; chromatin remodeling; vascular remodeling. (kwartler2023nuclearsmoothmuscle pages 7-11, cardenas2023aseedsequence pages 1-3, milewicz2023augmentingmitochondrialrespiration pages 6-9)
Cell types (CL suggestions): - Vascular smooth muscle cell (primary). (kwartler2023nuclearsmoothmuscle pages 7-11)
Anatomical systems (UBERON suggestions): - Aorta, cerebral arteries, iris sphincter muscle, ductus arteriosus, pulmonary artery, urinary bladder, intestine. (regalado2018clinicalhistoryand pages 1-2, munot2012anoveldistinctive pages 1-2)
Primary affected structures include: - Cardiovascular: ductus arteriosus, thoracic aorta, systemic arteries (including peripheral aneurysms). (regalado2018clinicalhistoryand pages 1-2) - CNS vasculature and brain: terminal internal carotids and intracranial arteries with distinctive straight course and stenosis/occlusion; white matter injury and infarcts. (munot2012anoveldistinctive pages 1-2, munot2012anoveldistinctive pages 4-4) - Eye: iris sphincter/pupil control. (regalado2018clinicalhistoryand pages 1-2) - Pulmonary vasculature/lung: pulmonary hypertension; rare ILD. (yang2021acta2mutationis pages 5-6, li2025casereportmultisystemic pages 2-4) - Visceral smooth muscle: bladder and gastrointestinal tract. (kaw2022expandingacta2genotypes pages 1-2, regalado2018clinicalhistoryand pages 1-2)
MSMDS is ultrarare and largely described through case reports/series and a small number of cohorts. - A 2024 compilation (as summarized in a 2025 case report) reported ~90 cases globally by April 2024, with ~80% of reports from Europe/USA and relatively few cases reported in East Asia. (li2025casereportmultisystemic pages 2-4)
Penetrance/expressivity are incompletely quantified across the broader literature; however, in the Arg179 natural-history cohort, congenital mydriasis was universal and aortic disease was fully penetrant by age 25. (regalado2018clinicalhistoryand pages 1-2)
Key diagnostic clues include the combination of congenital fixed dilated pupils (congenital mydriasis) and PDA/AP window with early neurovascular findings. (regalado2018clinicalhistoryand pages 1-2, munot2012anoveldistinctive pages 1-2)
In a 33-patient Arg179 cohort, 9 deaths occurred between ages 0.5 and 32 years, attributed to aortic, pulmonary, stroke complications, or unknown causes—indicating meaningful early mortality risk. (regalado2018clinicalhistoryand pages 1-2)
There is no established disease-modifying therapy in current clinical practice for MSMDS. Management is multidisciplinary and focused on prevention/mitigation of life-threatening vascular complications plus symptomatic care for organ-specific dysfunction. (regalado2018clinicalhistoryand pages 1-2, yang2021acta2mutationis pages 5-6)
ACTA2 vasculopathy consensus (VASCERN, 2019) provides structured imaging/monitoring recommendations for ACTA2-related vasculopathy (not MSMDS-specific) including: - At diagnosis: 2D transthoracic echo plus complete vascular imaging (neck to pelvis) by CTA/MRA from age 18; yearly 2D-TTE in children from diagnosis; adults complete vascular imaging every 2–5 years. (laar2019europeanreferencenetwork pages 2-4) - Blood pressure control (≤130/80 mmHg per ESC guidance). (laar2019europeanreferencenetwork pages 4-6) - β-blockers are commonly used; VASCERN notes limited direct pediatric evidence but advises offering therapy from age 4 years and emphasizes individualized monitoring programs. (laar2019europeanreferencenetwork pages 6-7) - Pregnancy counseling: preconception imaging of the entire aorta; maternal 2D-TTE monitoring every 4–12 weeks during pregnancy and at 6 months postpartum; avoid ARBs in pregnancy; consider prophylactic surgery for women with aortic root ≥45 mm and advise against pregnancy after prior dissection. (laar2019europeanreferencenetwork pages 4-6)
MSMDS/Arg179 SMDS-specific management recommendations (2018 cohort) include: - Consider elective aortic root repair around 45 mm, prefer valve-sparing when feasible; close monitoring of descending/thoracoabdominal segments due to potentially rapid enlargement. (regalado2018clinicalhistoryand pages 8-9) - Baseline brain MRI and head/neck MRA (avoid CT when possible) and ongoing monitoring; consider aspirin in asymptomatic cerebral vasculopathy with pediatric precautions; standard seizure management. (regalado2018clinicalhistoryand pages 8-9)
MAXO suggestions (examples): - Aortic imaging surveillance; echocardiography; magnetic resonance angiography; prophylactic aortic surgery; antihypertensive therapy; antiplatelet therapy (selected patients); genetic counseling; cascade testing; multidisciplinary care coordination.
