© 1997 American Heart Association, Inc.
Articles |
Therapeutic Response to Medium-Chain Triglycerides and 
-3 Fatty Acids in a Patient With the Familial Chylomicronemia Syndrome
From the Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (M.R., K.A.D., L.P., A.P.P., H.B.B., S.S.-F.), and the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle (J.D.B.).
Correspondence to Silvia Santamarina-Fojo, Molecular Disease Branch, National Institutes of Health, NHLBI, Bldg 10, Room 7N115, 10 Center Dr, MSC 1666, Bethesda, MD 20892-1666. E-mail silvia{at}mdb.nhlbi.nih.gov
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Abstract |
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Abstract We have studied the underlying molecular defect in a patient presenting with recurrent pancreatitis, hypertriglyceridemia, and virtually undetectable postheparin plasma lipoprotein lipase (LPL) mass and activity, who normalized her triglycerides 3 to 6 months after initiation of either medium-chain triglyceride (MCT) oil or
-3 fatty acid (-3-FA) therapy. After treatment,
postheparin plasma LPL activity and mass ranged from 24%
to 39% of normal and LPL specific activity was normal (1.0
nmol·ng-1·min-1).
On discontinuation of MCT oil or -3-FA, plasma
triglyceride increased to >2000 mg/dL. Northern blotting
revealed both normal size and abundance of LPL mRNA isolated from
adipocytes as well as macrophages. Sequence analysis of
the LPL gene, which included all 10 exons, intron-exon splice
junctions, and 1.7 kb of the 5'-flanking region, and of LPL cDNA failed
to identify any mutations. ApoC-II activity and mass assays revealed
the presence of normal levels of a fully functional cofactor as well as
the absence of circulating plasma inhibitors of lipase
function. In summary, we describe a unique patient presenting with
classical features of the familial chylomicronemia syndrome who
manifests an unusually beneficial therapeutic response to MCT oil and
-3-FA therapy. Unlike that in most patients with LPL deficiency, the
chylomicronemia in this patient is not caused by a mutation in the
structural LPL gene but possibly by a posttranscriptional defect. Thus,
a subset of LPL-deficient patients with unique genetic defects respond
to therapy by normalizing fasting plasma triglycerides; a
therapeutic trial with MCT oil should be considered in all patients
presenting with the familial chylomicronemia syndrome.
Key Words: familial chylomicronemia • lipoprotein lipase • medium-chain triglyceride • -3 fatty acids • hypertriglyceridemia
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Introduction |
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Lipoprotein lipase is a 55-kD glycoprotein secreted primarily by adipocytes, muscle cells, and monocyte-derived macrophages into the circulation, where it is bound via glycosaminoglycan structures to capillary endothelial cells.1 2 In the presence of its cofactor, apolipoprotein C-II (apoC-II), LPL hydrolyzes TGs present in circulating chylomicrons and VLDL to FFAs, which can be utilized as sources of energy or reesterified for storage.3
The cDNA sequence4 and the genomic structure5 6 of human LPL have been determined. The coding sequence is 1425 bp in length and translates into a mature protein of 448 residues preceded by a signal peptide of 27 amino acids. The LPL gene is composed of 10 exons spanning some 30 kb. Exon 10 encodes the relatively long (1.95 kb) untranslated 3' end of the mRNA.
