Brief overview of lipoprotein lipase deficiency
Don’t we all love a bucket of hot and spicy wings and fried chicken? Now, after a heavy and satisfying meal, our body needs to break the fat down. The mechanism of our body is well-networked and well-formulated to cater to every kind of reaction and outcome.
Lipoprotein lipase deficiency is a rare genetic disorder that shows its first symptoms during childhood. The function of the enzyme lipoprotein lipase is to hydrolyse triglycerides into fatty acids and glycerol. Fatty acids are the simplest unit of fat that is absorbed by the body.
Introduction to familial lipoprotein lipase deficiency (FLD)
Familial lipoprotein lipase deficiency (FLD) is a genetic disorder categorised as an autosomal recessive one. ¹ It is also a rare metabolic disorder in which the individual lacks the ability to break down triglycerides in the blood, which prevents the further breakdown of the triglycerides into fatty acids and glycerol and the transport of the fatty acids. Due to this, there is an increase in the number of chylomicrons, and this condition is called chylomicronemia. ²
Genetic basis of familial lipoprotein lipase deficiency (FLD)
Explanation of genetic inheritance (autosomal recessive)
Humans have 46 chromosomes (23 pairs). The way we inherit characters from our parents is through genes. We have two sets of chromosomes- autosomes (22 pairs), and the 23rd pair belongs to the sex chromosomes (X and Y). There are several ways through which the inheritance of a disease or a condition takes place, such as autosomal dominant, autosomal recessive, X-linked (The genes transmitted are linked to the X chromosome) dominant, X-linked recessive, Y-linked (The genes transmitted are linked to the Y chromosome).
To understand a pattern of inheritance, a pedigree chart is drawn. Say an individual suffers from a genetic disorder and wants to figure out how they received the genes. They would approach a genetic counsellor, who would analyse the individual’s family history and then draw a chart.
What does autosomal recessive mean?
The conditions that are said to be autosomal recessive occur through the passing of the disease/disorder/condition/characteristic-related genes from the autosomes. Since we are talking about a recessive case, a person would need two of the disease genes in order to be affected, whereas, for a dominant case, only one of the disease genes is enough. Autosomal recessive disorders are transmitted to men and women equally.
How does an individual get affected by an autosomal recessive condition?
If the gene for the disease is present in the parents alongside other normal genes, the parents are called unaffected carriers. Since it is a recessive condition, two of these genes would cause the disease. The offspring, in this case, would have the following pattern-
Child one- Receives the dominant genes (the unaffected ones), and hence is unaffected.
Children two and three- Receive one set of the disease genes and one set of the normal genes and, hence, a carrier of the disease. But they are unaffected.
Child four- Receives both the disease genes (the recessive, affected ones), and hence is affected by the condition.
How do genetic mutations affect lipoprotein lipase function?
The gene that codes for lipoprotein lipase is called the LPL gene, which is present on chromosome 8 in humans. ⁵ Mutations in the LPL gene, particularly amino acid substitution mutations, have been observed. Mutations in the gene exhibit a depreciation of the lipoprotein lipase activity, which makes the affected individual prone to dyslipidemia (It is the imbalance of lipids like cholesterol and triglycerides) and cardiovascular diseases.⁴
Lipoprotein Lipase Function
Explanation of lipoproteins and their role in transporting fats
The function of lipoprotein lipase is a principal enzyme that is involved in lipid metabolism. The enzyme, a secretory protein, is located on the walls of the capillaries and on the vascular endothelial surface. It is an extracellular enzyme. Its function is to carry out the hydrolysis of triglycerides into fatty acids and glycerol in the lipoproteins, such as chylomicrons, from the bloodstream.³
Role of lipoprotein lipase in breaking down triglycerides
The mechanism of lipoprotein lipase in breaking down triglycerides is by the employment of a cofactor called apolipoprotein-CII for the activation of the enzyme. The cofactor is carried by a chylomicron, a very low-density lipoprotein (VLDL), plus an intermediate-density lipoprotein (IDL). This causes the enzyme to activate. Lipoprotein lipase will then reduce the triglycerides into simpler forms- fatty acids and glycerol. The fatty acids are then transported to the skeletal muscle and adipocytes (Cells of the adipose tissue, commonly called the fat tissue). Simultaneously, the liver takes up the remainder of the chylomicron through receptor-mediated endocytosis.³
Importance of regular lipoprotein lipase activity for health
The enzyme lipoprotein lipase is essential for lipid homeostasis because it plays the lead role in the hydrolysis of triglycerides. Without the enzyme, individuals would have really high levels of chylomicrons in the blood, which leads to a condition called chylomicronemia. ¹⁶
Clinical presentation of FLD
Common symptoms and signs of familial lipoprotein lipase deficiency
It is said that most cases are shown to appear during childhood. As the nature of the disease prevents the digestion of fat, the accumulated triglycerides lead to other chronic issues surrounding the digestive system as well. The most prevalent symptom is intermittent abdominal pain, which can occur in the upper and central regions of the abdomen and can radiate back pain. The abdominal pain can range from mild to severe. Some people might even have to face pancreatitis. In the young, the liver and spleen would be enlarged. Half of the affected population is diagnosed with cutaneous xanthomas. Other symptoms include dementia, depression, and premature atherosclerosis.²