Nicotinamide riboside (NR) metabolic therapy (translational): - Trial: Nicotinamide Riboside (NR) to Treat Moyamoya-like Cerebrovascular Disease in Smooth Muscle Dysfunction Syndrome (SMDS), ClinicalTrials.gov NCT06280482, first posted 2024-02-28, actual start 2024-03-06; Phase 1; oral weight-based NR daily for 60 days; multiple endpoints including cerebral oxygenation/perfusion and aortic diameter. (NCT06280482 chunk 1) - URL: https://clinicaltrials.gov/study/NCT06280482 (registry URL based on NCT identifier; core protocol details extracted from trial record). (NCT06280482 chunk 1)
There is no primary prevention for de novo cases; prevention focuses on secondary/tertiary prevention of catastrophic events via early recognition, genetic confirmation, surveillance, and prophylactic/early intervention. - VASCERN emphasizes cascade testing and “proper genetic counselling involving psychosocial support.” (laar2019europeanreferencenetwork pages 6-7) - Pregnancy-related prevention includes preconception imaging, multidisciplinary counseling, and avoidance of teratogenic antihypertensives; postpartum surveillance is recommended. (laar2019europeanreferencenetwork pages 4-6)
Naturally occurring MSMDS in nonhuman species was not identified in the retrieved sources.
Mechanistic and translational work relies heavily on engineered cellular and mouse models: - Acta2R179C/+ mouse SMC models (preclinical): NR increased mitochondrial respiration and reduced glycolysis in mutant SMCs and attenuated moyamoya-like occlusive lesions and strokes after carotid injury. (milewicz2023augmentingmitochondrialrespiration pages 6-9) - iPSC-derived SMC differentiation models and human aortic scRNA-seq (2023): Arg179 mutations reduce nuclear αSMA interactions with chromatin remodeling machinery, causing global defects in differentiation and increased plasticity/proliferation/migration. (kwartler2023nuclearsmoothmuscle pages 7-11, kwartler2023nuclearsmoothmuscle pages 42-46)
The following table image (cropped from the primary 33-patient cohort publication) provides patient-by-patient clinical characteristics and ages at major events and can be used as primary visual evidence for natural-history data extraction. (regalado2018clinicalhistoryand media 32dd1498)
References
(regalado2018clinicalhistoryand pages 1-2): Ellen S. Regalado, Lauren Mellor-Crummey, Julie De Backer, Alan C. Braverman, Lesley Ades, Susan Benedict, Timothy J. Bradley, M.Elizabeth Brickner, Kathryn C. Chatfield, Anne Child, Cori Feist, Kathryn W. Holmes, Glen Iannucci, Birgit Lorenz, Paul Mark, Takayuki Morisaki, Hiroko Morisaki, Shaine A. Morris, Anna L. Mitchell, John R. Ostergaard, Julie Richer, Denver Sallee, Sherene Shalhub, Mustafa Tekin, Anthony Estrera, Patricia Musolino, Anji Yetman, Reed Pyeritz, and Dianna M. Milewicz. Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to acta2 arginine 179 alterations. Genetics in Medicine, 20:1206-1215, Oct 2018. URL: https://doi.org/10.1038/gim.2017.245, doi:10.1038/gim.2017.245. This article has 88 citations and is from a highest quality peer-reviewed journal.
