Monogenic basis of young-onset cryptogenic stroke: a multicenter study

Yuan, Wei-Zhuang; Shang, Liang; Tian, Dai-Shi; Wu, Shiwen; You, Yong; Tian, Chenglin; Wu, Bo; Li, Jun; Sun, Qinjian; Liu, Qing; Xu, Wei-Hai

doi:10.21037/atm-21-3843

Cited by 3 publications

(1 citation statement)

References 60 publications

(49 reference statements)

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“…In a study in which young adults with cryptogenic stroke were enrolled, cardiogenic disease genes were found (among which PRKAG2 was present), indicating that cryptogenic stroke could be caused by cardiogenic sources, even in the absence of structural heart abnormalities. The main mechanism for cerebral embolism in cardiogenic stroke is represented by dysrhythmias [18].…”

Section: Discussionmentioning

confidence: 99%

Intrafamilial Phenotypical Variability Linked to PRKAG2 Mutation—Family Case Report and Review of the Literature

Marcu

Vătăşescu

Onciul

et al. 2022

Life

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PRKAG2 syndrome (PS) is a rare, early-onset autosomal dominant phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM), that mainly presents with ventricular pre-excitation, cardiac hypertrophy and progressive conduction system degeneration. Its natural course, treatment and prognosis are significantly different from sarcomeric HCM. The clinical phenotypes of PRKAG2 syndrome often overlap with HCM due to sarcomere protein mutations, causing this condition to be frequently misdiagnosed. The syndrome is caused by mutations in the gene encoding for the γ2 regulatory subunit (PRKAG2) of 5′ Adenosine Monophosphate-Activated Protein Kinase (AMPK), an enzyme that modulates glucose uptake and glycolysis. PRKAG2 mutations (OMIM#602743) are responsible for structural changes of AMPK, leading to an impaired myocyte glucidic uptake, and finally causing storage cardiomyopathy. We describe the clinical and investigative findings in a family with several affected members (NM_016203.4:c.905G>A or p.(Arg302Gln), heterozygous), highlighting the various phenotypes even in the same family, and the utility of genetic testing in diagnosing PS. The particularity of this family case is represented by the fact that the index patient was diagnosed at age 16 with cardiac hypertrophy and ventricular pre-excitation while his mother, by age 42, only had Wolff–Parkinson–White syndrome, without left ventricle hypertrophy. Both the grandmother and the great-grandmother underwent pacemaker implantation at a young age because of conduction abnormalities. Making the distinction between PS and sarcomeric HCM is actionable, given the early-onset of the disease, the numerous life-threatening consequences and the high rate of conduction disorders. In patients who exhibit cardiac hypertrophy coexisting with ventricular pre-excitation, genetic screening for PRKAG2 mutations should be considered.

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Section: Discussionmentioning

confidence: 99%

Intrafamilial Phenotypical Variability Linked to PRKAG2 Mutation—Family Case Report and Review of the Literature

Marcu

Vătăşescu

Onciul

et al. 2022

Life

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Pathophysiology of cerebral small vessel disease: a journey through recent discoveries

Dupré,

Drieu,

Joutel

2024

Journal of Clinical Investigation

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Cerebral small vessel disease (cSVD) encompasses a heterogeneous group of age-related small vessel pathologies that affect multiple regions. Disease manifestations range from lesions incidentally detected on neuroimaging (white matter hyperintensities, small deep infarcts, microbleeds, or enlarged perivascular spaces) to severe disability and cognitive impairment. cSVD accounts for approximately 25% of ischemic strokes and the vast majority of spontaneous intracerebral hemorrhage and is also the most important vascular contributor to dementia. Despite its high prevalence and potentially long therapeutic window, there are still no mechanism-based treatments. Here, we provide an overview of the recent advances in this field. We summarize recent data highlighting the remarkable continuum between monogenic and multifactorial cSVDs involving NOTCH3 , HTRA1 , and COL4A1/A2 genes. Taking a vessel-centric view, we discuss possible cause-and-effect relationships between risk factors, structural and functional vessel changes, and disease manifestations, underscoring some major knowledge gaps. Although endothelial dysfunction is rightly considered a central feature of cSVD, the contributions of smooth muscle cells, pericytes, and other perivascular cells warrant continued investigation.

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When Paying Attention Pays Back: Missense Mutation c.1006G>A p. (Val336Ile) in PRKAG2 Gene Causing Left Ventricular Hypertrophy and Conduction Abnormalities in a Caucasian Patient: Case Report and Literature Review

Micaglio,

Tondi,

Benedetti

et al. 2024

IJMS

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PRKAG2 cardiomyopathy is a rare genetic disorder that manifests early in life with an autosomal dominant inheritance pattern. It harbors left ventricular hypertrophy (LVH), ventricular pre-excitation and progressively worsening conduction system defects. Its estimated prevalence among patients with LVH ranges from 0.23 to about 1%, but it is likely an underdiagnosed condition. We report the association of the PRKAG2 missense variant c.1006G>A p. (Val336Ile) with LVH, conduction abnormalities (short PR interval and incomplete right bundle branch bock) and early-onset arterial hypertension (AH) in a 44-year-old Caucasian patient. While cardiac magnetic resonance (CMR) showed a mild hypertrophic phenotype with maximal wall thickness of 17 mm in absence of tissue alterations, the electric phenotype was relevant including brady–tachy syndrome and recurrent syncope. The same variant has been detected in the patient’s sister and daughter, with LVH + early-onset AH and electrocardiographic (ECG) alterations + lipothymic episodes, respectively. Paying close attention to the coexistence of LVH and ECG alterations in the proband has been helpful in directing genetic tests to exclude primary cardiomyopathy. Hence, identifying the genetic basis in the patient allowed for familial screening as well as a proper follow-up and therapeutic management of the affected members. A review of the PRKAG2 cardiomyopathy literature is provided alongside the case report.

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Monogenic basis of young-onset cryptogenic stroke: a multicenter study

Cited by 3 publications

References 60 publications

Intrafamilial Phenotypical Variability Linked to PRKAG2 Mutation—Family Case Report and Review of the Literature

Intrafamilial Phenotypical Variability Linked to PRKAG2 Mutation—Family Case Report and Review of the Literature

Pathophysiology of cerebral small vessel disease: a journey through recent discoveries

When Paying Attention Pays Back: Missense Mutation c.1006G>A p. (Val336Ile) in PRKAG2 Gene Causing Left Ventricular Hypertrophy and Conduction Abnormalities in a Caucasian Patient: Case Report and Literature Review

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