Risk factors for developing FLD-related complications
The severity of the deficiency depends on the strength of chylomicronemia, which is basically the amount of unbroken chylomicrons present in the bloodstream.²
Complications from familial lipoprotein lipase deficiency (FLD)
Some of the complications from Familial Lipoprotein lipase Deficiency include Diabetes Mellitus, chronic pancreatitis, pancreatic calcifications, and steatorrhea (stool containing excess fat since it is not absorbed by the body. It tends to float, appear frothy, and is accompanied by a foul odour).¹²
Diagnosis and screening
Methods for diagnosing FLD
In order to come to a conclusion that the individual is indeed suffering from Familial Lipoprotein lipase Deficiency (FLD), it is important to take note of the concerned individual’s family history since this is a matter of a genetically transmitted condition. The techniques of genetic testing can be used here to confirm the mutation in the gene (LPL gene). Genetic testing makes use of the individual’s blood or tissues to analyse genetic material like DNA or chromosomes for any anomalies.¹²⁷ Blood tests can also be done to check the decrease in the activity of lipoprotein lipase through the injection of heparin.¹² Heparin is a polysaccharide found in the liver that is also an anti-coagulant of blood. It is known to stimulate the liberation of lipoprotein lipase in the body.²
Importance of early detection and screening for at-risk individuals
It is important that people opt for early detection of any condition based on the symptoms they face. Familial Lipoprotein lipase Deficiency (FLD), as we know, is a genetic condition, and it poses great risks to the affected person. To understand a couple’s genetic makeup, it is highly advised to approach a genetic counsellor to thoroughly understand the family history and learn about the health risks.¹ This enables a chance to prevent complications of the affected progeny when they grow up. If a genetic disease is diagnosed when the person is an infant or a juvenile, there are plenty of chances to stop further complications, such as gene therapy, which is still an ongoing study, research, and debate.
Management and treatment
Dietary and lifestyle recommendations for managing FLD
Since the whole plot of this deficiency revolves around the fact that the affected individual cannot hydrolyse triglycerides present in the bloodstream, it is evident that the diet must be as fat-free as possible. Studies have shown that it is optimum for such patients to ensure that their triglyceride levels in the blood plasma are maintained below 1000 milligrams/decilitre (mg/dL). It is also recommended to maintain an intake of 20 grams of fat per day. Alcohol is known to increase triglyceride levels and is advised to avoid. Drugs such as oral estrogens, diuretics, beta-adrenergic blockers, etc., are also known to increase triglyceride levels.¹ It is said that in cases of an enlarged liver, through lowered triglyceride levels, it can return to its original size.⁹
Potential for gene therapy and emerging treatment options
There is an option for gene therapy for Familial Lipoprotein lipase Deficiency (FLD). It is called alipogene tiparvovec gene therapy. This therapy involves a genetically engineered adeno-associated virus, genotype 1, which is known as alipogene tiparvovec. This virus consists of an LPL Ser447X variant. These two components form a vector called an adenovirus vector, which is injected intramuscularly. By doing this, a working copy of the LPL gene would be inserted into the affected individual’s body and hence would play a role in lowering or reducing the triglyceride levels. It is currently off the market because of low demand.¹
Treatment through medication
There is an orally administered drug called Pradigastat. Its role is to catalyse the last step in the synthesis of triglycerides, which reduces the chylomicron-triglyceride secretion.¹
Support and quality of life
Psychological and emotional impact of FLD on patients and families
Living with a genetic disorder can be frustrating and daunting. It definitely tends to take a toll on the patient mentally, emotionally, and physically. A study focusing on three people affected with Familial Lipoprotein lipase Deficiency (FLD) was conducted to understand these changes better. The report recorded the people saying that they were scared, anxious, depressed, etc., when they had to get hospitalised many times. The recurring scenes had a disturbing effect on them. Two people said that their spouses were worried and scared. This disease has even impacted daily life such as causing issues in socialising, being reliant on family and friends for support, and remaining in a constant mode of fear because they did not know when the next pancreatitis episode would show up and how severe it would turn out to be. Trouble in college and work life has also been recorded, along with financial difficulties.⁸
Strategies for improving the quality of life for individuals with FLD
Some of the strategies that can be implemented in order to improve the life of a person diagnosed with Familial Lipoprotein lipase Deficiency (FLD) are listed below:
- Encourage the affected individuals to seek counselling or therapy for their mental health. Most of the time, support groups are encouraged wherein many people diagnosed with the same condition or disease talk about their experiences and share their stories. This would provide a sense of belongingness to people and would give them some courage to fight.