(cardenas2023aseedsequence pages 1-3): Christian Lacks Lino Cardenas, Lauren C. Briere, David A. Sweetser, Mark E. Lindsay, and Patricia L. Musolino. A seed sequence variant in mir-145-5p causes multisystem smooth muscle dysfunction syndrome. Journal of Clinical Investigation, Mar 2023. URL: https://doi.org/10.1172/jci166497, doi:10.1172/jci166497. This article has 4 citations and is from a highest quality peer-reviewed journal.
(kaw2022expandingacta2genotypes pages 1-2): Anita Kaw, Kaveeta Kaw, Ellen M. Hostetler, Ana Beleza‐Meireles, Adam Smith‐Collins, Catherine Armstrong, Ingrid Scurr, Timothy Cotts, Rajani Aatre, Michael J. Bamshad, Dawn Earl, Abraham Groner, Katherine Agre, Yehuda Raveh, Callie S. Kwartler, and Dianna M. Milewicz. Expanding acta2 genotypes with corresponding phenotypes overlapping with smooth muscle dysfunction syndrome. American Journal of Medical Genetics Part A, 188:2389-2396, May 2022. URL: https://doi.org/10.1002/ajmg.a.62775, doi:10.1002/ajmg.a.62775. This article has 22 citations.
(laar2019europeanreferencenetwork pages 2-4): Ingrid M. B. H. van de Laar, Eloisa Arbustini, Bart Loeys, Erik Björck, Lise Murphy, Maarten Groenink, Marlies Kempers, Janneke Timmermans, Jolien Roos-Hesselink, Kalman Benke, Guglielmina Pepe, Barbara Mulder, Zoltan Szabolcs, Gisela Teixidó-Turà, Leema Robert, Yaso Emmanuel, Arturo Evangelista, Alessandro Pini, Yskert von Kodolitsch, Guillaume Jondeau, and Julie De Backer. European reference network for rare vascular diseases (vascern) consensus statement for the screening and management of patients with pathogenic acta2 variants. Orphanet Journal of Rare Diseases, Nov 2019. URL: https://doi.org/10.1186/s13023-019-1186-2, doi:10.1186/s13023-019-1186-2. This article has 48 citations and is from a peer-reviewed journal.
(li2025casereportmultisystemic pages 2-4): Qianying Li, Lidan Cui, Jun Su, and Yuelin Shen. Case report: multisystemic smooth muscle dysfunction syndrome: a rare genetic cause of infantile interstitial lung disease. Frontiers in Pharmacology, Jan 2025. URL: https://doi.org/10.3389/fphar.2024.1510969, doi:10.3389/fphar.2024.1510969. This article has 1 citations.
(laar2019europeanreferencenetwork pages 1-2): Ingrid M. B. H. van de Laar, Eloisa Arbustini, Bart Loeys, Erik Björck, Lise Murphy, Maarten Groenink, Marlies Kempers, Janneke Timmermans, Jolien Roos-Hesselink, Kalman Benke, Guglielmina Pepe, Barbara Mulder, Zoltan Szabolcs, Gisela Teixidó-Turà, Leema Robert, Yaso Emmanuel, Arturo Evangelista, Alessandro Pini, Yskert von Kodolitsch, Guillaume Jondeau, and Julie De Backer. European reference network for rare vascular diseases (vascern) consensus statement for the screening and management of patients with pathogenic acta2 variants. Orphanet Journal of Rare Diseases, Nov 2019. URL: https://doi.org/10.1186/s13023-019-1186-2, doi:10.1186/s13023-019-1186-2. This article has 48 citations and is from a peer-reviewed journal.
