Early Onset Parkinson Syndrome, Type A Aortic Aneurysm and Noncompaction Associated With the Novel Variant c.2225C>T in MYH11: A Case Report

Aortic aneurysm, left ventricular noncompaction, and early onset Parkinson syndrome have not been reported in association with MYH11 variants. The patient is a 44-year-old male who developed a progressive ascending aortic aneurysm at age 30, requiring aortic repair at the age of 40. In addition, he developed Parkinson syndrome at the age of 37. He also suffered from myopia, hypothyroidism, arterial hypertension, hyperlipidemia, pre-diabetes, hyperbilirubinemia, obstructive sleep apnea syndrome (OSAS), and muscle cramps. Echocardiography and cardiac MRI showed left ventricular noncompaction. Genetic analysis revealed the novel heterozygous variant c.2225C>T (p.Ala742Val) in MYH11. Family history was positive for arterial hypertension (mother), carcinoma (brother), and diabetes (sister, father). There was consanguinity between the parents. With appropriate treatment, Parkinson syndrome and cardiac anomalies remained stable and there were no complications due to noncompaction or aortic repair. Considering that embryonic vascularisation may be involved in the pathophysiology of noncompaction and that MYH11 is expressed in the myocardium, a causal relationship between the MYH11 variant and noncompaction is conceivable. In conclusion, this is the first case showing an aortic aneurysm associated with noncompaction and Parkinson syndrome in a carrier of the novel, heterozygous variant c.2225C>T in MYH11. Carriers of MYH11 variants should be prospectively and systematically screened for multisystem diseases as soon as the genetic defect is discovered in order not to delay any necessary treatment. First-degree relatives should be screened for the MYH11 variant of a family member to track the trait of inheritance and confirm its pathogenicity.


Case Presentation
The patient is a 44-year-old male with Parkinson syndrome diagnosed at the age of 37, and type A aortic aneurysm with bicuspid aortic valve first diagnosed at age 30 (transverse diameter 46 mm).At age 40 the aortic aneurysm required aortic repair after having reached an aortic transverse width of 80 mm.He had initially received a D2-receptor agonist for Parkinson syndrome, which had to be discontinued after developing a shopping addiction and replaced with L-DOPA and the mono-amino-oxidase (MAO)-B inhibitor rasagiline.Medical history was also positive for myopia, hypothyroidism, arterial hypertension, hyperlipidemia, prediabetes, hyperbilirubinemia, obstructive sleep apnea syndrome (OSAS), chronic gastritis, folic acid deficiency, vitamin-D deficiency, depression with panic attacks, right supraspinatus tendon impingement, traumatic brain injury at the age of 39 with mild cerebral bleeding from a car accident, and severe SARS-CoV-2 infection complicated by respiratory insufficiency and questionable myocarditis.He also reported occasional double vision and muscle cramps in his right calf and fingers.Family history was positive for arterial hypertension (mother), carcinoma (brother), and diabetes (sister, father).There was consanguinity between the parents.
The clinical neurological examination at the age of 44 revealed a flat affect, depression, stiff neck muscles, hypomimia, myopia, dysosmia, hypesthesia of digits 1-3 of the right upper extremity, resting tremor with right-sided predominance, which increased in posture and intention, mild right-sided ataxia, but pronounced static ataxia with tendency to fall.There was no cognitive impairment, hypoacusis or pupillary dysmotility.
Blood tests only showed a hemoglobin A1C (HbA1c) value of 6.1 (n, <5.7) and a bilirubin value of 2.27 mg/dl (n, 0.3-1.2mg/dl).Cerebral MRI revealed a small hemosiderin deposit in the right temporal region, a pineal cyst, and hypoplasia of the right vertebral artery, which was confirmed by carotid ultrasound.Nerve conduction studies of the right median and ulnar nerves revealed neither carpal tunnel syndrome nor ulnar sulcus syndrome.Transthoracic echocardiography revealed dilatation of the ascending aorta to 49 mm, focal aortic valve sclerosis, and hypertrabeculation, but was otherwise normal.Holter monitoring revealed no evidence of malignant ventricular arrhythmias (MVAs).Cardiac MRI showed left ventricular hypertrabeculation but normal cavity and wall dimensions and normal systolic function (Figure 1).There was no late gadolinium enhancement (LGE).Genetic testing of suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) using a panel revealed the heterozygous variant c.2225C>T (p.Ala742Val) in MYH11.A panel test on hereditary Parkinson syndrome (GBA, LRRK2, PARK2, PARK7, PINK1, SNCA, VPS35) was nonconclusive.His most recent medications included acetylsalicylic acid, atorvastatin, L-thyroxin, L-DOPA, rasagiline, amlodipine, candesartan, bisoprolol, and beclomethasone/formoterol.

