Mapping of familial hypercholesterolemia and dyslipidemias basic management infrastructure in Pakistan: a cross-sectional study.

Background: Familial hypercholesterolemia (FH) is an autosomal inherited disorder characterised by elevated low-density lipoprotein cholesterol and premature cardiovascular events. Despite being declared as a public health priority, FH remains highly underdiagnosed, generally due to the lack of awareness and shortcomings in the available infrastructure, particularly in lower income countries. Methods: To map the existing infrastructure for the management of FH, a survey was conducted among 128 physicians (cardiologists, paediatricians, endocrinologists, and internal medicine specialists) from different regions of Pakistan. Findings: The respondents encountered a limited number of adults or children with diagnosed FH. A very small proportion of the population had access to free cholesterol and genetic testing even when indicated by a physician. In general, cascade screening of the relatives was not performed. Uniform diagnostic criteria for FH had not been established even within the same institution or province. The use of statins and ezetimibe in addition to lifestyle changes were the most common recommended treatment option for FH patients. The respondents considered lack of financial resources as a major barrier for the management of FH and stressed on taking relevant measures for a uniform FH screening programs around the country. Interpretation: National FH screening programmes are not in place worldwide hence FH is commonly undiagnosed, and many individuals are at a high risk for cardiovascular diseases. Timely screening of population for FH requires knowledge about FH among the clinicians and the availability of fundamental infrastructure coupled with sufficient financial resources. Funding: The authors confirm independence from the sponsor. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. FS received funding from Higher Education Commission, Pakistan (Grant 20-15760) and UG received grants from Slovenian Research Agency (J3-2536, P3-0343).

A homozygous variant in the GPIHBP1 gene in a child with severe hypertriglyceridemia and a systematic literature review.

Background: Due to nonspecific symptoms, rare dyslipidaemias are frequently misdiagnosed, overlooked, and undertreated, leading to increased risk for severe cardiovascular disease, pancreatitis and/or multiple organ failures before diagnosis. Better guidelines for the recognition and early diagnosis of rare dyslipidaemias are urgently required. Methods: Genomic DNA was isolated from blood samples of a Pakistani paediatric patient with hypertriglyceridemia, and from his parents and siblings. Next-generation sequencing (NGS) was performed, and an expanded dyslipidaemia panel was employed for genetic analysis. Results: The NGS revealed the presence of a homozygous missense pathogenic variant c.230G>A (NM_178172.6) in exon 3 of the GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1) gene resulting in amino acid change p.Cys77Tyr (NP_835466.2). The patient was 5.5 years old at the time of genetic diagnosis. The maximal total cholesterol and triglyceride levels were measured at the age of 10 months (850.7 mg/dl, 22.0 mmol/L and 5,137 mg/dl, 58.0 mmol/L, respectively). The patient had cholesterol deposits at the hard palate, eruptive xanthomas, lethargy, poor appetite, and mild splenomegaly. Both parents and sister were heterozygous for the familial variant in the GPIHBP1 gene. Moreover, in the systematic review, we present 62 patients with pathogenic variants in the GPIHBP1 gene and clinical findings, associated with hyperlipoproteinemia. Conclusion: In a child with severe hypertriglyceridemia, we identified a pathogenic variant in the GPIHBP1 gene causing hyperlipoproteinemia (type 1D). In cases of severe elevations of plasma cholesterol and/or triglycerides genetic testing for rare dyslipidaemias should be performed as soon as possible for optimal therapy and patient management.

Genetic and Clinical Characteristics of Patients With Homozygous and Compound Heterozygous Familial Hypercholesterolemia From Three Different Populations: Case Series.

Homozygous familial hypercholesterolemia (HoFH) and compound heterozygous familial hypercholesterolemia (cHeFH) are rare disorders generated by disease-causing variants in both alleles of the LDLR or other familial hypercholesterolemia (FH)-related genes. HoFH and cHeFH are characterized by severely elevated low-density lipoprotein-cholesterol (LDL-C), frequently leading to early cardiovascular disease. We investigated the genetic and clinical characteristics of HoFH and cHeFH patients from the Slovenian FH registry and/or those who were previously diagnosed or managed at our institution (Slovenian, Pakhtun and Albanian ethnicity), where genetic testing is not available. Our study includes seven patients. Their median age at the time of clinical diagnosis was 6.3 years (2.9-12.9 years); 2/7 were females. Two patients were diagnosed through the universal FH screening and five patients were diagnosed due to the presence of xanthomas. All the mutations are present in LDLR gene: 7 different genotypes for HoFH (p.Cys167Leu, p.Asp178Asn, p.Cys243Tyr, p.Gly549Asp, p.Cys27Trp, p.Ile585Thr and p.Val797Met) and p.Gly549Asp/p.Gln384Pro genotype for cHeFH patient. The median initial level of LDL-C was 17.0 mmol/L [655 mg/dL] (range 7.6-21.6 mmol/L). The HoFH/cHeFH patients are clinically and genetically very diverse. The clinical criteria (as Simon Broome criteria) might be applicable already in children to raise suspicion of FH but in some cases fail to distinguish heterozygous FH and HoFH/cHeFH patients. However, genetic testing is helpful in confirming the diagnosis, also for a prompt awareness, better compliance to treatment and family screening.