Hyperlipoproteinemia, Type Id

A number sign (#) is used with this entry because hyperlipoproteinemia type ID is caused by homozygous or compound heterozygous mutation in the GPIHBP1 gene (612757) on chromosome 8q24.

Clinical Features

Wang and Hegele (2007) reported 2 sibs with chylomicronemia who were found to have a homozygous mutation in the GPIHBP1 gene. The female had relapsing pancreatitis beginning at age 22 and documented on numerous occasions to have refractory fasting chylomicronemia, even with fat restriction. She had no thyroid, renal, or hepatic disease and was not diabetic. She was not obese and consumed no alcohol. Her older brother had a similar biochemical profile, with a history of pancreatitis requiring hospitalization, refractory to medical treatment since age 25. At age 45, he required 3-vessel coronary artery bypass graft surgery for unstable angina symptoms that began at age 44. Three heterozygotes in this pedigree had plasma triglyceride concentrations in the top 5th percentile for age and sex, but no history of pancreatic or cardiovascular disease.

Beigneux et al. (2009) reported a 33-year-old male with chylomicronemia. The patient was born in Colombia and adopted by a Dutch family. As a child, he exhibited hepatosplenomegaly and failure to thrive; he was diagnosed with type I hyperlipoproteinemia at the age of 7 years. He had a normal BMI of 24.4 and normal glucose levels. Fasting chylomicronemia was documented on multiple occasions. The hyperlipidemia was partially responsive to diet; fasting plasma triglyceride levels fell from as high as 3,366 mg/dL to as low as 744 mg/dL when the patient adhered to a fat-free diet. He had had lipemia retinalis but had no history of eruptive xanthomas or pancreatitis.

Olivecrona et al. (2010) reported a family from northern Sweden in which 3 of 4 sibs had congenital chylomicronemia. Lipoprotein lipase (LPL; 609708) activity and mass in pre- and postheparin plasma were low, and LPL release into plasma after heparin injection was delayed. LPL activity and mass in adipose tissue biopsies appeared normal. Breast milk from the affected female subjects contained normal to elevated LPL mass and activity levels. The milk had a lower than normal milk lipid content, and the fatty acid composition was compatible with the milk lipids derived from de novo lipogenesis, rather than from the plasma lipoproteins. In addition to chylomicronemia, the proband had hepatosplenomegaly, for which she was referred to a pediatric clinic at 9 months of age. Blood sampling revealed lipemic serum, and she developed abdominal pain early in life. She tolerated 1 pregnancy by reducing dietary fat to less than 15% of caloric intake. During subsequent pregnancies, however, she underwent prophylactic plasmaphereses during the second and third trimesters. Her brother was diagnosed at 10 years of age due to fatigue and lipemic serum. He had never been ill or had any episodes of abdominal pain, but he did have mild splenomegaly on physical examination. The proband's sister had severe hypertriglyceridemia and chylomicronemia as well as episodes of pancreatitis.

Franssen et al. (2010) reported a boy with severe chylomicronemia who was diagnosed at 1 year of age during a bout of pancreatitis. Fasting plasma triglyceride levels were 4,005 mg/dL. His weight was less than the 10th percentile for his age, and funduscopy revealed lipemia retinalis; however, he had neither hepatosplenomegaly nor eruptive xanthomas. The patient's hyperlipidemia was partially responsive to a low-fat diet, which caused his plasma triglyceride level to drop from approximately 4,000 to 1,575 mg/dL. His parents and his 3 sibs were healthy, with normal plasma lipid and apolipoprotein levels.

Charriere et al. (2011) reported 2 patients with hyperchylomicronemia. One patient was a 35-year-old man who had been referred at age 26 years for severe acute pancreatitis with hyperchylomicronemia (triglycerides, 26 mmol/L). He remained mostly hyperchylomicronemic with recurrent acute pancreatitis. His LPL activity was undetectable; his mother and daughter had normal lipid parameters. The other patient was a young child who was diagnosed with hyperchylomicronemia at 6 months of age during an episode of acute pancreatitis (triglycerides, 19.6 mmol/L). During childhood, triglycerides remained moderately increased under strict diet, with several episodes of hyperchylomicronemia but without recurrence of acute pancreatitis. His LPL activity was undetectable; both parents and his younger brother had normal lipid profiles.

