A case of premature and recurrent myocardial infarction associated with ABCA.1 gene mutationK Subramaniam1, LA Babu2, N Shah3
1 Department of Endocrinology, Silverline Hospital, Kochi, Kerala, India
2 Department of Medicine, Silverline Hospital, Kochi, Kerala, India
3 Neuberg Centre for Genomic Medicine, Ahmedabad, Gujarat, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.JPGM_70_20
Source of Support: None, Conflict of Interest: None
Keywords: Coronary artery disease, low HDL, Tangier disease
Premature coronary heart disease (CHD) has no well-defined criteria as there are several cutoffs proposed by different experts, the commonest being <55 years in men and <65 years in women. The general consensus is that this group of individuals have recognized or unrecognized familial trait of some abnormality (genetic, environmental, diet, etc.). We report such an individual with premature CHD with interesting features.
A 41-year-old man first met us in June 2011 for dose regulation of levothyroxine (he was on 75 μg), which he had been taking for previous 4 years. He was euthyroid then and was lost to follow up subsequently.
He returned in March 2019 for regulation of levothyroxine dose and on probing, he gave the history of having recurrent myocardial infarctions (MI) since 2012. He had 3 primary percutaneous interventions with stenting between 2013 and 2015 followed by coronary bypass grafting in 2016, followed again by stenting of the graft and angioplasty of right coronary artery stent in 2017. Since 2018, he has had 2 further MIs and was stented [Figure 1]. He was on optimum medical management by cardiologist. His latest echocardiogram revealed normal left ventricular function without wall motion abnormality.
His mother had MI at the age of 56 years and had expired due to heart failure. None of the extended family members had any cardiovascular event. His elder sister is healthy and his 2 adolescent children were healthy [Figure 2]. He weighed 71 kg with BMI of 23.2 kg/m2 and his waist circumference was 92 cm. His blood pressure was 112/72 mmHg. He had normal habitus without xanthoma, ectopia lentis, and organomegaly. The biochemical investigations are listed in [Table 1]. Arterial Doppler of both legs and carotids showed diffuse atherosclerotic changes. MR imaging of the brain showed few lacunar infarcts in both cerebral hemispheres.
Mildly elevated homocysteine level and mildly reduced Protein C level could not explain the phenotype and, therefore, clinical exome sequencing was done. It was performed covering specific genes involved in premature CHD, prothrombotic disorders, hereditary dyslipidemias, and homocysteine metabolism. A heterozygous missense variant of ABCA1 (ATP binding cassette transporter A1) gene, [NM_005502.3] c.103A>G (p.Ile35Val) along with another heterozygous nonsense mutation c.679C>T (p.Arg227Ter) were detected. These mutations were confirmed by Sanger sequencing [Figure 3].
After the report, his previous HDL reports were reviewed and it was noted that except for one instance where HDL was 5 mg/dL, other reports showed values between 15 and 38 mg/dL [Table 2]. Nerve conduction study, to rule out occult peripheral neuropathy, was normal; cornea was clear with slit-lamp examination and tonsils were normal on examination. Family screening with lipid profile and genetic testing was advised to look for segregation of variants but proband's only sister did not consent for genetic testing (her HDL was persistently >40 mg/dL tested several times). The proband and his wife decided to test their children by lipid parameters alone (in which HDL >40 mg/dL) and declined genetic testing in them.
“This is the story of an island, a family, and a strange malady” – this was the way Friedrickson et al. reported the first case report of Tangier disease (derives its etymology from the island where the first cases lived). The genetic abnormality is in ABCA1, which is membrane protein concerned with export of esterified cholesterol and phospholipids onto apo-A1 and promotes efflux of cholesterol from vascular endothelium and macrophages. Due to the loss of protein function, various tissues (especially reticuloendothelial tissues) become laden with cholesterol and hence manifest abnormality. Nascent apo-A1 undergoes rapid renal clearance, thereby reducing HDL and mild-to-moderate hypertriglyceridemia ensues due to increased hepatic VLDL secretion. The pathognomonic features of the disease include low to absent HDL levels, low to normal total cholesterol levels with normal triglycerides, and orange tonsils. Similar to several other genetic disorders, there have been several forme fruste manifestations of the disease. Presentations like isolated hepatosplenomegaly, thrombocytopenia, and premature cardiovascular disorders have been documented. In fact, there has been instance where the individual did not manifest any other abnormality (cornea was normal, no peripheral neuropathy, tonsils were allegedly normal) except low HDL and premature CAD or just a low HDL without clinical features. Our gentleman had such a rare presentation wherein other typical manifestations of Tangier disease were missing.
The predictive bioinformatics algorithms (DANN, LRT, MetaLR) showed pathogenic predictions for Ile35Val missense variant (reported as variant of unknown significance) and algorithm GERP showed it to be in a highly conserved region. The second variant p.Arg227Ter was also predicted to result in truncated protein with loss of function of protein. Hence, the patient had compound heterozygous variants one with a variant of unknown significance and another which was likely pathogenic.
CHD is known to occur in 25% of patients with Tangier disease and 22% had other vascular diseases. In a review article, Schmidt described heterozygous mutation of ABCA1 gene wherein there was increased genetic risk of CHD with normal HDL levels. The c.2328G>C (p.Lys776Asn) mutation heterozygous carriers were having mildly lower HDL levels with 2-3 times increased risk of CHD. Such increase risk was not explained completely by HDL levels alone and hence the non-HDL atherogenic role of ABCA1 was proposed. Since ABCA1 was identified as engulfment receptor on macrophages required for proper apoptosis, dysfunctional protein-induced impaired apoptosis results in inflammation and atherogenesis independent of HDL efflux.
Tangier disease presenting with atypical neurological symptoms and diagnosed with nerve biopsy has been reported from India., Several features appear unique in our patient—HDL levels being marginally low only once even when tested serially without treatment for several years, severe recurrent CHD with no neuropathy, and normal tonsils.
In conclusion, a forme fruste manifestation of Tangier disease with increased CHD risk and low-normal HDL levels without neurological and reticuloendothelial tissue involvement is rarely encountered in clinical practice. A thorough evaluation of individuals with severe and recurrent CHD, including genetic testing, is mandatory in order to know the exact etiology which would help us to tailor the treatment and screen at-risk close relatives.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]