Congenital generalized lipodystrophy type 1 (CGL1) is a rare metabolic disorder inherited in an autosomal recessive pattern. It has been related to mutations of the AGPAT2 gene. Affected individuals are greatly lacking body fat, but preserve mechanical adipose tissue. Despite recent advances in CGL1 therapy - recombinant analogs of human leptin have been proven highly effective to control metabolic complications of the disease - life quality and expectancy of CGL1 patients remain decreased.
The near-total absence of body fat is characteristic of congenital generalized lipodystrophies and is usually apparent at birth. Less frequently, it is recognized in the neonatal period, in infancy or in childhood, as has been shown in a recently published study: The mean age of patients at the onset of fat loss has been reported to be 0.3 months, with a range of from birth to 12 years . At the same time, extreme muscularity is observed. Veins of arms and legs are rather prominent since they are not hidden by subcutaneous fat. Body composition and fat distribution pattern may raise suspicion as to the molecular type of lipodystrophy : CGL1 patients are usually lacking subcutaneous, intrathoracic and intraabdominal fat, while mechanical adipose tissue is present. These patients' palms and soles dispose of normal subcutaneous fat . Considerable amounts of adipose tissue are also recognized within the orbita, periarticularly, in the renal sinus, and in the pubic and perineal areas. With regards to the patients' general appearance, acromegaly-like large jaws, hands, and feet may be noted .
Hepatomegaly and splenomegaly may be found during the postnatal examination and may provoke umbilical prominence or even umbilical hernia . In some patients, hepatosplenomegaly only develops during childhood. Initially, hepatic enlargement is due to the accumulation of fat in this organ, but liver disease may progress from hepatic steatosis to liver fibrosis, liver cirrhosis and liver failure.
Furthermore, acanthosis nigricans is typical of CGL1 and other types of congenital generalized lipodystrophy, but is not necessarily present before puberty. Predilection sites for this pigmentary anomaly are the neck, axillae and groin. Other skin areas may be affected, though. Acanthosis nigricans is considered an early indicator of insulin resistance and is usually detected years before diabetes mellitus becomes symptomatic . Indeed, CGL1-associated diabetes mellitus doesn't generally cause asthenia, weight loss, polyuria, or polydipsia until the second decade of life.
By the time CGL1 patients reach puberty, additional symptoms may manifest in females. Breast development is undisturbed with regards to glandular tissue, but subcutaneous fat is largely missing. Affected women often complain about irregular menstruation, but may also suffer from primary or secondary amenorrhea and polycystic ovary syndrome. Mild hirsutism and clitoromegaly may also be associated with the disease. Most female patients are unable to conceive while males are usually fertile.
Severe hypoleptinemia may induce an increase in appetite. In those patients suffering from hypertriglyceridemia, eruptive xanthomas can frequently been observed. This condition also predisposes for recurrent pancreatitis, particularly in case of poorly controlled diabetes mellitus.
Entire Body System
0002591 Prominent umbilicus Prominent belly button Prominent navel [ more ] 0001544 Reduced intraabdominal adipose tissue 0025128 Reduced intrathoracic adipose tissue 0003809 Reduced subcutaneous adipose tissue Reduced fat tissue below the skin 0003758 Splenomegaly [rarediseases.info.nih.gov]
Some women display hyperandrogyny, clinically manifested by severe hirsutism and alterations in the menstrual cycle such as oligomenorrhea. [scirp.org]
The minor criteria are hypertrophic cardiomyopathy, mental retardation, hypertrichosis/hirsutism, precocious puberty in females, and bone cyst., Both of our patients fulfilled all major criteria and one minor criterion (hypertrichosis), but both [ijpd.in]
Affected women may suffer from clitoromegaly, hirsutism, irregular menstrual periods and ovarian cysts, which may be related to hormonal changes. [ivami.com]
Minor criteria include hypertrophic cardiomyopathy, psychomotor retardation, hirsutism, precocious puberty in females, bone cysts, and phlebomegaly. [ijdvl.com]
Decreased serum leptin 0003292 Elevated hepatic transaminase High liver enzymes 0002910 Generalized muscular appearance from birth 0003716 Hepatic steatosis Fatty infiltration of liver Fatty liver [ more ] 0001397 Hepatomegaly Enlarged liver 0002240 Hirsutism [rarediseases.info.nih.gov]
- Advanced Bone Age
The 3 patients exhibited rapid growth with advanced bone age, dilation of the cerebral ventricles, hepatosplenomegaly with cirrhosis, generalized muscular overdevelopment, hypertrichosis, hypertension, punctate corneal opacities, and brownish pigmentation [emedicine.medscape.com]
bone age Early bone maturation [ more ] 0005616 Acute pancreatitis Acute pancreatic inflammation 0001735 Autosomal recessive inheritance 0000007 Cirrhosis Scar tissue replaces healthy tissue in the liver 0001394 Clitoral hypertrophy Enlarged clitoris [rarediseases.info.nih.gov]
- Large Hand
hands large hand 0001176 Lipodystrophy Inability to make and keep healthy fat tissue 0009125 Long foot Disproportionately large feet large feet long feet [ more ] 0001833 Macrotia Large ears 0000400 Mandibular prognathia Big lower jaw Increased projection [rarediseases.info.nih.gov]
- Large Feet
[…] hands large hand 0001176 Lipodystrophy Inability to make and keep healthy fat tissue 0009125 Long foot Disproportionately large feet large feet long feet [ more ] 0001833 Macrotia Large ears 0000400 Mandibular prognathia Big lower jaw Increased projection [rarediseases.info.nih.gov]
- Labial Hypertrophy
0002240 Hirsutism Excessive hairiness 0001007 Hyperinsulinemia 0000842 Hypertriglyceridemia Increased plasma triglycerides Increased serum triglycerides Increased triglycerides [ more ] 0002155 Insulin-resistant diabetes mellitus at puberty 0000877 Labial [rarediseases.info.nih.gov]
The Omani male patient (Case 2) had glandular hypospadias with chordee, and normal testicular size and consistency. His endocrine evaluation revealed normal testosterone response to human chorionic gonadotrophin stimulation. [cags.org.ae]
Congenital generalized lipodystrophies are hereditary disorders and thus, it should be determined whether family members have suffered from symptoms similar to those observed in the patient at hand . Also, consanguinity of the parents considerably increases the likelihood of diseases inherited in an autosomal recessive fashion, as is the case with CGL1.