Patients with a functional deficiency of LPL present with the familial chylomicronemia syndrome, an autosomal recessive disorder characterized by severe fasting hypertriglyceridemia and massive accumulation of chylomicrons due to impaired hydrolysis.1 7 Affected individuals often present in infancy or childhood with recurrent episodes of abdominal pain or pancreatitis. The diagnosis of LPL deficiency is established by the absence of LPL enzyme activity in adipose tissue or postheparin plasma, assayed in the presence of an exogenous source of apoC-II.1 Rare causes of familial chylomicronemia syndrome include apoC-II deficiency8 9 10 or the presence of a circulating inhibitor of LPL.11 12
The treatment of patients with familial chylomicronemia and
specifically with LPL deficiency is limited to restriction of fat
calories. Thus, although hypolipidemic agents such as fibrates and
nicotinic acid may be used in the treatment of patients with severe
chylomicronemia, these drugs are rarely able to reduce fasting plasma
TGs to levels <1000 mg/dL.7 MCTs7 13 and
more recently of -3-FA7 14 oils has been recommended
for the treatment of patients with this disorder; however, with few
exceptions,14 this approach has failed to have a
significant hypolipidemic effect on these patients. Thus, to date, no
medical regimen has been consistently effective in reducing
plasma TGs in patients with the chylomicronemia syndrome due to LPL
deficiency.
In the present report, we have investigated the LPL gene of a
patient presenting classical features of the familial
chylomicronemia syndrome, including marked
hypertriglyceridemia and recurrent episodes
of pancreatitis. Despite markedly reduced LPL mass and activity
measured in postheparin plasma, the abundance of LPL mRNA
in patient macrophages and adipocytes was normal. Unlike most
LPL-deficient patients, sequence analysis of the patient's
gene revealed no structural abnormalities, and the specific activity of
LPL in postheparin plasma was similar to native LPL. In
addition, the patient manifested an unusually beneficial response to
treatment with either MCT oil or -3-FA that resulted in
normalization of fasting plasma TGs 3 months after initiation of
therapy. Thus, a subset of patients presenting with LPL deficiency
appear to have unique genetic defects that allows them to respond to
therapy by normalizing TGs. A therapeutic trial with MCT oil should be
considered in all patients presenting with the familial
chylomicronemia syndrome.
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Methods |
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Characterization of the Subject
The patient is an 8-year-old black female who, at 3 years of age, presented with recurrent episodes of pancreatitis requiring multiple hospitalizations. On physical examination, hepatosplenomegaly, lipemia retinalis, and eruptive xanthomas were present and her fasting plasma lipid values demonstrated marked hypertriglyceridemia (Table 1
). The patient did not respond well to a low-fat diet
or treatment with nicotinic acid. When the patient was 5 years old, the
diagnosis of LPL deficiency was established by demonstrating virtual
absence of LPL activity in postheparin plasma and
establishing (Table 1) the presence of normal plasma concentrations of
a fully functional apoC-II cofactor. The proband currently follows a
low-fat (20 g/d) diet, which includes 4 to 6 g of -3-FA
(eicosapentaenoic, 438 mg per capsule;
docosahexaenoic, 312 mg per capsule). On this regimen, recent fasting
plasma lipoprotein values were (mg/dL): TG 130, total
cholesterol 218, HDL cholesterol 32, and VLDL
cholesterol 20. The evaluation of the patient detailed
below, including the fat biopsy and separation of
monocyte-macrophages, was performed recently when the patient
was 8 years of age and had a body weight of 29.3 kg.
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Lipoproteins, Apolipoproteins, and Plasma Lipid Analysis
Lipoproteins were isolated by sequential
ultracentrifugation as previously
described.15 Plasma TGs and cholesterol were
quantitated colorimetrically by the
glycerophosphate–oxidase peroxidase and
cholesterol–oxidase peroxidase reactions, respectively,
using commercial standardized test kits (Boehringer Mannheim).
Plasma apoC-II levels were measured by an enzyme-linked immunosorbent
assay technique as described previously,16 and plasma
apoC-II particles were determined by an electroimmunodiffusion
technique as recommended by the manufacturer (Sebia).