Discussion
The patient is of interest for a novel heterozygous variant of MYH11, which manifested phenotypically as aortic aneurysm, Parkinson syndrome, and noncompaction.Whether the detected heterozygous MYH11 variant was actually responsible for the clinical manifestations remains speculative, but several previous studies reported that heterozygous MYH11 variants can be pathogenic (Table 1) [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].Except for aortic aneurysm [7,8], the other clinical manifestations of the index patient were not reported in association with MYH11 variants.A causal relationship between the MYH11 variant c.2225C>T and arterial hypertension and hyperlipidemia is unlikely, as they have not been reported in association with other MYH11 variants.However, since MYH11 is expressed in cardiomyocytes and neurons, it is conceivable that LVHT and Parkinson syndrome are causally linked.
LVHT is a morphologic abnormality of the left ventricular myocardium that is usually congenital and rarely acquired [9].It is associated with various genetic defects and chromosomal aberrations, but a causal relationship between all of these genetic defects and noncompaction has not yet been proven.The diagnosis of noncompaction is usually made using echocardiography or cardiac MRI according to different criteria if there is an increased number of trabeculae distal to the papillary muscles.In some cases, LGE can be documented when a contrast medium is applied.Noncompaction can be complicated by cardioembolism due to the formation of thrombi in the intertrabecular spaces, heart failure, and MVAs with sudden cardiac death.None of these possible complications were noted in the index patient.However, one argument for causality is that, in addition to aortic dissection, other cardiac anomalies such as patent ductus arteriosus [11] or bicuspid aortic valves (index case) have also been reported in MYH11 mutation carriers (Table 1) [13].
The cause of double vision and muscle cramps remains speculative, but there are various speculations to explain these symptoms.Skeletal muscle myopathy has previously been reported in carriers of MYH11 variants.Involvement of the cerebral arteries or the extremity arteries is also conceivable.However, the fact that no previous or acute stroke was detected on cerebral MRI and arterial pulses were easily palpable on clinical examination and his carotid ultrasound was normal argues against cerebrovascular or peripheral artery involvement.One argument against myopathy in the index case is that creatine kinase levels were within the normal range on every measurement.
A limitation of the study is that other family members were not screened for aortic aneurysm or noncompaction, the index patient's parents were not screened for the MYH11 variant, and the index patient was not tested for chromosomal abnormalities.Detection of the index patient's MYH11 variant in firstdegree relatives could provide a strong argument for causality between the variant and the phenotype.It would also have a strong impact on genetic counselling, particularly for relatives who wish to have children.

Conclusions
This case is the first to suggest that the novel, heterozygous variant c.2225C>T in MYH11 can manifest phenotypically not only with aortic aneurysm as previously reported but also with noncompaction and Parkinson syndrome.However, a causal connection between the novel MYH11 variant and heart and brain diseases still needs to be clarified.The case also supports the notion that both homozygous and heterozygous MYH11 variants can be pathogenic and cause multisystem diseases, primarily affecting the arteries of the heart and brain, the urinary tract, the biliary system, and the gastrointestinal tract.Future studies should focus on a possible causal relationship between the novel MYH11 variant and myocardial abnormalities, as well as between the MYH11 variant and cerebral disease, including Parkinson syndrome.Future studies should also examine the pathogenicity of the c.2225C>T variant.Carriers of MYH11 variants should be prospectively and systematically screened for multisystem diseases as soon as the genetic defect is discovered in order not to delay necessary treatment.First-degree relatives should be screened for the MYH11 variant of a family member to track the trait of inheritance and confirm its pathogenicity.

FIGURE 1 :
FIGURE 1: Cardiac MRI images Cardiac MRI showing extensive hypertrabeculation of the left ventricular myocardium distally to the papillary muscles.Panel A: Short-axis view (DYN_ sBTFE_5sl); Panel B: Short-axis view (Trufi Cine SAX); Panel C: Long-axis view (Trufi Cine 4CH); Panel D: Axial view (T1 Map SAX MOCO T1).After the application of the contrast medium, noLGE could be documented.