(regalado2018clinicalhistoryand pages 8-9): Ellen S. Regalado, Lauren Mellor-Crummey, Julie De Backer, Alan C. Braverman, Lesley Ades, Susan Benedict, Timothy J. Bradley, M.Elizabeth Brickner, Kathryn C. Chatfield, Anne Child, Cori Feist, Kathryn W. Holmes, Glen Iannucci, Birgit Lorenz, Paul Mark, Takayuki Morisaki, Hiroko Morisaki, Shaine A. Morris, Anna L. Mitchell, John R. Ostergaard, Julie Richer, Denver Sallee, Sherene Shalhub, Mustafa Tekin, Anthony Estrera, Patricia Musolino, Anji Yetman, Reed Pyeritz, and Dianna M. Milewicz. Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to acta2 arginine 179 alterations. Genetics in Medicine, 20:1206-1215, Oct 2018. URL: https://doi.org/10.1038/gim.2017.245, doi:10.1038/gim.2017.245. This article has 88 citations and is from a highest quality peer-reviewed journal.
(yang2021acta2mutationis pages 5-6): Wen-Xian Yang, Hang-Hu Zhang, Jia-Ni Hu, Li Zhao, Yan-Yun Li, and Xiao-Li Shao. Acta2 mutation is responsible for multisystemic smooth muscle dysfunction syndrome with seizures: a case report and review of literature. World Journal of Clinical Cases, 9:8789-8796, Oct 2021. URL: https://doi.org/10.12998/wjcc.v9.i29.8789, doi:10.12998/wjcc.v9.i29.8789. This article has 10 citations.
(logeswaran2017twopatientswith pages 3-4): Thushiha Logeswaran, Christoph Friedburg, Karoline Hofmann, Hakan Akintuerk, Saskia Biskup, Michael Graef, Ali Rad, Axel Weber, Bernd A. Neubauer, Dietmar Schranz, Patrice Bouvagnet, Birgit Lorenz, and Andreas Hahn. Two patients with the heterozygous r189h mutation in acta2 and complex congenital heart defects expands the cardiac phenotype of multisystemic smooth muscle dysfunction syndrome. American Journal of Medical Genetics Part A, 173:959-965, Apr 2017. URL: https://doi.org/10.1002/ajmg.a.38102, doi:10.1002/ajmg.a.38102. This article has 18 citations.
(laar2019europeanreferencenetwork pages 4-6): Ingrid M. B. H. van de Laar, Eloisa Arbustini, Bart Loeys, Erik Björck, Lise Murphy, Maarten Groenink, Marlies Kempers, Janneke Timmermans, Jolien Roos-Hesselink, Kalman Benke, Guglielmina Pepe, Barbara Mulder, Zoltan Szabolcs, Gisela Teixidó-Turà, Leema Robert, Yaso Emmanuel, Arturo Evangelista, Alessandro Pini, Yskert von Kodolitsch, Guillaume Jondeau, and Julie De Backer. European reference network for rare vascular diseases (vascern) consensus statement for the screening and management of patients with pathogenic acta2 variants. Orphanet Journal of Rare Diseases, Nov 2019. URL: https://doi.org/10.1186/s13023-019-1186-2, doi:10.1186/s13023-019-1186-2. This article has 48 citations and is from a peer-reviewed journal.
(laar2019europeanreferencenetwork pages 6-7): Ingrid M. B. H. van de Laar, Eloisa Arbustini, Bart Loeys, Erik Björck, Lise Murphy, Maarten Groenink, Marlies Kempers, Janneke Timmermans, Jolien Roos-Hesselink, Kalman Benke, Guglielmina Pepe, Barbara Mulder, Zoltan Szabolcs, Gisela Teixidó-Turà, Leema Robert, Yaso Emmanuel, Arturo Evangelista, Alessandro Pini, Yskert von Kodolitsch, Guillaume Jondeau, and Julie De Backer. European reference network for rare vascular diseases (vascern) consensus statement for the screening and management of patients with pathogenic acta2 variants. Orphanet Journal of Rare Diseases, Nov 2019. URL: https://doi.org/10.1186/s13023-019-1186-2, doi:10.1186/s13023-019-1186-2. This article has 48 citations and is from a peer-reviewed journal.