Gonzaga-Jauregui et al. (2014) reported a 5-week-old Hispanic girl who presented with severe hypertriglyceridemia (triglycerides, 12,031 mg/dL) and a combination of lower gastrointestinal bleeding and chylomicronemia. Initial colonoscopy was consistent with colitis, which resolved with reduction of triglycerides. She had a low HDL of 11 mg/dL and reduced LPL activity.

Plengpanich et al. (2014) reported 3 sibs with chylomicronemia. Their plasma triglycerides ranged from 673 to 3,164 mg/dL, and HDL cholesterol was lowered to 16, 32, and 13, respectively. The proband was identified at 40 years of age after presenting with epigastric discomfort and a plasma triglyceride level of 2,050 mg/dL. Her BMI was normal, and her fasting plasma triglyceride level at 46 years of age was 3,164 mg/dL. Fasting glucose and thyroid-stimulating hormone levels were normal. She had no eruptive xanthomas, and reported 2 uneventful pregnancies. Two of her brothers had a history of chylomicronemia but had lower plasma triglyceride levels than the proband. The preheparin plasma LPL levels in the 3 affected sibs were much lower than those in other family members. The postheparin plasma levels in the proband were extremely low (127 ng/mL), less than 5% of those in normolipidemic control subjects.

Molecular Genetics

Wang and Hegele (2007) screened the coding regions of the GPIHBP1 gene in 160 unrelated adults with fasting chylomicronemia and plasma triglycerides greater than 10 mmol/L, each of whom had normal sequence of the LPL (609708) and APOC2 (608083) genes and identified 1 patient who was homozygous for a missense mutation (G56R; 612757.0001). Her affected brother was homozygous for the same mutation. Both sibs had recurrent pancreatitis. Functional studies by Gin et al. (2007) called into question the pathogenicity of this variant.

In a 33-year-old man with hyperlipoproteinemia type I since childhood, Beigneux et al. (2009) identified homozygosity for a missense mutation in the GPIHBP1 gene (Q115P; 612757.0002). The same homozygous mutation was found in an unrelated patient with severe hypertriglyceridemia by Surendran et al. (2012).

In a 3-year-old boy with chylomicronemia, Franssen et al. (2010) identified homozygosity for a missense mutation in the GPIHBP1 gene (C65Y; 612757.0009), which was subsequently reported in homozygosity in an unrelated patient by Surendran et al. (2012).

In 3 Swedish sibs with severe chylomicronemia, Olivecrona et al. (2010) identified compound heterozygous mutations in the GPIHBP1 gene (C65S, 612757.0003 and C68G, 612757.0004).

In a 35-year-old man with severe chylomicronemia, Charriere et al. (2011) identified a homozygous missense mutation in the GPIHBP1 gene (G175R; 612757.0005). In a child with the same disorder, they identified compound heterozygosity for a missense mutation (C89F; 612757.0006) inherited from the father and a deletion of GPIHBP1 (612757.0011) inherited from the mother. Charriere et al. (2011) suggested that a signal peptide polymorphism (C14F) that occurred in cis with the C89F variant may have potentiated the effect of C89F, which caused a drastic LPL-binding defect to GPIHBP1.

In a 5-week-old Hispanic girl with severe hypertriglyceridemia, Gonzaga-Jauregui et al. (2014) identified compound heterozygosity for a missense (T111P; 612757.0007) and a frameshift (612757.0008) mutation in the GPIHBP1 gene.

In 3 sibs with hypertriglyceridemia, Plengpanich et al. (2014) identified homozygosity for a missense mutation in the GPIHBP1 gene (S107C; 612757.0010).

Pathogenesis

Franssen et al. (2010) studied the patient with chylomicronemia reported by Beigneux et al. (2009) with a Q115P mutation in the GPIHBP1 gene (612757.0002). When this patient was given a 6-hour infusion of heparin, a significant amount of LPL appeared in the plasma, resulting in a fall in the plasma triglyceride levels from 1,780 to 120 mg/dL.