Quantitation of Plasma HL Activity and LPL Activity and
Mass
Heparin (60 U/kg) was injected intravenously after a
12-hour fast. Blood was collected in lithium heparin tubes before and
10 minutes after heparin injection for determination of the enzyme
activities of LPL and HL, as well as LPL mass. Total
postheparin plasma lipolytic activity was quantitated as
reported,17 using glycerol tri[1-14C]oleate
(Amersham) as the substrate. HL and LPL activities were determined in
triplicate by selectively blocking LPL with the monoclonal antibody
5D2.18 The mean of eight LPL mass measurements was
determined by an enzyme-linked immunosorbent assay using the monoclonal
antibody 5D2 as described.18
Inhibition Assay of Lipolytic Activity
The analysis for a circulating plasma
inhibitor was performed as described in detail
elsewhere.11 Briefly, bovine LPL was incubated in the
absence of the apoC-II activator, with serum from a normal
subject (protein concentration 
50 mg/mL), and with the proband's
plasma, either posttreatment or
hypertriglyceridemic (pretreatment). In
addition, incubation was performed with a plasma sample from the
patient diluted by 50% with either normolipidemic serum or
Krebs-Ringer phosphate buffer supplemented with heparin (0.01
mg/mL).
Preparation of Monocyte-Derived Macrophages
Human monocyte-derived macrophages were prepared from
250 mL of acid citrate/dextrose–treated mononuclear cells (2.5 g of
dextrose/2.2 g of sodium citrate/0.73 g of citric acid per 100 mL)
obtained from the patient or from a healthy donor (control
macrophages) by monocytopheresis (model CS-3000, Fenwal
Laboratories). Mononuclear cells were separated by
centrifugation of the mononuclear-enriched plasma in
Ficoll/Hypaque separation media (Pharmacia), and 1x107
cells were plated per 30-mm well (Costar Corporation) in 3 mL of
RPMI-1640 medium containing 10% (vol/vol) of human serum and 1%
glutamine.
Fat Biopsy from Normal Control Subject and From the
Patient
A subcutaneous fat biopsy from the patient and a 40-year-old
female control subject was performed from the pad by infiltration of
local anesthesia, followed by 2-cm incision and removal of
approximately 1 g fat. The excised tissue was immediately frozen
in liquid nitrogen and stored at -70°C for subsequent RNA
isolation.
RNA Isolation and Northern Blot Hybridization Analysis
Total RNA was isolated from fat biopsy or from monocyte-derived
macrophages cultured for 2 weeks of either the normal control
subject or the patient, as previously described.19 The gel
for Northern blot analysis was prepared with 1% agarose in the
presence of 6% (vol/vol) formaldehyde. Total RNA (10 µg) was
electrophoresed at 25 V for 16 hours, transferred to Nytran membrane
(Schleicher & Schuell), and hybridized with both LPL and ß-actin cDNA
probes as described.20
Reverse Transcriptase and PCR Amplification of LPL cDNA
LPL cDNAs from a control subject and from the LPL-deficient
subject were synthesized by incubating 1 µg of corresponding total
RNA isolated from monocyte-derived macrophages with 15 U
Moloney murine leukemia virus reverse transcriptase (Pharmacia LKB
Biotechnology, Inc) and 0.2 µmol/L each of two primers that
spanned bases 129 to 147 and 1636 to 1665 of the LPL
cDNA.4 The translated sequence of LPL is encoded by bases
175 through 1602 of the LPL cDNA. The buffer and
deoxynucleotide triphosphates were obtained from the Gene
Amp DNA amplification reagent kit (Perkin-Elmer) and used as
recommended for the polymerase chain reaction. After incubation at
37°C for 2 hours the newly generated cDNA was amplified by the
automated PCR technique,21 using Thermus
aquaticus DNA polymerase (Perkin-Elmer Cetus) and two different
internal primers that spanned bases 141 to 170 and 1621 to 1650 of LPL.
The PCR reaction, which consisted of 30 cycles, was performed under the
following conditions: 1-minute denaturation at 94°C, 1-minute primer
annealing at 55°C, and 2-minute extension at 72°C. DNA was
identified on a 1% agarose gel by staining with ethidium bromide.
