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Timely diagnosis of sitosterolemia by next generation sequencing in two children with severe hypercholesterolemia
- Source :
- Atherosclerosis. 262:71-77
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Background and aims Severe hypercholesterolemia associated or not with xanthomas in a child may suggest the diagnosis of homozygous autosomal dominant hypercholesterolemia (ADH), autosomal recessive hypercholesterolemia (ARH) or sitosterolemia, depending on the transmission of hypercholesterolemia in the patient's family. Sitosterolemia is a recessive disorder characterized by high plasma levels of cholesterol and plant sterols due to mutations in the ABCG5 or the ABCG8 gene leading to a loss of function of the ATP-binding cassette (ABC) heterodimer transporter G5-G8. Methods We aimed to perform the molecular characterization of two children with severe primary hypercholesterolemia. Results Case #1 was a 2 year-old girl with high LDL-cholesterol (690 mg/dl) and tuberous and intertriginous xanthomas. Case #2 was a 7 year-old boy with elevated LDL-C (432 mg/dl) but no xanthomas. In both cases, at least one parent had elevated LDL-cholesterol level. For molecular diagnosis, we applied targeted next generation sequencing (NGS), which unexpectedly revealed that both patients were compound heterozygous for nonsense mutations: Case #1 in ABCG5 gene [p.(Gln251*)/p.(Arg446*) ] and Case #2 in ABCG8 gene [p.(Ser107*)/p.(Trp361*)]. Both children had extremely high serum sitosterol and campesterol levels, thus confirming the diagnosis of sisterolemia. A low-fat/low-sterol diet was promptly adopted with and without the addition of ezetimibe for Case #1 and Case #2, respectively. In both patients, serum total and LDL-cholesterol decreased dramatically in two months and progressively normalized. Conclusions Targeted NGS allows the rapid diagnosis of sitosterolemia in children with severe hypercholesterolemia, even though their family history does not unequivocally suggest a recessive transmission of hypercholesterolemia. A timely diagnosis is crucial to avoid delays in treatment.
- Subjects :
- Male
0301 basic medicine
DNA Mutational Analysis
030204 cardiovascular system & hematology
Compound heterozygosity
Severity of Illness Index
Gastroenterology
0302 clinical medicine
ABCG8 gene
ATP Binding Cassette Transporter, Subfamily G, Member 5
Family history
Child
Diet, Fat-Restricted
Anticholesteremic Agents
High-Throughput Nucleotide Sequencing
Phytosterols
Up-Regulation
Phenotype
Treatment Outcome
Codon, Nonsense
Autosomal Recessive Hypercholesterolemia
Child, Preschool
Female
lipids (amino acids, peptides, and proteins)
Cardiology and Cardiovascular Medicine
Sitosterolemia
medicine.drug
Heterozygote
medicine.medical_specialty
Plasma phytosterols
ABCG5 gene
Hypercholesterolemia
Next generation sequencing
Lipoproteins
Nonsense mutation
ABCG8
Intertriginous
Biology
Lipid Metabolism, Inborn Errors
03 medical and health sciences
Ezetimibe
Predictive Value of Tests
Internal medicine
medicine
Humans
Genetic Predisposition to Disease
ATP Binding Cassette Transporter, Subfamily G, Member 8
Cholesterol, LDL
medicine.disease
Intestinal Diseases
030104 developmental biology
Endocrinology
Biomarkers
Subjects
Details
- ISSN :
- 00219150
- Volume :
- 262
- Database :
- OpenAIRE
- Journal :
- Atherosclerosis
- Accession number :
- edsair.doi.dedup.....fcf3c391193fb5dd3d48f4d068570e88