Familial hyperchylomicronemia: Difference between revisions

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{{SK}} Type I hyperlipoproteinemia, Burger-Grutz syndrome, primary hyperlipoproteinemia, lipoprotein lipase deficiency, LPL deficiency, idiopathic hyperlipemia, essential hyperlipemia, familial hyperlipemia, lipase D deficiency, hyperlipoproteinemia type IA, familial chylomicronemia, familial lipoprotein lipase deficiency, and familial hyperchylomicronemia.


'''To view Lipoprotein disorders main page [[ Lipoprotein disorders | Click here]]'''<br>
'''To view Hyperlipoproteinemia main page [[ Hyperlipoproteinemia | Click here]]''' <br>


{{SK}} Type I hyperlipoproteinemia, Burger-Grutz syndrome, Primary hyperlipoproteinemia, lipoprotein lipase deficiency, LPL deficiency, Idiopathic hyperlipemia, Essential hyperlipemia, Familial hyperlipemia, Lipase D deficiency, Hyperlipoproteinemia type IA, Familial chylomicronemia, Familial lipoprotein lipase deficiency, and Familial hyperchylomicronemia.
==Overview==
==Overview==
This very rare form is due to a deficiency of [[lipoprotein lipase]] (LPL) or altered [[apolipoprotein C2]], resulting in elevated [[chylomicron]] which are the particles that transfer fatty acids from the [[digestive tract]] to the [[liver]]. Lipoprotein lipase is also responsible for the initial breakdown of endogenously made triacylglycerides in the form of very low density lipoprotein ([[VLDL]]). As such, one would expect a defect in LPL to also result in elevated VLDL. Its prevalence is 0.1% of the population.
This very rare hyperlipidemia is due to a deficiency of [[lipoprotein lipase]] (LPL) or altered [[apolipoprotein C2]], resulting in elevated [[chylomicron]] which are the particles that transfer fatty acids from the [[digestive tract]] to the [[liver]]. Lipoprotein lipase is also responsible for the initial breakdown of endogenously made triacylglycerides in the form of very low density lipoprotein ([[VLDL]]). As such, one would expect a defect in LPL to also result in elevated VLDL. Its prevalence is one in 1,000,000 population.
==Historical Perspective==
*In 1932, Familial LPL deficency was first described by Burger and Grutz<ref name="national organization of rare disorders2"><nowiki>{{</nowiki>http://rarediseases.org/rare-diseases/familial-lipoprotein-lipase-deficiency<nowiki>}}/Accessed on 7 November,2016</nowiki></ref>
*In 1967, Fredrickson using paper electrophosresis, classified lipoprotein disorder<ref name="pmid329619322">{{cite journal| author=Culliton BJ| title=Fredrickson's bitter end at Hughes. | journal=Science | year= 1987 | volume= 236 | issue= 4807 | pages= 1417-8 | pmid=3296193 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3296193  }}</ref>
==Classification==
==Classification==
===Type 1A===  
There is no established classification system for Type I hyperlipoproteinemia. However, based on the pathogenesis involved type 1 hyperlipoproteinemia can be classified into:<ref name="pmid23525082">{{cite journal| author=Brahm A, Hegele RA| title=Hypertriglyceridemia. | journal=Nutrients | year= 2013 | volume= 5 | issue= 3 | pages= 981-1001 | pmid=23525082 | doi=10.3390/nu5030981 | pmc=3705331 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23525082  }}</ref>
It occurs due to deficiency of [[lipoprotein lipase]] enzyme.
===Type 1B===
Altered [[apolipoprotein C2]] causes type 1B hyperlipoproteinemia
===Type 1C===
Presence of [[LPL]] inhibitor is the cause of type 1C hyperlipoproteinemia
==Historical Perspective==
 
 