Amplified DNA was subcloned into TA-cloning system (Invitrogen) for
sequencing studies. Oligonucleotide primers were
synthesized by the phosphoramidite method in a DNA synthesizer (model
380B; Applied Biosystems Inc).
DNA Isolation and PCR Amplification
Genomic DNA was extracted from leukocytes as described
earlier.22 Synthetic oligonucleotide
primers based on the published LPL gene sequence5 6 were
prepared as indicated below. Each exon (including the entire exon 10)
of the LPL gene was individually amplified from 1 µg of genomic DNA
by the PCR technique and 330 ng of each of two LPL-specific primers
(the primers used were complementary to 20 bp of intron sequence
flanking each exon). In addition, amplification of 1718 bp of the
5'-flanking region was performed by using a reaction mixture of 50
mmol/L KCl; 10 mmol/L Tris-HCL, pH 8.3; 1.5 mmol/L
MgCl2; and 125 µmol/L each of dGTP, dATP, dTTP, and
dCTP with 5 units of Taq DNA polymerase (Perkin-Elmer Cetus)
in 100-µL reaction volumes. The cycle profile included denaturation
at 95°C for 1 minute, annealing at 55°C for 1 minute, and
polymerization at 72°C for 2 minutes for a total of 30 cycles.
DNA Sequencing
Double-stranded DNA sequencing of PCR-amplified genomic DNA
cloned into a TA vector according to the supplier's instructions was
performed with the dideoxy chain–termination method of Sanger et
al.23 A total of six independent clones for each amplified
fragment were sequenced.
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Results |
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Lipoprotein Profile and Postheparin Plasma HL and LPL Activities
The plasma lipid and lipoprotein profiles of the patient and control subjects are summarized in Table 1
. On
presentation, the patient was markedly
hypertriglyceridemic, with reduced plasma
concentrations of LDL and HDL. ApoC-II concentration and cofactor
function as well as postheparin HL activity were normal to
slightly reduced. However, LPL activity in postheparin
plasma was markedly reduced, indicating that the cause of the
chylomicronemia syndrome in the patient was most likely due to LPL
deficiency.
Inhibition Assay of Lipolytic Activity
To rule out the presence of a potential inhibitor of
the lipolytic system, a mixing experiment was performed (Table 2). Plasma aliquots (25 µL) from a normal subject as
well as from the patient at a time when she was markedly
hypertriglyceridemic (pretreatment) and
after normalization of her TGs on -3-FA therapy (posttreatment) were
separately incubated with bovine LPL, resulting in similar activities
ranging from 69.4 to 101.5 nmol
FFA·min-1·mL-1,
respectively (Table 2). Dilution (1:1) of normal plasma as well as
patient pretreatment and posttreatment plasma with the same quantity of
heparin-containing Krebs-Ringer phosphate buffer resulted in activities
ranging from 80.9 to 89.1 nmol
FFA·min-1·mL-1,
indicating that 12.5 µL of either normal or patient plasma was still
capable of full in vitro activation of bovine LPL. Comparable results
were obtained after mixing the proband's plasma pretreatment or
posttreatment with a similar volume of normal plasma. Thus, the
presence of an inhibitor of the lipolytic system in the
patient's plasma could not be demonstrated.
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Effects of Administration of MCT Oil and -3-FA on Serum Lipids
and Clinical Features
Although the patient's fasting plasma TGs remained unchanged
after initial therapy with a combination of a low-fat (<20 g/d) diet
and/or 500 mg niacin daily (data not shown), the administration (15 to
30 g/d) of an MCT oil–containing diet induced a dramatic decrease of
the patient's plasma TGs and cholesterol concentrations
(Fig 1). On this therapy the patient experienced no
further episodes of abdominal pain or pancreatitis and the plasma
lipoprotein profile remained normal for a period of 2 years. Because of
potential complications, including micronodular
cirrhosis24 25 described in some patients receiving MCT
oil for prolonged periods of time, the patient's lipid response to
this regimen was reassessed. Three months after discontinuation of MCT
oil, the patient's plasma TG concentrations increased to >2000 mg/dL
(Table 3 and Fig 1), confirming the therapeutic benefits
of MCT oil in this patient. To evaluate the potential beneficial
effects of -3-FA treatment, our patient was started on a daily dose
of 4 g. Three months after initiation of -3-FA therapy, her
plasma TGs again normalized (Fig 1, upper panel). Interestingly,
temporary discontinuation of -3-FA by the patient for 1 month
resulted in a transient rise in TG to levels around 1000 mg/dL (Fig 1, approximately month 66). Parallel decreases in patient plasma total
cholesterol concentrations were also evident (Fig 1, lower
panel).
