Lipase Deficiency, Combined


A number sign (#) is used with this entry because of evidence that combined lipase deficiency with severe hypertriglyceridemia is caused by homozygous mutation in the LMF1 gene (611761) on chromosome 16p13.

Clinical Features

Auwerx et al. (1990) described a large family with familial hepatic triglyceride lipase (HTGL; 151670) deficiency and a coexisting reduced lipoprotein lipase (LPL; 609708) similar to the heterozygous state of LPL deficiency. The proband was detected because of hypertriglyceridemia and chylomicronemia. Analysis of genomic DNA from these subjects by restriction enzyme digestion showed no major abnormalities in the structure of either the HTGL gene or the LPL gene. The authors incorrectly referred to 'compound heterozygotes for HTGL and LPL deficiency'; they should have referred to these individuals as 'double heterozygotes,' because the genes represent separate loci on separate chromosomes (chromosome 15 and chromosome 8, respectively).

The hypertriglyceridemia in the cld mouse (see Animal Model) is characterized by severe chylomicronemia that is caused by deficiency of lipoprotein lipase and exacerbated by partial deficiency of hepatic triglyceride lipase (HTGL; 151670). The mutation, however, affects neither the LPL nor the HTGL gene, but a transmembrane protein designated Lmf1 by Peterfy et al. (2007). To investigate the potential role of the LMF1 gene in human disease, Peterfy et al. (2007) screened 11 individuals with hypertriglyceridemia and decreased lipase activity for mutations. They identified a 48-year-old woman carrying an LMF1 mutation in homozygosity in whom severe hypertriglyceridemia was first noted at age 18 years. She had her first attack of pancreatitis at age 27, and had had at least 15 subsequent attacks. She began to develop lipodystrophy at age 44 that progressed to complete involvement of limbs and buttocks, sparing her face and abdomen. Also at age 44, type 2 diabetes was diagnosed, which was controlled with metformin. Bilateral large tuberous xanthomas on elbows, knees, and feet were present. Even in compliance with strict dietary fat restrictions, triglyceride concentration was 7 times the average of 31 control subjects at the lowest measurement, and increased markedly to over 70 times the control value when diet was not regulated. The severe hypertriglyceridemia was found to be due to LPL deficiency, as determined by a 93% decrease in LPL activity in the plasma of the affected individual. In addition, hepatic lipase activity was decreased by half, confirming the status of combined lipase deficiency.

Cefalu et al. (2009) screened 22 individuals with severe hypertriglyceridemia and identified 1 with a homozygous mutation in the LMF1 gene. The proband was a 42-year-old Tunisian man living in Sicily, Italy. His parents were apparently unrelated. His mother died at age 62 years of a respiratory disease; the 65-year-old father and his 7 sibs were all healthy. Severe hypertriglyceridemia was first noted at age 32 years when the patient had an episode of acute pancreatitis. A diet restriction to 15% of fat intake (less than 7% of saturated fat) and treatment with fibrates and omega-3 fatty acids were prescribed, but compliance was poor, and the patient had a second episode of pancreatitis at age 38 years. He was overweight, with a BMI of 29. Triglycerides were 2,400 mg/dL, total cholesterol was 374 mg/dL, and HDL cholesterol levels were 44 mg/dL. He had a third episode of acute pancreatitis at age 41 years and then developed type 2 diabetes.

Molecular Genetics

In a patient with combined deficiency of lipoprotein lipase and hepatic lipase, concomitant hypertriglyceridemia, and associated disorders, Peterfy et al. (2007) detected homozygosity for a premature termination mutation in the LMF1 gene (Y439X; 611761.0001). The authors considered LMF1 to be an important candidate gene in hypertriglyceridemia through its profound effect on lipase activity.

In a 42-year-old Tunisian man with severe hypertriglyceridemia in whom genetic analysis was negative for mutations in the LPL, APOC2 (608083), and APOA5 (606368) genes, Cefalu et al. (2009) identified a homozygous nonsense mutation in the LMF1 gene (W464X; 611761.0002).

Animal Model

Paterniti et al. (1983) described a mouse mutation, cld, that results in combined deficiency of LPL and HTGL. Homozygous mice develop lethal hyperchylomicronemia within 2 days postpartum as a consequence of nursing. The mutation is located on mouse chromosome 17 which carries the H2 locus homologous to HLA on human chromosome 6. Indeed, the cld mutation was discovered as a 'parasitic lethal gene' acting postnatally in the T/t complex of mice. Several possibilities to account for deficiency of 2 enzymes were discussed by the authors.

Davis et al. (1990) stated that in the mouse the Ldl and Hl (hepatic lipase) genes are on chromosomes 8 and 9, respectively. Since the cld mutation and lipase genes reside on separate chromosomes in the mouse, combined lipase deficiency cannot represent a contiguous gene syndrome. In cld mice, Davis et al. (1990) found Lpl synthetic rates to be 70% of control rates; values for Lpl in cld post-heparin plasma were markedly reduced to only 7% of control values, suggesting that most of the Lpl was not secreted. Davis et al. (1990) concluded that a selective impairment of intracellular transport and secretion of Lpl and Hl underlies the disorder in the mouse.

Peterfy et al. (2007) described the phenotype of the cld/cld mouse. Shortly after ingesting dietary milk, neonatal cld/cld mice develop severe hypertriglyceridemia owing to an accumulation of chylomicrons that gradually pack the lumina of capillaries and sinusoids. Mutant mice show a progressive increase in triglyceride, which measures 1,000 mg/dl several hours after birth and rises as high as 20,000 mg/dl 2 to 3 days later. The severe hypertriglyceridemia causes an increase in blood viscosity, ischemia, and cyanosis, and the inability of tissues to access circulating triglycerides results in starvation, poor thermoregulation, and death 2 to 3 days after birth. Mice heterozygous for the mutation have normal triglyceride concentrations and no known abnormalities.