Type 1a: Lipoprotein lipase deficiency


Type 1b: Apolipoprotein c-IIdeficiency


Type 1c: Presence of lipoprotein lipase inhibitor


==Pathophysiology==
==Pathophysiology==
*Type I hyperlipoproteinemia is a rare autosomal recessive disorder of lipoprotein metabolism. <ref name="pmid27578112">{{cite journal| author=Pingitore P, Lepore SM, Pirazzi C, Mancina RM, Motta BM, Valenti L et al.| title=Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia. | journal=J Clin Lipidol | year= 2016 | volume= 10 | issue= 4 | pages= 816-23 | pmid=27578112 | doi=10.1016/j.jacl.2016.02.015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27578112  }} </ref><ref name="pmid23475957">{{cite journal| author=Young SG, Zechner R| title=Biochemistry and pathophysiology of intravascular and intracellular lipolysis. | journal=Genes Dev | year= 2013 | volume= 27 | issue= 5 | pages= 459-84 | pmid=23475957 | doi=10.1101/gad.209296.112 | pmc=3605461 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23475957  }} </ref><ref name="pmid15115692">{{cite journal| author=Pasalić D, Jurcić Z, Stipancić G, Ferencak G, Leren TP, Djurovic S et al.| title=Missense mutation W86R in exon 3 of the lipoprotein lipase gene in a boy with chylomicronemia. | journal=Clin Chim Acta | year= 2004 | volume= 343 | issue= 1-2 | pages= 179-84 | pmid=15115692 | doi=10.1016/j.cccn.2004.01.029 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15115692  }} </ref>
*Type I hyperlipoproteinemia is a rare [[autosomal recessive disorder]] of lipoprotein metabolism.<ref name="pmid275781122">{{cite journal| author=Pingitore P, Lepore SM, Pirazzi C, Mancina RM, Motta BM, Valenti L et al.| title=Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia. | journal=J Clin Lipidol | year= 2016 | volume= 10 | issue= 4 | pages= 816-23 | pmid=27578112 | doi=10.1016/j.jacl.2016.02.015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27578112  }}</ref><ref name="pmid234759572">{{cite journal| author=Young SG, Zechner R| title=Biochemistry and pathophysiology of intravascular and intracellular lipolysis. | journal=Genes Dev | year= 2013 | volume= 27 | issue= 5 | pages= 459-84 | pmid=23475957 | doi=10.1101/gad.209296.112 | pmc=3605461 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23475957  }}</ref><ref name="pmid151156922">{{cite journal| author=Pasalić D, Jurcić Z, Stipancić G, Ferencak G, Leren TP, Djurovic S et al.| title=Missense mutation W86R in exon 3 of the lipoprotein lipase gene in a boy with chylomicronemia. | journal=Clin Chim Acta | year= 2004 | volume= 343 | issue= 1-2 | pages= 179-84 | pmid=15115692 | doi=10.1016/j.cccn.2004.01.029 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15115692}}</ref><ref name="pmid11334614">{{cite journal| author=Gilbert B, Rouis M, Griglio S, de Lumley L, Laplaud P| title=Lipoprotein lipase (LPL) deficiency: a new patient homozygote for the preponderant mutation Gly188Glu in the human LPL gene and review of reported mutations: 75 % are clustered in exons 5 and 6. | journal=Ann Genet | year= 2001 | volume= 44 | issue= 1 | pages= 25-32 | pmid=11334614 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11334614 }}</ref>
===Pathogenesis===
===Pathogenesis===
*Lipoprotein lipase(LPL) hydrolysis Triglyceride-rich lipoproteins (TG) such as chylomicrons and very low-density lipoproteins. It catalyzes, the removal of TG from bloodstream generating free fatty acids for tissues.
*Lipoprotein lipase(LPL) hydrolyzes triglyceride-rich lipoproteins (TG) such as [[chylomicrons]] and very low-density lipoproteins. It catalyzes, the removal of [[Triglyceride|TG]] from the bloodstream generating free fatty acids for tissues.
*For full enzymatic activity, LPL requires following cofactors:-
*For full enzymatic activity, LPL requires following cofactors:<ref name="pmid275781122" />
**Apolipoprotein C-II and apolipoprotein A-V that are LPL activators
**[[Apolipoprotein C-II]] and apolipoprotein A-V that are LPL activators
**Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein
**[[Glycosylphosphatidylinositol]]-anchored high-density lipoprotein-binding protein
**Lipase maturation factor 1
**[[Lipase maturation factor 1]]
*Development of [[Type I hyperlipoproteinemia]] is the result of functional mutations in one of all these genes result in type I hyperlipoproteinemia.
*Familial lipoprotein lipase inhibitor inherited in an [[autosomal dominant]] fashion. Inhibit the action of [[lipoprotein lipase]], resulting in decreased postheparin plasma LPL activity, elevated adipose tissue LPL activity, and normal plasma levels of functional [[apoC-I1]].<ref name=":02">https://ghr.nlm.nih.gov/gene/LPL#conditions</ref>
====Familial lipoprotein lipase inhibitor====
**Familial lipoprotein lipase inhibitor seems to be inherited as an autosomal dominant trait.
**Postheparin plasma LPL activity is decreased, adipose tissue LPL activity is elevated, and plasma levels of functional apoC-I1 are normal.  
*Functionally inactive or absent lipoprotein lipase emzyme, results in massive accumulation of chylomicrons, with extremely high level of plasma triglycerides.


*Functionally inactive or absent lipoprotein lipase enzyme, results in massive accumulation of chylomicrons, with extremely high level of plasma triglycerides.
===Genetics===
*More than 220 mutations in the LPL gene have been found to cause familial lipoprotein lipase deficiency. The most common mutation in people of European ancestry replaces the protein building block (amino acid) glycine with the amino acid glutamic acid at position 188 in the enzyme (written as Gly188Glu or G188E).<ref name=":02" />
==Causes==
==Causes==
The cause of type 1 hyperlipidemia remains genetic.
The cause of type 1 hyperlipidemia remains genetic.<ref name="national organization of rare disorders2" /><ref name="rare diseasediorders2">https://rarediseases.info.nih.gov/diseases/6414/hyperlipoproteinemia-type-1 Accessed on 7 November,2016</ref><ref name="pmid275781122" /><ref name="pmid11893776">{{cite journal| author=Peterson J, Ayyobi AF, Ma Y, Henderson H, Reina M, Deeb SS et al.| title=Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene. | journal=J Lipid Res | year= 2002 | volume= 43 | issue= 3 | pages= 398-406 | pmid=11893776 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11893776  }}</ref>
 
{| class="wikitable"
! colspan="1" rowspan="1" |Gene 1
! colspan="1" rowspan="1" |Variants Detected 2
! colspan="1" rowspan="1" |Variant Detection Frequency by Test Method 3
| colspan="1" rowspan="2" |''LPL''
| colspan="1" rowspan="1" |Sequence variants 4 (including p.Gly188Glu 5)
| colspan="1" rowspan="1" |~97% 6
|-
| colspan="1" rowspan="1" |Partial- and whole-gene deletions and duplications
| colspan="1" rowspan="1" |~3% 8
|}
==Differential diagnosis==
==Differential diagnosis==
However, the majority of individuals with chylomicronemia and plasma triglyceride concentration greater than 2000 mg/dL do not have familial LPL deficiency; rather, they have one of the more common genetic disorders of triglyceride metabolism (i.e., familial combined hyperlipidemia and monogenic familial hypertriglyceridemia) occurring simultaneously with, and independently of, a common acquired secondary form of hypertriglyceridemia [Brunzell & Deeb 2001].
{| class="wikitable"
 
!
Secondary causes of hypertriglyceridemia are diabetes mellitus, paraproteinemic disorders, use of alcohol, and therapy with estrogen, glucocorticoids, Zoloft®, isotretinoin, and certain antihypertensive agents. In one series of 123 individuals evaluated for marked hypertriglyceridemia, 110 had an acquired cause of hypertriglyceridemia combined with a common genetic form of hypertriglyceridemia, five had familial LPL deficiency, five had other rare genetic forms of hypertriglyceridemia, and three had an unknown cause.
|}
 
==Epidemiology and Demographics==
==Epidemiology and Demographics==
Familial hyperchylomicronemia, is a rare autosomal recessive disorder of lipoprotein metabolism estimated to affect approximately one per million individuals. In some ethnic groups, the frequency of this disorder is several fold higher (i.e., French Canadians, Afrikaner).
Epidemiological and demographics of familial hyperchylomicronemia are discussed below:<ref name="pmid275781122" /><ref name="rare diseasediorders2" /><ref name="national organization of rare disorders2" />
Prevalence
===Prevalence===
 
*The prevalence of familial LPL deficiency is approximately one in 1,000,000 in the general US population
The prevalence of familial LPL deficiency is approximately one in 1,000,000 in the general US population.
===Demographics===
 
====Age====
The disease has been described in all races. The prevalence is much higher in some areas of Quebec, Canada, as a result of a founder effect.
*25% of affected children develop symptoms before one year of age.
 