(kwartler2023nuclearsmoothmuscle pages 7-11): Callie S. Kwartler, Albert J. Pedroza, Anita Kaw, Pujun Guan, Shuangtao Ma, Xue-yan Duan, Caroline Kernell, Charis Wang, Jose Emiliano Esparza Pinelo, Mikayla S. Borthwick Bowen, Jiyuan Chen, Yuan Zhong, Sanjay Sinha, Xuetong Shen, Michael P. Fischbein, and Dianna M. Milewicz. Nuclear smooth muscle α-actin participates in vascular smooth muscle cell differentiation. Nature Cardiovascular Research, 2:937-955, Sep 2023. URL: https://doi.org/10.1038/s44161-023-00337-4, doi:10.1038/s44161-023-00337-4. This article has 25 citations and is from a peer-reviewed journal.
(kwartler2023nuclearsmoothmuscle pages 42-46): Callie S. Kwartler, Albert J. Pedroza, Anita Kaw, Pujun Guan, Shuangtao Ma, Xue-yan Duan, Caroline Kernell, Charis Wang, Jose Emiliano Esparza Pinelo, Mikayla S. Borthwick Bowen, Jiyuan Chen, Yuan Zhong, Sanjay Sinha, Xuetong Shen, Michael P. Fischbein, and Dianna M. Milewicz. Nuclear smooth muscle α-actin participates in vascular smooth muscle cell differentiation. Nature Cardiovascular Research, 2:937-955, Sep 2023. URL: https://doi.org/10.1038/s44161-023-00337-4, doi:10.1038/s44161-023-00337-4. This article has 25 citations and is from a peer-reviewed journal.
(milewicz2023augmentingmitochondrialrespiration pages 6-9): D. Milewicz, Anita Kaw, Ting Wu, Zbigniew Starosolski, Zhen Zhou, Albert J. Pedroza, Suravi Majumder, Xue-yan Duan, Kaveeta Kaw, Jose Emiliano Esparza Pinelo, Michael P. Fischbein, Philip L. Lorenzi, Lin Tan, Sara Martinez, Iqbal Mahmud, L. Devkota, Heinrich Taegtmeyer, K. Ghaghada, Sean P Marrelli, and Callie S. Kwartler. Augmenting mitochondrial respiration in immature smooth muscle cells with an acta2 pathogenic variant mitigates moyamoya-like cerebrovascular disease. Research Square, Oct 2023. URL: https://doi.org/10.21203/rs.3.rs-3304679/v1, doi:10.21203/rs.3.rs-3304679/v1. This article has 2 citations.
(NCT06280482 chunk 1): Dianna M Milewicz. Nicotinamide Riboside (NR) to Treat Moyamoya-like Cerebrovascular Disease in Smooth Muscle Dysfunction Syndrome (SMDS). The University of Texas Health Science Center, Houston. 2024. ClinicalTrials.gov Identifier: NCT06280482
(munot2012anoveldistinctive pages 1-2): P. Munot, D. E. Saunders, D. M. Milewicz, E. S. Regalado, J. R. Ostergaard, K. P. Braun, T. Kerr, K. D. Lichtenbelt, S. Philip, C. Rittey, T. S. Jacques, T. C. Cox, and V. Ganesan. A novel distinctive cerebrovascular phenotype is associated with heterozygous arg179 acta2 mutations. Brain, 135:2506-2514, Jul 2012. URL: https://doi.org/10.1093/brain/aws172, doi:10.1093/brain/aws172. This article has 149 citations and is from a highest quality peer-reviewed journal.
