Homozygous autosomal recessive hypercholesterolaemia in a South Asian child presenting with multiple cutaneous xanthomata

2020 ◽  
pp. 000456322096175
Author(s):  
V Thadchanamoorthy ◽  
Kavinda Dayasiri ◽  
S I Majitha ◽  
Amanda J Hooper ◽  
John R Burnett
Keyword(s):  
Autosomal Recessive ◽  
Ldl Receptor ◽  
Good Effect ◽  
Atherosclerotic Cardiovascular Disease ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Cutaneous Lesions ◽  
Increased Risk ◽  
Autosomal Recessive Hypercholesterolemia ◽  
Coa Reductase

Autosomal recessive hypercholesterolemia (ARH; OMIM #603813) is an extremely rare disorder of lipid metabolism caused by loss-of-function variants in the LDL receptor adapter protein 1 ( LDLRAP1) gene, which is characterized by severe hypercholesterolaemia and an increased risk of premature atherosclerotic cardiovascular disease. We report the case of an 11-year-old girl who presented with multiple painless yellowish papules around her elbows and knees of two-year duration. She had been reviewed by several general practitioners, with some of the papules having been excised, but without a specific diagnosis being made. The child was referred to a paediatric service for further evaluation and treatment of the cutaneous lesions, which appeared xanthomatous in nature. A lipid profile showed severe hypercholesterolaemia. Next generation sequencing analysis of a monogenic hypercholesterolaemia gene panel revealed homozygosity for a pathogenic frameshift mutation, c.71dupG, p.Gly25Argfs*9 in LDLRAP1. Her parents and brother, who were asymptomatic, were screened and found to be heterozygous carriers of the LDLRAP1 variant. There was no known consanguinity in the family. She was commenced on the HMG-CoA reductase inhibitor, atorvastatin, to good effect, with a ∼76% reduction in LDL-cholesterol at a dose of 50 mg per day. At six-month follow-up, there had been no obvious regression of the xanthomata, but importantly, no enlargement of, or the development of new papular lesions, have occurred. In summary, we report a child who presented with multiple cutaneous xanthomata and was confirmed to have ARH by the presence of a homozygous novel pathogenic frameshift variant in LDLRAP1.

Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

2020 ◽  
Author(s):  
Yousef Binamer ◽  
Muzamil A. Chisti
Keyword(s):  
Autosomal Recessive ◽  
Common Mechanism ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Skin Atrophy ◽  
Whole Exome ◽  
Infancy And Childhood ◽  
Genetics And Genomics ◽  
New Feature ◽  
Generation Sequencing

AbstractKindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

Abstract 1921: Clinical Impact of Heterozygous Carrier of Autosomal Recessive Hypercholesterolemia on Asymptomatic Hyperlipidemic Patients: Evidence From Familial Gene Analysis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hayato Tada ◽  
Masa-aki Kawashiri ◽  
Tohru Noguchi ◽  
Chiaki Nakanishi ◽  
Masayuki Tsuchida ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Genetic Defect ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Serum Triglyceride ◽  
Adaptor Protein ◽  
Receptor Internalization ◽  
Single Mutation ◽  
Heterozygous Carrier ◽  
Autosomal Recessive Hypercholesterolemia

Autosomal recessive hypercholesterolemia (ARH) is an extremely rare genetic defect, and is recognized only around 50 cases in all over the world. The genetic cause of ARH is mutation in an adaptor protein involved in low-density lipoprotein (LDL) receptor internalization, which results in marked elevation of serum LDL cholesterol (LDL-C) and premature atherosclerosis. Therefore, few data exist regarding the clinical significance about the heterozygous carrier of ARH. We recently identified the second ARH patient (Ins C 599 ) in Japan and his some relatives who have the same single mutation (heterozygous). We identified 11 heterozygous ARH carriers (male=5, mean age=48.2) and 7 non-carriers (male=3, mean age=53.3) in the same family. In addition, we screened the same mutations in unrelated consecutive 500 hyperlipidemic patients (male=32, mean age=49.4) with mean LDL-C of 225.2±6.1mg/dl using PCR to determine its frequency and examined their clinical features. We identified an unrelated heterozygous ARH carrier and a non-carrier in the same family among unrelated to the original family. Serum LDL-C levels of heterozygous ARH carriers (mean=153.8±35.8mg/dl) were significantly higher than those of non-carriers (mean=108.2±41.4mg/dl, p<0.05). Serum triglyceride (151.9±110.7mg/dl vs 140.4±48.8mg/dl) and high-density lipoprotein cholesterol (57.4±11.0mg/dl vs 54.0±11.9mg/dl) levels were not different between them. Interestingly, heterozygous ARH carriers didn’t show any xanthomas including Achilles tendon (6.4±1.1mm vs 5.7±1.1mm) in contrast to FH, which is frequently associated with typical xanthoma. These results demonstrate that heterozygous ARH (Ins C 599 ) carriers show higher LDL-C levels compared with non-carrier family member without tendon xanthomas observed in FH. We suggest that heterozygous ARH (Ins C 599 ) carrier may explain a part of primary hypercholesterolemia.