*The majority of patients develop symptoms before ten years of age.
Consanguinity is often observed in families with homozygous familial LPL deficiency.
*Few individuals develop symptoms, at the time of pregnancy.
 
====Gender====
==Risk Factors==
*Males and females are equally affected by familial chylomicronemia..
Risk to Family Members
====Race====
 
*The disease has been described in all races.
Parents of a proband
*The prevalence is much higher in some areas of Quebec, Canada, as a result of a founder effect.
 
The parents of an affected individual are obligate heterozygotes and therefore carry a single copy of a pathogenic variant in LPL.
Heterozygotes (carriers) are asymptomatic but may have moderate hypertriglyceridemia and may be at mild risk for premature atherosclerosis.
Sibs of a proband
 
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic but may have moderate hypertriglyceridemia and may be at mild risk for premature atherosclerosis.
Offspring of a proband. The offspring of an individual with familial lipoprotein lipase deficiency are obligate heterozygotes (carriers) for a pathogenic variant in LPL.
 
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.
 
Carrier Detection
 
Carrier testing is possible if the pathogenic variants in the family are known.
 
Related Genetic Counseling Issues
 
See Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
 
Family planning
 
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Prenatal Testing and Preimplantation Genetic Diagnosis
 
Once the LPL pathogenic variants have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for familial lipoprotein lipase deficiency are possible options.
 
Requests for prenatal testing for conditions which (like familial lipoprotein lipase deficiency) do not affect intellect and have effective treatment available are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate. In practice, prenatal testing is rarely requested because of the availability of effective treatment.
 
==Screening==
==Screening==
*There are no screening guidelines for .
*There are no screening guidelines for Familial hyperchylomicronemia.<ref name="rare diseasediorders2" /><ref name="pmid275781122" /><ref name="medline plus2">https://medlineplus.gov/ency/article/000405.htm</ref>
*Evaluation of Relatives at Risk.It is appropriate to measure plasma triglyceride concentration in at-risk sibs during infancy; early diagnosis and implementation of dietary fat intake restriction can prevent symptoms and related medical complications.
*It may be appropriate to measure plasma triglyceride concentration in at-risk siblings during infancy; early diagnosis and implementation of dietary fat intake restriction can prevent symptoms and related medical complications.
==Natural History, Complications, and Prognosis==
Natural history, complications and prognosis of type 1 hyperlipoproteinemia include:<ref name="medline plus2" /><ref name="pmid12387965" /><ref name="pmid9738727" />


==Natural History, Complications, and Prognosis==
===Natural History===
===Natural History===
If left untreated, pancreatitis can develop into a chronic condition that can damage the pancreas and, in rare cases, be life-threatening.
*If left untreated, [[pancreatitis]] can develop into a chronic condition that can damage the pancreas and, in rare cases it could be life-threatening.
 
===Complications===
===Complication===
*Pancreatitis and recurrent episodes of abdominal pain may develop.
Pancreatitis and recurrent episodes of abdominal pain may develop.
*Intestinal ischemia
 
*Depression,
Xanthomas are not usually painful unless they are rubbed a lot.
*Memory loss
 
*Intellectual decline
===Prognosis===
===Prognosis===
*People with this condition who follow a very low-fat diet can live into adulthood.
*People with this condition who follow a very low-fat diet have a good prognosis.  
 
==Diagnosis==
==Diagnosis==
To confirm/establish the diagnosis in a proband. Persistent severe hypertriglyceridemia (1000-2000 mg/dL) in an infant or child that is responsive to dietary fat intake is indicative of LPL deficiency.
===History and symptoms===
 
Presumptive diagnosis can be made, when an infant presents with a history of failure to thrive or recurrent abdominal pain with a documented high fasting plasma triglyceride concentration.<ref name="GeneReviews2"><nowiki>{{</nowiki>https://www.ncbi.nlm.nih.gov/books/NBK1308/<nowiki>}} Accessed on 7 November,2016</nowiki></ref><ref name="medline plus2" />
When LPL deficiency is first suspected, a history of failure to thrive as an infant or recurrent abdominal pain as a child should be sought.
A fasting plasma triglyceride concentration should be obtained at least once for documentation.
Note: Neither measurement of post-heparin plasma LPL enzyme activity nor LPL molecular genetic testing is required to make a presumptive clinical diagnosis.
 
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
 
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
 
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.
 
==History/symptoms==
Abdominal pain (may appear as colic in infancy)
Loss of appetite
Nausea
Pain in the muscles and bones (musculoskeletal pain)
Vomiting
The signs and symptoms of hyperlipoproteinemia type 1 usually begin during childhood. Approximately 25 percent of affected individuals develop symptoms before age 1. The characteristic features of hyperlipoproteinemia type 1 include:
Abdominal pain (may manifest as colic in infancy)
Nausea, vomiting, loss of appetite
Failure to thrive in infancy
Musculoskeletal pain (pain in the muscles and bones)
Xanthomas (small, yellow, fat deposits in the skin)
Pancreatitis
Enlarged liver and spleen
 
Familial lipoprotein lipase (LPL) deficiency usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Males and females are affected equally.
 
Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age ten years; however, some individuals present for the first time during pregnancy. The severity of symptoms correlates with the degree of chylomicronemia, which varies by dietary fat intake.
 
The abdominal pain, which can vary from mildly bothersome to incapacitating, is usually mid-epigastric with radiation to the back. It may be diffuse and mimic an acute abdomen, often leading to unnecessary abdominal exploratory surgery. The pain probably results from chylomicronemia leading to pancreatitis.
 
Kawashiri et al [2005] reported that individuals with LPL deficiency can lead a fairly normal life on a diet very low in total fat content. The secondary complications of pancreatitis — diabetes mellitus, steatorrhea, and pancreatic calcification — are unusual in individuals with familial LPL deficiency and rarely occur before middle age. Pancreatitis in LPL deficiency may rarely be associated with total pancreatic necrosis and death.
 
About 50% of individuals with familial LPL deficiency have eruptive xanthomas, small yellow papules localized over the trunk, buttocks, knees, and extensor surfaces of the arms. Xanthomas are deposits of lipid in the skin that result from the extravascular phagocytosis of chylomicrons by macrophages. They can appear rapidly when plasma triglyceride concentration exceeds 2000 mg/dL.
 
Xanthomas may become generalized. As a single lesion, they may be several millimeters in diameter; rarely, they may coalesce into plaques. They are usually not tender unless they occur at a site susceptible to repeated abrasion.


Hepatomegaly and splenomegaly often occur when plasma triglyceride concentrations are markedly increased. The organomegaly results from triglyceride uptake by macrophages, which become foam cells.
Symptoms of  Type I hyperlipoproteinemia include:<ref name="rare diseasediorders2" /><ref name="medline plus2" /><ref name="pmid232573032">{{cite journal| author=Robinson JG| title=What is the role of advanced lipoprotein analysis in practice? | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 25 | pages= 2607-15 | pmid=23257303 | doi=10.1016/j.jacc.2012.04.067 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23257303  }}</ref><ref name="pmid9738727">{{cite journal| author=Feoli-Fonseca JC, Lévy E, Godard M, Lambert M| title=Familial lipoprotein lipase deficiency in infancy: clinical, biochemical, and molecular study. | journal=J Pediatr | year= 1998 | volume= 133 | issue= 3 | pages= 417-23 | pmid=9738727 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9738727  }}</ref>
*Abdominal pain (may appear as colic in infancy)
*Loss of appetite, fatigue and irritability
*Nausea
*Pain in the muscles and bones (musculoskeletal pain)
*Vomiting
*Small yellow papules localized over the trunk, buttocks, knees, and extensor surfaces of the arms
*Blood in stools(Intestinal ischemia)
*In rare cases, neurological features of depression, memory loss, and mild intellectual decline (dementia) develop
===Physical examination===
Signs of Type 1 hyperlipoproteinemia include:<ref name="rare diseasediorders2" /><ref name="medline plus2" /><ref name="pmid232573032" /><ref name="pmid9738727" /><ref name="pmid12387965" />
* Enlarged liver and spleen
* Failure to thrive in infancy
* Fatty deposits in the skin (xanthomas)
* Pale retinas and white-colored blood vessels in the retinas
* Pancreatitis that keeps returning
* Yellowing of the eyes and skin (jaundice)
<gallery>
File:Xanthoma-close-up.jpg
</gallery>
===Laboratory findings===
*Diagnosis of Type I hyperlipoproteinemia is confirmed by detection of low or absent LPL enzyme activity in an assay system, that contains either normal plasma or apoprotein C-II excluding hepatic lipase.


When triglyceride concentrations exceed 4000 mg/dL, the retinal arterioles and venules, and often the fundus itself, develop a pale pink color ("lipemia retinalis"), caused by light scattering by large chylomicrons. This coloration is reversible and vision is not affected.
*Laboratory findings consistent with the Type I hyperlipoproteinemia include the following:<ref name="national organization of rare disorders2" /><ref name="rare diseasediorders2" /><ref name="pmid232573032" />
 
Reversible neuropsychiatric findings, including mild dementia, depression, and memory loss, have also been reported with chylomicronemia
 
==Physical examination==
Signs of this condition include:
 
Enlarged liver and spleen
Failure to thrive in infancy
Fatty deposits in the skin (xanthomas)
High triglyceride levels in the blood
Pale retinas and white-colored blood vessels in the retinas
Pancreatitis that keeps returning
Yellowing of the eyes and skin (jaundice
 
==Laboratory finding==
{| class="wikitable"
{| class="wikitable"
! colspan="9" |Laboratory finding
! colspan="11" |Laboratory finding
|-
|-
|Phenotype
|Phenotype
Line 171: Line 117:
|Serum total
|Serum total
cholesterol
cholesterol
|Serum  
|HDL
|VLDL
|Serum
triglycerides
triglycerides
|Plasma
|Plasma
appearance
appearance
|Postheparin
|Postheparin
lipolytic  
lipolytic


activity
activity
|Glucose  
|Glucose
tolerance
tolerance
|Carbohydrate
|Carbohydrate
Line 186: Line 134:
|-
|-
|Hyperlipoproteinemia type 1
|Hyperlipoproteinemia type 1
|Chylomicrons  
|Chylomicrons '''↑↑↑↑'''
|Normal to
|Normal to
elevated
elevated
|Elevated
|'''↓↓↓'''
|'''↓'''
|'''↑↑↑↑'''
|Creamy
|Creamy
|Decreased  
|Decreased
|Normal
|Normal
|May be abnormal
|May be abnormal
|Markedly abnormal  
|Markedly abnormal
|}
|}
 
===Molecular Genetic Testing===
Testing
*Diagnosis can be confirmed by molecular genetic testing that can detect mutations in the LPL gene.<ref name="pmid275781122" />
 
*The test is often not necessary to confirm a diagnosis of type I hyperlipidemia.
Chylomicronemia / plasma triglyceride concentration
 