- A strict diet devoid of fat or with very tiny amounts of fat would ensure that the triglyceride levels are within the range recommended for the diagnosed people.
Familial Lipoprotein lipase Deficiency (FLD) is a rare, genetically transmitted condition that follows a pattern of autosomal recessive inheritance. Lipoprotein lipase is the enzyme that aims to hydrolyse triglycerides in the blood into fatty acids and glycerol so that they can be absorbed by the tissues of the body. It is always recommended for people to go for early detection of a disease upon seeing abnormal behaviour or symptoms since it reduces the chances of complications and other health risks. It would also be easier to curb the condition through medication and diet alterations. It is also recommended that the couple approach a genetic counsellor in order to understand the family history of health conditions. It is also always beneficial that people enter a marriage outside of the family to reduce the risks of genetic conditions, which are prone to be transmitted in cases of consanguinity.
The genetic disorder familial lipoprotein lipase deficiency (FLD) is autosomal recessive. The function of lipoprotein lipase is a principal enzyme that is involved in lipid metabolism. In lipid homeostasis, lipoprotein lipase plays an essential role in hydrolyzing triglycerides. Humans have the LPL gene that codes for lipoprotein lipase, which is located on chromosome 8. A high level of chylomicrons in the blood would result without the enzyme.
It is said that most cases are shown to appear during childhood. The most prevalent symptom is intermittent abdominal pain, which can occur in the upper and central regions of the abdomen and can radiate back pain. The abdominal pain can range from mild to severe. Some people might even have to face pancreatitis.
The techniques of genetic testing can be used here which can give us a confirmation about the mutation in the gene (LPL gene). Blood tests can also be done to check the decrease in the activity of lipoprotein lipase through the injection of heparin. Treatment methods include the restriction of fat in the diet, medication, and gene therapy.
It is always encouraged to speak with a genetic counsellor to understand your family's health history and the potential health risks present.
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- D. Bruce K, Tang M, Reigan P, H. Eckel R. Genetic variants of lipoprotein lipase and regulatory factors associated with Alzheimer’s disease risk. Int J Mol Sci [Internet]. 2020 Nov 6 [cited 2023 Aug 30];21(21):8338. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664401/
- Kumari A, Kristensen KK, Ploug M, Winther AML. The importance of lipoprotein lipase regulation in atherosclerosis. Biomedicines [Internet]. 2021 Jul 6 [cited 2023 Aug 30];9(7):782. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301479/
- Alliance G, Screening Services TNYMAC for G and N. Genetic testing. In: Understanding Genetics: A New York, Mid-Atlantic Guide for Patients and Health Professionals [Internet]. Genetic Alliance; 2009 [cited 2023 Aug 31]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK115571/
- Neelamekam S, Kwok S, Malone R, Wierzbicki AS, Soran H. The impact of lipoprotein lipase deficiency on health-related quality of life: a detailed, structured, qualitative study. Orphanet Journal of Rare Diseases [Internet]. 2017 Sep 19 [cited 2023 Aug 31];12(1):156. Available from: https://doi.org/10.1186/s13023-017-0706-1
- Burnett JR, Hooper AJ, Hegele RA. Familial lipoprotein lipase deficiency. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2023 Aug 31]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1308/