Pathogenesis of atherosclerosis: lipid metabolism

2017 ◽  
Author(s):  
Olov Wiklund ◽  
Jan Borén
Keyword(s):  
Risk Factor ◽  
Current Data ◽  
Atherosclerotic Cardiovascular Disease ◽  
Causative Role ◽  
Receptor Ligands ◽  
Increased Risk ◽  
Low Hdl ◽  
Arterial Intima ◽  
Coa Reductase

Lipids are carried in plasma as microparticles, lipoproteins, composed of a core of hydrophobic lipids and a surface of amphipathic lipids. In addition, the particles carry proteins (i.e. apolipoproteins). The proteins have key functions in the metabolism as receptor ligands, enzymes or activators. Lipoproteins are classified based on density into: chylomicrons, VLDL, IDL, LDL, and HDL. Retention of apoB-containing lipoproteins (LDL, IDL, and VLDL) in the arterial intima is the initiating event in the development of atherosclerosis. Retention is mediated by binding of apoB to structural proteoglycans in the intima. Increased plasma concentration of apoB-containing lipoproteins is the main risk factor for atherosclerotic cardiovascular disease (CVD) and the causative role of LDL has been demonstrated in several studies. Lp(a) is a subclass of LDL and elevated Lp(a) is an independent risk-factor, primarily genetically mediated. Genetic data support that high Lp(a) causes atherosclerosis. Elevated triglycerides in plasma are associated with increased risk for CVD. Whether triglycerides directly induce atherogenesis is still unclear, but current data strongly support that remnant particles from triglyceride-rich lipoproteins are causal. HDL are lipoproteins that have been considered to be important for reversed cholesterol transport. Low HDL is a strong risk-factor for CVD. However, the causative role of HDL is debated and intervention studies to raise HDL have not been successful. Reduction of LDL is the main target for prevention and treatment, using drugs that inhibit the enzyme HMG-CoA reductase, i.e. statins. Other drugs for LDL reduction and to modify other lipoproteins may further reduce risk, and new therapeutic targets are explored.

scholarly journals Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1

2002 ◽  
Vol 110 (11) ◽  
pp. 1695-1702 ◽  
Author(s):  
Emily R. Eden ◽  
Dilipkumar D. Patel ◽  
Xi-Ming Sun ◽  
Jemima J. Burden ◽  
Michael Themis ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Ldl Receptor ◽  
Receptor Function ◽  
Autosomal Recessive Hypercholesterolemia ◽  
In Cells

scholarly journals ARH directs megalin to the endocytic recycling compartment to regulate its proteolysis and gene expression

2013 ◽  
Vol 202 (1) ◽  
pp. 113-127 ◽  
Author(s):  
Mehul Shah ◽  
Oscar Y. Baterina ◽  
Vanessa Taupin ◽  
Marilyn G. Farquhar
Keyword(s):  
Gene Expression ◽  
Transcriptional Repression ◽  
Autosomal Recessive ◽  
Ldl Receptor ◽  
Endocytic Recycling ◽  
Regulated Intramembrane Proteolysis ◽  
Early Endosomes ◽  
Recycling Pathway ◽  
Autosomal Recessive Hypercholesterolemia ◽  
Receptor Family

Receptors internalized by endocytosis can return to the plasma membrane (PM) directly from early endosomes (EE; fast recycling) or they can traffic from EE to the endocytic recycling compartment (ERC) and recycle from there (slow recycling). How receptors are sorted for trafficking along these two pathways remains unclear. Here we show that autosomal recessive hypercholesterolemia (ARH) is required for trafficking of megalin, a member of the LDL receptor family, from EE to the ERC by coupling it to dynein; in the absence of ARH, megalin returns directly to the PM from EE via the connecdenn2/Rab35 fast recycling pathway. Binding of ARH to the endocytic adaptor AP-2 prevents fast recycling of megalin. ARH-mediated trafficking of megalin to the ERC is necessary for γ-secretase mediated cleavage of megalin and release of a tail fragment that mediates transcriptional repression. These results identify a novel mechanism for sorting receptors for trafficking to the ERC and link ERC trafficking to regulated intramembrane proteolysis (RIP) and expression of megalin.

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