Affected individuals
Chylomicrons are large lipoprotein particles that appear in the circulation shortly after the ingestion of dietary fat; normally, they are cleared from plasma after an overnight fast. In familial LPL deficiency, clearance of chylomicrons from the plasma is impaired, causing triglycerides to accumulate in plasma and the plasma to have a milky ("lactescent" or "lipemic") appearance.
Plasma triglyceride concentrations
In the presence of chylomicrons plasma triglyceride concentrations can be estimated fairly accurately by visual inspection. Plasma triglyceride concentrations are usually greater than 2000 mg/dL in the untreated state.
It is important to measure the plasma triglyceride concentration once as a baseline.
Routine measurement of non-fasting plasma triglyceride concentration can be used when fasting samples are difficult to obtain (e.g., in infants).
Plasma triglyceride concentration is an excellent measure of compliance with dietary fat restrictions.
Carriers. Heterozygotes have normal to moderately elevated plasma triglyceride concentrations.
Measurement of lipoprotein lipase enzyme activity
 
Affected individuals. The diagnosis of familial lipoprotein lipase deficiency is confirmed by detection of low or absent LPL enzyme activity in an assay system that contains either normal plasma or apoprotein C-II (a cofactor of LPL) and excludes hepatic lipase (HL).
LPL enzyme activity can be assayed in plasma ten minutes following intravenous administration of heparin (60 U/kg body wt). The absence of lipoprotein lipase enzyme activity in postheparin plasma is diagnostic of familial LPL deficiency.
LPL enzyme activity may be assayed directly in biopsies of adipose tissue.
LPL enzyme activity can be measured in selected children and young adults. For more information, contact the author at ude.notgnihsaw.u@lleznurb.
Carriers. Heterozygotes exhibit a 50% decrease of LPL enzyme activity in plasma following intravenous administration of heparin.
Molecular Genetic Testing
 
Gene. LPL is the only gene in which pathogenic variants are known to cause familial lipoprotein lipase deficiency.
 
Clinical testing
 
Table 1.
 
Summary of Molecular Genetic Testing Used in Familial Lipoprotein Lipase Deficiency
 
Gene 1 Test Method Variants Detected 2 Variant Detection Frequency by Test Method 3
LPL Sequence analysis Sequence variants 4 (including p.Gly188Glu 5) ~97% 6
Deletion/duplication analysis 7 Partial- and whole-gene deletions and duplications ~3% 8
1.
See Table A. Genes and Databases for chromosome locus and protein.
 
2.
See Molecular Genetics for information on allelic variants.
 
3.
The ability of the test method used to detect a pathogenic variant that is present in the indicated gene
 
4.
Examples of pathogenic variants detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
 
5.
The pathogenic variant p.Gly188Glu, common in Europe, is present in fewer than 40% of individuals with LPL deficiency.
 
6.
Brunzell & Deeb [2001], Gilbert et al [2001]
 
7.
Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
 
8.
Brunzell & Deeb [2001]
 
Testing Strategy
 
To confirm/establish the diagnosis in a proband. Persistent severe hypertriglyceridemia (1000-2000 mg/dL) in an infant or child that is responsive to dietary fat intake is indicative of LPL deficiency.
 
When LPL deficiency is first suspected, a history of failure to thrive as an infant or recurrent abdominal pain as a child should be sought.
A fasting plasma triglyceride concentration should be obtained at least once for documentation.
Note: Neither measurement of post-heparin plasma LPL enzyme activity nor LPL molecular genetic testing is required to make a presumptive clinical diagnosis.
 
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
 
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
 
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family
 
==Treatment==
==Treatment==
The main therapeutical approach of Type I hyperlipoproteinemia is based on diet treatment to reduce triglyceride (TG) levels.20 TG-lowering drugs, such as niacin and fibrates, are not effective in patients with type I hyperlipoproteinemia.21 Orlistat, a gastric lipase inhibitor that reduces fat availability, has been used successfully in the treatment of moderate and severe LPL deficiency.22 and 23 Recently, gene replacement using alipogene tiparvovec has been the very first therapy approved by European Medicines Agency for the treatment of type I hyperlipoproteinemia.24 Alipogene tiparvovec introduces a human LPL gene into the body, resulting in the production of functional LPL. 25 However, this gene therapy is indicated only in adults with genetic diagnosis of LPL deficiency who have had recurrent pancreatitis and with a residual lipoprotein mass in the circulation. 24 and 26 Thus, careful genetic screening and functional testing of LPL are required to identify patients eligible for this new therapeutic approach.
Treatment for hyperlipoproteinemia type 1 is intended to control blood triglyceride levels. There is currently no pharmacotherapy approved for the treatment of familial hyperchylomicronemia in the United States The mainstay of treatment includes dietary modification and control.
 
===Medical Therapy===
Pregnancy Management
There is currently no pharmacotherapy approved for the treatment of familial hyperchylomicronemia in the United States
 
===Dietary Management===
During pregnancy in a woman with LPL deficiency, extreme dietary fat restriction to less than two grams per day during the second and third trimester with close monitoring of plasma triglyceride concentration can result in delivery of a normal infant with normal plasma concentrations of essential fatty acids [Al-Shali et al 2002].
Dietary management of hyperlipoproteinemia type 1 include the following:<ref name="rare diseasediorders2" /><ref name="GeneReviews2" /> <ref name="medline plus2" />
 
*Controlling blood triglyceride levels with a very low-fat diet
One woman with LPL deficiency delivered a normal child following a one-gram fat diet and treatment with gemfibrozil (600 mg 1x/day) [Tsai et al 2004]. Despite concerns about the possibility of essential fatty acid deficiency in the newborn, normal essential fatty acids were found in cord blood, as were normal levels of fibrate metabolites.
*It is recommended that individuals with this condition eat no more than 20 grams of fat per day.
 