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Table 3 summarizes the changes in postheparin LPL mass,
activity, and specific activity induced by treatment with either MCT
oil or -3-FA. Before therapy, LPL postheparin plasma
mass and activity were markedly reduced to <7% of normal levels.
However, after therapy with either MCT oil or -3-FA, LPL
postheparin mass and activity increased (P<.03
and P<.005, respectively) to at least 24% of that of
control subjects. LPL specific activity remained within normal range
before and after treatment.
Northern Blot Analysis of LPL mRNA Isolated From Either Fat
Biopsy or Macrophages
Analysis of control and patient total RNA isolated from
either adipocytes or monocyte-derived macrophages demonstrated
the presence of normal size and abundance of LPL mRNA (Figs 2 and 3) after normalization for ß-actin
mRNA. Thus, despite the markedly reduced postheparin plasma
levels of LPL in this patient, the LPL message was normal.
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Sequencing of the Patient's LPL Gene
Sequence analysis of the LPL gene (all 10 exons,
intron-exon splice junctions, and 1718 bp of the 5'-flanking region)
failed to identify any mutations. In addition, LPL cDNA was obtained by
reverse transcription of mRNA and sequenced, confirming the absence of
any defects in the coding region of the patient's LPL gene.
Family Analysis
Table 4 illustrates the plasma lipid and
lipoprotein values as well as LPL mass and activity in
postheparin plasma of the patient under treatment and the
patient's first-degree relatives. While the patient's TGs are in the
normal range under treatment with -3-FA, her LPL mass and activity
are <40% of normal. The patient's first-degree relatives all have
normal lipid and lipoprotein values without treatment. In addition, LPL
mass and activity in postheparin plasma of both parents
were normal.
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Discussion |
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In the present article, we investigate the underlying molecular defect in a patient presenting with the classical features of the familial chylomicronemia syndrome, including lipemia retinalis, hepatosplenomegaly, eruptive xanthomas, and recurrent episodes of abdominal pain and pancreatitis.1 7 Like many patients with this genetic disorder, marked hypertriglyceridemia and fasting chylomicronemia were identified early in childhood. Initial evaluation of patient postheparin plasma lipolytic activity established the diagnosis of LPL deficiency, and other potential causes of the chylomicronemia syndrome, such as apoC-II deficiency1 7 and circulating inhibitors of the lipolytic system11 12 were eliminated. As is often the case in LPL deficiency, our patient did not demonstrate any beneficial response to treatment with dietary fat restriction, fibric acid derivatives, or nicotinic acid.
Despite the patient's presentation with classical clinical and biochemical features of the familial chylomicronemia syndrome, further characterization of the patient's underlying gene defect as well as response to therapy revealed some unique features. In the past decade the genetic defects in a large number of patients with LPL deficiency have been identified,1 26 27 including several major gene rearrangements28 29 30 and splicing defects,31 32 as well as mutations that lead to the introduction of a premature stop codon.33 34 35 36 Most of the identified LPL gene defects, however, have been missense mutations that result in the expression of a nonfunctional enzyme.26 Unlike those of most LPL-deficient patients, our patient's LPL gene and cDNA failed to display any functionally significant mutations on extensive sequence analysis.
