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Congenital lipodystrophy type 2
CL2 leads to a significant reduction in body fat, which can result in various metabolic complications such as severe insulin resistance and high blood lipid levels. It typically affects individuals from birth or early childhood.
Overview
Congenital lipodystrophy type 2, also known as Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), is a rare genetic condition where the body has very little or almost no fat tissue from birth or early infancy [PMID:33671286]. This widespread loss of fat, known as generalised lipoatrophy, affects both the fat under the skin and the fat surrounding internal organs. Because fat tissue plays a crucial role in storing energy and regulating metabolism, its absence leads to a range of metabolic health issues.
Individuals with CL2 often develop complications similar to those seen in type 2 diabetes, even at a young age. These can include severe insulin resistance, high levels of triglycerides in the blood, and fatty liver disease. The condition is part of a group of disorders called lipodystrophies, all of which involve problems with fat tissue development or maintenance.
Symptoms & clinical features
The primary clinical feature of CL2 is the noticeable absence of subcutaneous fat, especially on the limbs, face, and buttocks, giving a very muscular appearance due to the prominent visibility of muscles and veins [PMID:33671286]. This can be present from birth. Along with the lack of fat, other common features include enlarged liver and spleen (hepatosplenomegaly), darkened thickened skin, particularly in skin folds (acanthosis nigricans), and excess hair growth (hirsutism) [PMID:33671286].
Metabolic complications are a significant aspect of CL2. Severe insulin resistance is common, meaning the body's cells do not respond effectively to insulin, leading to high blood glucose levels. This can progress to diabetes that is difficult to manage. High triglyceride levels and low levels of 'good' cholesterol (HDL) are also frequently observed, increasing the risk for cardiovascular problems. Some individuals may also experience learning difficulties or developmental delay, though this is not a universal feature.
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Affected organs
CL2 primarily affects the fat tissue throughout the body, leading to its near-complete absence. This widespread lipoatrophy has secondary effects on several other organ systems due to disrupted metabolism.
The liver is commonly affected, often becoming enlarged due to the accumulation of fat, a condition known as fatty liver disease (hepatic steatosis). The pancreas can be impacted by severe insulin resistance, leading to impaired insulin production over time. The heart can be affected by the long-term consequences of high blood lipid levels and diabetes, increasing the risk of cardiovascular disease. Skeletal muscles may appear hypertrophied (enlarged) due to the lack of overlying fat, and the bones might show increased density.
Risks & severity
Congenital lipodystrophy type 2 is a severe condition, often presenting with significant health challenges from infancy. The complete or near-complete lack of fat tissue leads to profound metabolic disturbances. Individuals are at a high risk of developing severe insulin-resistant diabetes, which can be challenging to control with standard treatments. This often begins in childhood or adolescence.
Long-term complications can include progressive liver disease, which may advance to cirrhosis, and pancreatitis. There is an increased risk of cardiovascular disease due to very high triglyceride levels and other lipid abnormalities. Some individuals may experience kidney complications. The severity of these metabolic complications can vary between individuals, even within the same family, but generally, the condition is associated with a significantly reduced quality of life and often a shortened life expectancy if not managed carefully.
Genetic causes
Congenital lipodystrophy type 2 is caused by changes (pathogenic variants) in the BSCL2 gene. This gene provides instructions for making a protein called seipin, which plays a critical role in the formation and maintenance of lipid droplets within cells, particularly in fat cells (adipocytes) [PMID:33671286]. Lipid droplets are essential for storing fat efficiently.
When the BSCL2 gene has a pathogenic variant, it can lead to a non-functional or abnormally functional seipin protein. This disruption impairs the normal development and storage capacity of fat cells, resulting in the characteristic widespread loss of fat tissue seen in CL2. Without functional fat tissue, the body cannot properly store excess energy, leading to the metabolic complications observed in the condition.
- BSCL2 BSCL2 lipid droplet biogenesis associated, seipin
Inheritance pattern
Congenital lipodystrophy type 2 is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the altered BSCL2 gene - one from each parent - to develop the condition.
If a person inherits only one copy of the altered gene, they are considered a 'carrier' but typically do not show symptoms of CL2. When two carriers have children, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two altered copies of the gene and develop the condition, a 50% (2 in 4) chance that the child will be a carrier, and a 25% (1 in 4) chance that the child will inherit two normal copies of the gene and will not have the condition or be a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
The diagnosis of congenital lipodystrophy type 2 is typically suspected based on clinical features, such as the characteristic appearance of widespread fat loss present from birth or early childhood, along with metabolic abnormalities like severe insulin resistance, high blood glucose, and elevated triglycerides [PMID:33671286].