(munot2012anoveldistinctive pages 4-4): P. Munot, D. E. Saunders, D. M. Milewicz, E. S. Regalado, J. R. Ostergaard, K. P. Braun, T. Kerr, K. D. Lichtenbelt, S. Philip, C. Rittey, T. S. Jacques, T. C. Cox, and V. Ganesan. A novel distinctive cerebrovascular phenotype is associated with heterozygous arg179 acta2 mutations. Brain, 135:2506-2514, Jul 2012. URL: https://doi.org/10.1093/brain/aws172, doi:10.1093/brain/aws172. This article has 149 citations and is from a highest quality peer-reviewed journal.
(kwartler2023nuclearsmoothmuscle pages 24-28): Callie S. Kwartler, Albert J. Pedroza, Anita Kaw, Pujun Guan, Shuangtao Ma, Xue-yan Duan, Caroline Kernell, Charis Wang, Jose Emiliano Esparza Pinelo, Mikayla S. Borthwick Bowen, Jiyuan Chen, Yuan Zhong, Sanjay Sinha, Xuetong Shen, Michael P. Fischbein, and Dianna M. Milewicz. Nuclear smooth muscle α-actin participates in vascular smooth muscle cell differentiation. Nature Cardiovascular Research, 2:937-955, Sep 2023. URL: https://doi.org/10.1038/s44161-023-00337-4, doi:10.1038/s44161-023-00337-4. This article has 25 citations and is from a peer-reviewed journal.
(munot2012anoveldistinctive pages 7-8): P. Munot, D. E. Saunders, D. M. Milewicz, E. S. Regalado, J. R. Ostergaard, K. P. Braun, T. Kerr, K. D. Lichtenbelt, S. Philip, C. Rittey, T. S. Jacques, T. C. Cox, and V. Ganesan. A novel distinctive cerebrovascular phenotype is associated with heterozygous arg179 acta2 mutations. Brain, 135:2506-2514, Jul 2012. URL: https://doi.org/10.1093/brain/aws172, doi:10.1093/brain/aws172. This article has 149 citations and is from a highest quality peer-reviewed journal.
(munot2012anoveldistinctive pages 6-7): P. Munot, D. E. Saunders, D. M. Milewicz, E. S. Regalado, J. R. Ostergaard, K. P. Braun, T. Kerr, K. D. Lichtenbelt, S. Philip, C. Rittey, T. S. Jacques, T. C. Cox, and V. Ganesan. A novel distinctive cerebrovascular phenotype is associated with heterozygous arg179 acta2 mutations. Brain, 135:2506-2514, Jul 2012. URL: https://doi.org/10.1093/brain/aws172, doi:10.1093/brain/aws172. This article has 149 citations and is from a highest quality peer-reviewed journal.
(regalado2018clinicalhistoryand media 32dd1498): Ellen S. Regalado, Lauren Mellor-Crummey, Julie De Backer, Alan C. Braverman, Lesley Ades, Susan Benedict, Timothy J. Bradley, M.Elizabeth Brickner, Kathryn C. Chatfield, Anne Child, Cori Feist, Kathryn W. Holmes, Glen Iannucci, Birgit Lorenz, Paul Mark, Takayuki Morisaki, Hiroko Morisaki, Shaine A. Morris, Anna L. Mitchell, John R. Ostergaard, Julie Richer, Denver Sallee, Sherene Shalhub, Mustafa Tekin, Anthony Estrera, Patricia Musolino, Anji Yetman, Reed Pyeritz, and Dianna M. Milewicz. Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to acta2 arginine 179 alterations. Genetics in Medicine, 20:1206-1215, Oct 2018. URL: https://doi.org/10.1038/gim.2017.245, doi:10.1038/gim.2017.245. This article has 88 citations and is from a highest quality peer-reviewed journal.