These findings were confirmed by demonstrating the presence of reduced but functionally active LPL in patient postheparin plasma at various times during treatment. In addition, characterization of patient monocyte-derived macrophage and adipocyte LPL mRNA by Northern blot hybridization analysis demonstrated normal size and abundance of LPL message compared with LPL mRNA isolated from the tissues of a 40-year-old female control subject. The patient's tissues were isolated when she was 8 years old and under treatment. Although increased by treatment, LPL mass and activity were still less than a third of that of control values, while the LPL mRNA levels were normal, thus suggesting a posttranscriptional defect. Because we were unable to obtain a muscle biopsy, we cannot rule out that reduced transcription of the LPL gene in muscle tissue alone caused the LPL deficiency in this patient. To our knowledge, selective LPL deficiency in one tissue is extremely rare and has been observed only once. Brunzell et al37 described a patient with normal postheparin plasma LPL activity in spite of absent LPL activity in adipose tissue. Taken together, our results suggest that we identified for the first time a potential posttranscriptional defect as the underlying cause of the chylomicronemia syndrome in an LPL-deficient patient.
To further characterize the defect in this patient, we studied her parents and sisters. All four first-degree relatives had normal lipid profiles, including TG concentrations in the normal range. In addition, both parents had postheparin plasma LPL mass and activity similar to that of normal control subjects. Obligate heterozygotes of LPL deficiency usually show reduced levels of LPL mass18 and/or activity,18 38 which suggests that the defect in the patient is either inherited as a truly recessive mutation, due to a new mutation not found in the parents, or acquired through environmental factors.
In addition, this patient exhibited an unusually beneficial response to
treatment with either MCT oil or -3-FA that resulted in a persistent
reduction of fasting plasma TGs as well as normalization of the
lipoprotein profile 3 months after initiation of either therapy. The
rationale for the treatment of patients with the chylomicronemia
syndrome with MCT oil has been previously described.1 7
MCTs are absorbed directly into the portal circulation and do not
appear to contribute to the generation of chylomicron TGs in these
affected individuals.13 In spite of its common use in
patients with familial hypercholesterolemia,
there are only limited published data about the efficacy of MCT oil in
the treatment of hypercholesterolemia. In less
hypertriglyceridemic patients with
non–insulin-dependent diabetes mellitus, MCT oil did not have a
consistent TG-lowering effect.39 In fact, MCT oil
elevated the plasma TG levels in several of these patients, as had been
earlier observed in nondiabetic subjects.39
The mechanism of action responsible for the hypolipidemic effects of
-3-FA in patients with
hypertriglyceridemia is better understood.
Several studies have demonstrated that -3-FA inhibits hepatic
synthesis and/or secretion of VLDL TGs.40 41 42 43 This agent
has not been frequently utilized in the treatment of
hypertriglyceridemia secondary to genetic
disorders of the lipolytic system, since the major defect in this group
of patients is the inability to hydrolyze circulating plasma TGs rather
than hepatic TG overproduction. Nevertheless, despite the
marked differences in the physiological function of
MCT oil and -3-FA, the effectiveness of these two treatment
modalities in our patient was confirmed by temporarily discontinuing
the administration of these agents, which resulted in the development
of marked hypertriglyceridemia.
A similar response has been described in two other patients
presenting with the chylomicronemia syndrome and markedly reduced
or absent LPL activity in postheparin plasma. Thus,
Karmally et al14 described normalization of the
lipoprotein profile in response to treatment with -3-FA in a patient
presenting with fasting plasma TGs of >2000 mg/dL and Shirai et
al44 demonstrated a similar beneficial response to MCT oil
therapy in another affected individual. Although the molecular defect
in the LPL gene of the first patient has not been investigated,
sequence analysis of the LPL gene in the second demonstrated
heterozygosity for a previously described premature termination
mutation at serine 447,45 which results in the expression
of a functional lipase capable of hydrolyzing emulsified triolein in
vitro. Thus, in a manner similar to that in our patient,
characterization of the LPL gene failed to identify a mutation that
could account for the absence of LPL activity in
postheparin plasma. Unlike our patient, however, this
affected individual had undetectable levels of LPL activity, even under
treatment, when measured with the standard artificial emulsion,
suggesting that contrary to results found with our patient, there was
no increase of LPL mass under treatment.44 Neither of the
reported patients received a trial with both MCT oil and -3-FA.