*Medium-chain fatty acids (such as coconut oil) can be incorporated into the diet, as they are absorbed by the body in a different manner.
*Dietary counseling may be helpful to maintain adequate calorie and nutrient intake.
===Pregnancy Management===
*Pregnant women may experience significant changes in lipid level in second and third trimester, and may require strategies to lower fat intake. Pregnancy management of type 1hyperlipoproteinemia involves the following:<ref name="pmid119833472">{{cite journal| author=Al-Shali K, Wang J, Fellows F, Huff MW, Wolfe BM, Hegele RA| title=Successful pregnancy outcome in a patient with severe chylomicronemia due to compound heterozygosity for mutant lipoprotein lipase. | journal=Clin Biochem | year= 2002 | volume= 35 | issue= 2 | pages= 125-30 | pmid=11983347 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11983347  }}</ref>
*Periodic assessment of plasma triglycerides is highly recommended
*Comprehensive analysis of risks versus benefits is required before the use of fibrates, nicotinic acid and omega-3 fatty acid
===Investigative Therapies===
*Orlistat, in conjunction with a low fat diet has been used to treat some patients with familial hyperchilomicronemia caused by compound heterozygous LPL deficiency.<ref name="pmid234154322">{{cite journal| author=Blackett P, Tryggestad J, Krishnan S, Li S, Xu W, Alaupovic P et al.| title=Lipoprotein abnormalities in compound heterozygous lipoprotein lipase deficiency after treatment with a low-fat diet and orlistat. | journal=J Clin Lipidol | year= 2013 | volume= 7 | issue= 2 | pages= 132-9 | pmid=23415432 | doi=10.1016/j.jacl.2012.11.006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23415432  }}</ref>
===Gene Therapy===
*Alipogene tipavovec(Glybera) gene therapy was approved by European commission(2012), in treating adult patients with recurrent episodes of pancreatitis.<ref name="pmid274124552">{{cite journal| author=Gaudet D, Stroes ES, Méthot J, Brisson D, Tremblay K, Bernelot Moens SJ et al.| title=Long-Term Retrospective Analysis of Gene Therapy with Alipogene Tiparvovec and Its Effect on Lipoprotein Lipase Deficiency-Induced Pancreatitis. | journal=Hum Gene Ther | year= 2016 | volume=  | issue=  | pages=  | pmid=27412455 | doi=10.1089/hum.2015.158 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27412455  }}</ref>
==Prevention==
==Prevention==


Genetic counseling.
=== Primary Prevention ===
 
*There are no primary preventive measures to protect against type I hyperlipoproteinemia. There is currently no known intervention to prevent someone from inheriting this condition.<ref name="rare diseasediorders2" />
Familial lipoprotein lipase deficiency is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
*Genetic counseling is recommended for patients and family members.<ref name="pmid277719612">{{cite journal| author=Ahmad Z, Halter R, Stevenson M| title=Building a better understanding of the burden of disease in familial chylomicronemia syndrome. | journal=Expert Rev Clin Pharmacol | year= 2016 | volume=  | issue=  | pages= 1-3 | pmid=27771961 | doi=10.1080/17512433.2017.1251839 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27771961  }}</ref>
 
===Secondary prevention===
Prevention of Primary Manifestations
Secondary prevention involves the following:<ref name="medline plus2" /><ref name="pmid27771961">{{cite journal| author=Ahmad Z, Halter R, Stevenson M| title=Building a better understanding of the burden of disease in familial chylomicronemia syndrome. | journal=Expert Rev Clin Pharmacol | year= 2016 | volume=  | issue=  | pages= 1-3 | pmid=27771961 | doi=10.1080/17512433.2017.1251839 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27771961  }}</ref>
 
*Prevention of acute recurrent pancreatitis decreases the risk of development of diabetes mellitus and fat malabsorption.
Medical nutrition therapy. Maintaining the plasma triglyceride concentration at less than 2000 mg/dL keeps the individual with familial LPL deficiency free of symptoms. This can be accomplished by restriction of dietary fat to no more than 20 g/day or 15% of total energy intake.
*Maintaining the plasma triglyceride concentration at less than 2000 mg/dl, keeps the individual with familial LPL deficiency free of symptoms. This can be accomplished by restriction of dietary fat to no more than 20 g/day or 15% of total energy intake.
 
*Periodic assessment of plasma triglycerides levels is highly recommended.
Prevention of Secondary Complications
*Patients should avoid agents that increased endogenous triglyceride levels like alcohol, diuretics, oral estrogens, isoretinoin, glucocorticords, and beta-blockers.
 
==References==
Prevention of acute recurrent pancreatitis decreases the risk of development of diabetes mellitus. Fat malabsorption is very rare.
 
 
 
 
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Vishal Devarkonda, M.B.B.S[2]Aysha Aslam, M.B.B.S[3]

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Synonyms and keywords: Type I hyperlipoproteinemia, Burger-Grutz syndrome, Primary hyperlipoproteinemia, lipoprotein lipase deficiency, LPL deficiency, Idiopathic hyperlipemia, Essential hyperlipemia, Familial hyperlipemia, Lipase D deficiency, Hyperlipoproteinemia type IA, Familial chylomicronemia, Familial lipoprotein lipase deficiency, and Familial hyperchylomicronemia.

Overview

This very rare hyperlipidemia is due to a deficiency of lipoprotein lipase (LPL) or altered apolipoprotein C2, resulting in elevated chylomicron which are the particles that transfer fatty acids from the digestive tract to the liver. Lipoprotein lipase is also responsible for the initial breakdown of endogenously made triacylglycerides in the form of very low density lipoprotein (VLDL). As such, one would expect a defect in LPL to also result in elevated VLDL. Its prevalence is one in 1,000,000 population.