Confirmation of CL2 involves genetic testing to identify pathogenic variants in the BSCL2 gene. In the UK, individuals suspected of having CL2 may be referred to clinical genetics services by their GP or another specialist clinician for assessment and consideration of genetic testing. Genetic testing for lipodystrophies is available through the NHS Genomic Medicine Service (GMS) and is typically covered by relevant R-codes for rare metabolic disorders. A genetic counsellor can provide further information and support throughout the diagnostic process.
Management & lifestyle
While there is currently no cure for congenital lipodystrophy type 2, management focuses on addressing the metabolic complications and improving quality of life. This often involves a multi-disciplinary team approach, including endocrinologists, dietitians, and other specialists, depending on the specific complications.
Dietary management is crucial, often involving a low-fat, high-carbohydrate diet to help manage blood lipid levels and blood glucose. Medications, such as insulin sensitizers and lipid-lowering drugs, may be used to control blood sugar and triglyceride levels. In some cases, leptin replacement therapy (metreleptin) may be considered, which has shown to improve metabolic control in some individuals with lipodystrophy, although its availability and suitability are subject to specialist assessment and NHS guidelines. Regular monitoring for complications like liver disease, heart problems, and kidney issues is essential, along with appropriate interventions as needed.
UK care pathway
In the UK, individuals with suspected genetic conditions like congenital lipodystrophy type 2 are typically referred by their General Practitioner (GP) or other specialist to an NHS clinical genetics service. These services assess the clinical features and family history to determine the most appropriate genetic testing pathway.
Genetic testing for CL2 falls under the NHS Genomic Medicine Service (GMS) and may be requested using specific R-codes for inherited endocrine conditions. Genetic counsellors within these services provide vital support, offering information about the condition, inheritance patterns, and implications for family members. They can help individuals and families navigate the diagnostic process and understand the results.
Frequently asked questions
Can CL2 affect fertility or pregnancy?
Individuals with CL2 can experience reproductive challenges due to hormonal imbalances caused by severe insulin resistance. Women may have irregular periods or polycystic ovaries. Pregnancy in women with CL2 requires careful medical management due to the risk of complications such as gestational diabetes.
Is CL2 contagious?
No, congenital lipodystrophy type 2 is a genetic condition caused by changes in a person's DNA. It cannot be caught from another person or passed on through contact.
What is the typical life expectancy for someone with CL2?
Life expectancy for individuals with CL2 can vary. The severe metabolic complications, particularly diabetes, cardiovascular disease, and liver disease, can significantly impact prognosis. Early diagnosis and diligent management of these complications are crucial for improving long-term health outcomes.
Are there any research studies or clinical trials for CL2?
As CL2 is a rare condition, research is ongoing to better understand its mechanisms and develop new treatments. Individuals may wish to discuss potential clinical trials or research studies with their specialist doctor or clinical genetics team, as participation can offer access to novel therapies or contribute to scientific knowledge.
How does diet play a role in managing CL2?
Diet is a cornerstone of CL2 management. A carefully constructed low-fat, high-carbohydrate diet, often advised by a specialist dietitian, is essential to help control blood glucose and triglyceride levels, which are often severely elevated due to the lack of fat tissue.
References
- Sánchez-Iglesias S, Fernández-Pombo A, Cobelo-Gómez S. Celia's Encephalopathy (BSCL2-Gene-Related): Current Understanding. Journal of clinical medicine. 2021. PMID: 33916074
- Zowalaty AEE, Ye X. Seipin deficiency leads to defective parturition in mice. Biology of reproduction. 2017. PMID: 29088395
- Chung J, Wu X, Lambert TJ. LDAF1 and Seipin Form a Lipid Droplet Assembly Complex. Developmental cell. 2019. PMID: 31708432
- Wee K, Yang W, Sugii S. Towards a mechanistic understanding of lipodystrophy and seipin functions. Bioscience reports. 2014. PMID: 25195639
- Li Y, Yang X, Peng L. Role of Seipin in Human Diseases and Experimental Animal Models. Biomolecules. 2022. PMID: 35740965
- Zhou H, Lei X, Benson T. Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals. Journal of lipid research. 2015. PMID: 26269358
- Gyani S, Mazumder MD, Mittal M. Berardinelli-Seip congenital lipodystrophy type-2: a case series of three Indian children. Journal of pediatric endocrinology & metabolism : JPEM. 2026. PMID: 41612862
- Qannan A, Bejaoui Y, Izadi M. Accelerated epigenetic aging and DNA methylation alterations in Berardinelli-Seip congenital lipodystrophy. Human molecular genetics. 2023. PMID: 36715159