The exact mechanism by which MCT oil and -3-FA may result in
enhanced LPL levels in our patient remains unclear. In fact, previous
studies have suggested either no change42 46 or
decreased47 48 postheparin plasma LPL activity
in miniature pigs or rats fed -3-FA. As previously suggested,
incorporation of MCTs44 or -3-FA42 into
chylomicrons and VLDL could lead to enhanced lipolysis of these TG-rich
lipoproteins; however, this mechanism cannot explain the increase in
LPL mass and activity seen in our patient. Our patient's dramatic
lipid response to therapy with MCT oil or -3-FA was associated with
increased postheparin plasma LPL mass and activity with
specific activities remaining in the normal range pretreatment and
posttreatment. These changes, which resulted in increased
postheparin plasma LPL activity to levels of up to 39%
that of normal, suggest a potential mechanism by which these two agents
may mediate the normalization of plasma TGs in this patient. Thus, MCT
oil and -3-FA appear to enhance LPL activity by increasing
postheparin plasma LPL concentrations to levels permitting
normal TG hydrolysis.
These results suggest that a therapeutic trial with MCT oil is warranted in all patients presenting with the familial chylomicronemia syndrome. Micronodular liver cirrhosis has been observed after long-term administration of MCT oil, but only in patients with abetalipoproteinemia.24 25 It is less likely that cirrhosis will also be observed in patients with effective means of secreting lipoproteins from the liver. In fact, prolonged treatment of 10 or more years with MCT oil in 20 patients with chylomicronemia did not lead to a single case of micronodular cirrhosis (personal communication, Prof Eric Bruckert, Hôpital de la Pitié, Paris, France). Untreated severe hypertriglyceridemia, on the other hand, can lead to chronic pancreatitis, with subsequent insulin-dependent diabetes mellitus and its sequelae.1
In summary, we have investigated the underlying molecular defect in a
unique patient presenting with classical features of LPL
deficiency. Despite markedly reduced LPL postheparin plasma
activity, tissue LPL mRNA concentrations were normal and no functional
mutations were identified in the patient's LPL gene indicating the
presence of a gene defect that modified LPL expression
posttranscriptionally. In addition, the patient demonstrated an
unusually beneficial response to treatment with either MCT oil or
-3-FA, which resulted in enhanced expression of LPL with normal
specific activity in patient postheparin plasma and
normalization of plasma TGs. On the basis of these studies, we propose
that a subset of patients with LPL deficiency with unique gene defects
that lead to reduced expression of LPL exhibit a dramatic response to
therapy with MCT oil. A therapeutic trial with MCT should be considered
in all patients presenting with the familial chylomicronemia
syndrome.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We would like to thank Janet Chang for isolation of the monocytes.
Received October 16, 1995; accepted September 24, 1996.
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References |
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- Karmally W, Goldberg I, Ginsberg H. Normalization of plasma triglyceride and high-density lipoprotein cholesterol by omega-3 fatty acid supplementation of a low-fat diet in a patient with lipoprotein lipase deficiency. Circulation. 1989;80(suppl II):II-332. Abstract.
- Havel RJ, Eder HA, Bragdon JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955;34:1345-1353.
- Kashyap ML, Srivastava LS, Chen CY, Perisutti CG, Campbell M, Lutmer RF, Glueck CJ. Radioimmunoassay of human apolipoprotein CII: a study in normal and hypertriglyceridemic subjects. J Clin Invest. 1977;60:171-180.
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