Historical Perspective

  • In 1932, Familial LPL deficency was first described by Burger and Grutz[1]
  • In 1967, Fredrickson using paper electrophosresis, classified lipoprotein disorder[2]

Classification

There is no established classification system for Type I hyperlipoproteinemia. However, based on the pathogenesis involved type 1 hyperlipoproteinemia can be classified into:[3]

Type 1a: Lipoprotein lipase deficiency

Type 1b: Apolipoprotein c-IIdeficiency

Type 1c: Presence of lipoprotein lipase inhibitor

Pathophysiology

Pathogenesis

  • Lipoprotein lipase(LPL) hydrolyzes triglyceride-rich lipoproteins (TG) such as chylomicrons and very low-density lipoproteins. It catalyzes, the removal of TG from the bloodstream generating free fatty acids for tissues.
  • For full enzymatic activity, LPL requires following cofactors:[4]
  • Familial lipoprotein lipase inhibitor inherited in an autosomal dominant fashion. Inhibit the action of lipoprotein lipase, resulting in decreased postheparin plasma LPL activity, elevated adipose tissue LPL activity, and normal plasma levels of functional apoC-I1.[8]
  • Functionally inactive or absent lipoprotein lipase enzyme, results in massive accumulation of chylomicrons, with extremely high level of plasma triglycerides.

Genetics

  • More than 220 mutations in the LPL gene have been found to cause familial lipoprotein lipase deficiency. The most common mutation in people of European ancestry replaces the protein building block (amino acid) glycine with the amino acid glutamic acid at position 188 in the enzyme (written as Gly188Glu or G188E).[8]

Causes

The cause of type 1 hyperlipidemia remains genetic.[1][9][4][10]

Gene 1 Variants Detected 2 Variant Detection Frequency by Test Method 3 LPL Sequence variants 4 (including p.Gly188Glu 5) ~97% 6
Partial- and whole-gene deletions and duplications ~3% 8

Differential diagnosis

Epidemiology and Demographics

Epidemiological and demographics of familial hyperchylomicronemia are discussed below:[4][9][1]

Prevalence

  • The prevalence of familial LPL deficiency is approximately one in 1,000,000 in the general US population

Demographics

Age

  • 25% of affected children develop symptoms before one year of age.
  • The majority of patients develop symptoms before ten years of age.
  • Few individuals develop symptoms, at the time of pregnancy.

Gender

  • Males and females are equally affected by familial chylomicronemia..

Race

  • The disease has been described in all races.
  • The prevalence is much higher in some areas of Quebec, Canada, as a result of a founder effect.

Screening

  • There are no screening guidelines for Familial hyperchylomicronemia.[9][4][11]
  • It may be appropriate to measure plasma triglyceride concentration in at-risk siblings during infancy; early diagnosis and implementation of dietary fat intake restriction can prevent symptoms and related medical complications.

Natural History, Complications, and Prognosis

Natural history, complications and prognosis of type 1 hyperlipoproteinemia include:[11][12][13]

Natural History

  • If left untreated, pancreatitis can develop into a chronic condition that can damage the pancreas and, in rare cases it could be life-threatening.

Complications

  • Pancreatitis and recurrent episodes of abdominal pain may develop.
  • Intestinal ischemia
  • Depression,
  • Memory loss
  • Intellectual decline

Prognosis

  • People with this condition who follow a very low-fat diet have a good prognosis.

Diagnosis

History and symptoms

Presumptive diagnosis can be made, when an infant presents with a history of failure to thrive or recurrent abdominal pain with a documented high fasting plasma triglyceride concentration.[14][11]

Symptoms of Type I hyperlipoproteinemia include:[9][11][15][13]

  • Abdominal pain (may appear as colic in infancy)
  • Loss of appetite, fatigue and irritability
  • Nausea
  • Pain in the muscles and bones (musculoskeletal pain)
  • Vomiting
  • Small yellow papules localized over the trunk, buttocks, knees, and extensor surfaces of the arms
  • Blood in stools(Intestinal ischemia)
  • In rare cases, neurological features of depression, memory loss, and mild intellectual decline (dementia) develop

Physical examination

Signs of Type 1 hyperlipoproteinemia include:[9][11][15][13][12]

  • Enlarged liver and spleen
  • Failure to thrive in infancy
  • Fatty deposits in the skin (xanthomas)
  • Pale retinas and white-colored blood vessels in the retinas
  • Pancreatitis that keeps returning
  • Yellowing of the eyes and skin (jaundice)

Laboratory findings

  • Diagnosis of Type I hyperlipoproteinemia is confirmed by detection of low or absent LPL enzyme activity in an assay system, that contains either normal plasma or apoprotein C-II excluding hepatic lipase.
  • Laboratory findings consistent with the Type I hyperlipoproteinemia include the following:[1][9][15]
Laboratory finding
Phenotype Lipoprotein(s)

Elevated

Serum total

cholesterol

HDL VLDL Serum

triglycerides

Plasma

appearance

Postheparin

lipolytic

activity

Glucose

tolerance

Carbohydrate

inducibility

Fat tolerance
Hyperlipoproteinemia type 1 Chylomicrons ↑↑↑↑ Normal to

elevated

↓↓↓ ↑↑↑↑ Creamy Decreased Normal May be abnormal Markedly abnormal

Molecular Genetic Testing

  • Diagnosis can be confirmed by molecular genetic testing that can detect mutations in the LPL gene.[4]
  • The test is often not necessary to confirm a diagnosis of type I hyperlipidemia.

Treatment

Treatment for hyperlipoproteinemia type 1 is intended to control blood triglyceride levels. There is currently no pharmacotherapy approved for the treatment of familial hyperchylomicronemia in the United States The mainstay of treatment includes dietary modification and control.

Medical Therapy

There is currently no pharmacotherapy approved for the treatment of familial hyperchylomicronemia in the United States

Dietary Management

Dietary management of hyperlipoproteinemia type 1 include the following:[9][14] [11]

  • Controlling blood triglyceride levels with a very low-fat diet
  • It is recommended that individuals with this condition eat no more than 20 grams of fat per day.
  • Medium-chain fatty acids (such as coconut oil) can be incorporated into the diet, as they are absorbed by the body in a different manner.
  • Dietary counseling may be helpful to maintain adequate calorie and nutrient intake.

Pregnancy Management

  • Pregnant women may experience significant changes in lipid level in second and third trimester, and may require strategies to lower fat intake. Pregnancy management of type 1hyperlipoproteinemia involves the following:[16]
  • Periodic assessment of plasma triglycerides is highly recommended
  • Comprehensive analysis of risks versus benefits is required before the use of fibrates, nicotinic acid and omega-3 fatty acid

Investigative Therapies

  • Orlistat, in conjunction with a low fat diet has been used to treat some patients with familial hyperchilomicronemia caused by compound heterozygous LPL deficiency.[17]

Gene Therapy

  • Alipogene tipavovec(Glybera) gene therapy was approved by European commission(2012), in treating adult patients with recurrent episodes of pancreatitis.[18]

Prevention

Primary Prevention

  • There are no primary preventive measures to protect against type I hyperlipoproteinemia. There is currently no known intervention to prevent someone from inheriting this condition.[9]
  • Genetic counseling is recommended for patients and family members.[19]

Secondary prevention

Secondary prevention involves the following:[11][20]

  • Prevention of acute recurrent pancreatitis decreases the risk of development of diabetes mellitus and fat malabsorption.
  • Maintaining the plasma triglyceride concentration at less than 2000 mg/dl, keeps the individual with familial LPL deficiency free of symptoms. This can be accomplished by restriction of dietary fat to no more than 20 g/day or 15% of total energy intake.
  • Periodic assessment of plasma triglycerides levels is highly recommended.
  • Patients should avoid agents that increased endogenous triglyceride levels like alcohol, diuretics, oral estrogens, isoretinoin, glucocorticords, and beta-blockers.

References

  1. 1.0 1.1 1.2 1.3 {{http://rarediseases.org/rare-diseases/familial-lipoprotein-lipase-deficiency}}/Accessed on 7 November,2016
  2. Culliton BJ (1987). "Fredrickson's bitter end at Hughes". Science. 236 (4807): 1417–8. PMID 3296193.
  3. Brahm A, Hegele RA (2013). "Hypertriglyceridemia". Nutrients. 5 (3): 981–1001. doi:10.3390/nu5030981. PMC 3705331. PMID 23525082.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Pingitore P, Lepore SM, Pirazzi C, Mancina RM, Motta BM, Valenti L; et al. (2016). "Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia". J Clin Lipidol. 10 (4): 816–23. doi:10.1016/j.jacl.2016.02.015. PMID 27578112.
  5. Young SG, Zechner R (2013). "Biochemistry and pathophysiology of intravascular and intracellular lipolysis". Genes Dev. 27 (5): 459–84. doi:10.1101/gad.209296.112. PMC 3605461. PMID 23475957.
  6. Pasalić D, Jurcić Z, Stipancić G, Ferencak G, Leren TP, Djurovic S; et al. (2004). "Missense mutation W86R in exon 3 of the lipoprotein lipase gene in a boy with chylomicronemia". Clin Chim Acta. 343 (1–2): 179–84. doi:10.1016/j.cccn.2004.01.029. PMID 15115692.
  7. Gilbert B, Rouis M, Griglio S, de Lumley L, Laplaud P (2001). "Lipoprotein lipase (LPL) deficiency: a new patient homozygote for the preponderant mutation Gly188Glu in the human LPL gene and review of reported mutations: 75 % are clustered in exons 5 and 6". Ann Genet. 44 (1): 25–32. PMID 11334614.
  8. 8.0 8.1 https://ghr.nlm.nih.gov/gene/LPL#conditions
  9. 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 https://rarediseases.info.nih.gov/diseases/6414/hyperlipoproteinemia-type-1 Accessed on 7 November,2016
  10. Peterson J, Ayyobi AF, Ma Y, Henderson H, Reina M, Deeb SS; et al. (2002). "Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene". J Lipid Res. 43 (3): 398–406. PMID 11893776.
  11. 11.0 11.1 11.2 11.3 11.4 11.5 11.6 https://medlineplus.gov/ency/article/000405.htm
  12. 12.0 12.1
  13. 13.0 13.1 13.2 Feoli-Fonseca JC, Lévy E, Godard M, Lambert M (1998). "Familial lipoprotein lipase deficiency in infancy: clinical, biochemical, and molecular study". J Pediatr. 133 (3): 417–23. PMID 9738727.
  14. 14.0 14.1 {{https://www.ncbi.nlm.nih.gov/books/NBK1308/}} Accessed on 7 November,2016
  15. 15.0 15.1 15.2 Robinson JG (2012). "What is the role of advanced lipoprotein analysis in practice?". J Am Coll Cardiol. 60 (25): 2607–15. doi:10.1016/j.jacc.2012.04.067. PMID 23257303.
  16. Al-Shali K, Wang J, Fellows F, Huff MW, Wolfe BM, Hegele RA (2002). "Successful pregnancy outcome in a patient with severe chylomicronemia due to compound heterozygosity for mutant lipoprotein lipase". Clin Biochem. 35 (2): 125–30. PMID 11983347.
  17. Blackett P, Tryggestad J, Krishnan S, Li S, Xu W, Alaupovic P; et al. (2013). "Lipoprotein abnormalities in compound heterozygous lipoprotein lipase deficiency after treatment with a low-fat diet and orlistat". J Clin Lipidol. 7 (2): 132–9. doi:10.1016/j.jacl.2012.11.006. PMID 23415432.
  18. Gaudet D, Stroes ES, Méthot J, Brisson D, Tremblay K, Bernelot Moens SJ; et al. (2016). "Long-Term Retrospective Analysis of Gene Therapy with Alipogene Tiparvovec and Its Effect on Lipoprotein Lipase Deficiency-Induced Pancreatitis". Hum Gene Ther. doi:10.1089/hum.2015.158. PMID 27412455.
  19. Ahmad Z, Halter R, Stevenson M (2016). "Building a better understanding of the burden of disease in familial chylomicronemia syndrome". Expert Rev Clin Pharmacol: 1–3. doi:10.1080/17512433.2017.1251839. PMID 27771961.
  20. Ahmad Z, Halter R, Stevenson M (2016). "Building a better understanding of the burden of disease in familial chylomicronemia syndrome". Expert Rev Clin Pharmacol: 1–3. doi:10.1080/17512433.2017.1251839. PMID 27771961.

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