A comprehensive metabolic panel should be obtained in order to detect characteristic anomalies even in the absence of the respective clinical symptoms . The triad of insulin resistance with or without overt diabetes mellitus, hypertriglyceridemia and hepatic steatosis - associated with abnormal liver function tests - is considered to be characteristic of, yet no specific for congenital generalized lipodystrophies  . In detail, biochemical analyses typically yield the following results :
Diagnostic imaging may provide valuable hints on the molecular type of congenital generalized lipodystrophy. Whole-body magnetic resonance imaging allows for the assessment of body fat distribution. In CGL1 patients, a distribution pattern as described in the previous paragraph is to be expected. Sonography is the technique of choice to assess the overall size of the liver and the progress of fibrotic remodeling in follow-ups. Furthermore, radiography and computer tomography may reveal the presence of lytic lesions along the long bones, a condition that predisposes for pathological fractures . The inability to replace hematopoietic marrow by bone marrow fat may be the cause of those lesions. Lytic lesions of the skeleton are mainly seen in CGL1 and rarely occur in other types of congenital generalized lipodystrophy.
Genetic analyses have to be conducted to identify the causal mutation of the AGPAT2 gene.
- Ventricular Hypertrophy
Echocardiography of IV-1 revealed patent foramen ovale and mild left ventricular hypertrophy with intact inter-ventricular septum, while IV-3 showed small secundum atrial septal defect with left to right shunt, minimal right ventricular dilatation, and [diagnosticpathology.biomedcentral.com]
There is no causal therapy for CGL1. Metabolic complications that arise due to the genetic disorder have to be treated symptomatically, by putting into practice dietary measures and by means of pharmacotherapy:
- In general, patients suffering from congenital generalized lipodystrophy are recommended to avoid excessive food intake and restrict the ingestion of fat and carbohydrates. Due to the lack of adipose tissue, energy storage is limited and fluctuations in energy supply are poorly compensated.
- Before recombinant analogs of human leptin have been used to treat generalized lipodystrophies, conventional antidiabetics and lipid-lowering drugs had been the mainstay of therapy . However, adequate control of metabolic anomalies has rarely been achieved. By contrast, leptin analogs significantly improve insulin resistance and diabetes mellitus as well as hypertriglyceridemia and related complications.
- Still, many patients require additional medication, either because they never respond satisfactorily to leptin analogs or because the efficacy of that therapy decreases due to the formation of antibodies against the recombinant hormone . With regards to mitigating insulin resistance and hyperglycemia, thiazolidinediones such as pioglitazone and troglitazone have been shown to be more effective than metformin. However, in severe cases, glycemic control can only be achieved by high doses of insulin .
Diabetes mellitus, heart disease, and hepatopathy are frequent complications of CGL1 and decrease the life expectancy of affected individuals . CGL1 patients are at particularly high risks of cardiovascular accidents, liver cirrhosis, and hepatocellular carcinoma . According to a meta-analysis published recently, the mean age at mortality was 12.5 years for patients suffering from any congenital generalized lipodystrophy .
CGL1 is caused by mutations of the AGPAT2 gene. Both null and missense mutations of the AGPAT2 gene have been described in CGL1 patients, but although compound heterozygosity may be related to minor residual enzyme activity, the type of mutation doesn't seem to correlate with disease severity.
The AGPAT2 gene encodes for member 2 of the 1-acylglycerol-3-phosphate O-acyltransferase family, an enzyme required for the conversion of lysophosphatidic acid to phosphatidic acid. This reaction needs to be catalyzed as part of the triglyceride and phospholipid biosynthesis. AGPAT2 expression is highest in adipose tissue and thus, CGL1 is mainly a lipodystrophic disease.
To date, about 500 cases of congenital generalized lipodystrophy have been described. The overall prevalence of those diseases comprised in this group has been roughly estimated to 1 in 10,000,000 inhabitants , but it may be even lower . Reliable data regarding incidence and prevalence of single types of congenital generalized lipodystrophy cannot be provided, though.
Most cases have been reported in families of African ancestry, in Lebanon, Brazil, and Scandinavia. Consistent with the fact that CGL1 and other types of congenital generalized lipodystrophy are inherited in an autosomal recessive pattern, consanguineous marriage and low genetic variability considerably increase the risk of homozygosity in offspring .
Individuals suffering from congenital generalized lipodystrophy lack functional adipocytes. Consequently, lipids are stored in other tissues, namely in muscles and liver, and in fact, patients may present with skeletal muscle hypertrophy and hepatomegaly at birth  . Nevertheless, the mean percentage of body fat remains below 10%  . In other studies, mean values of less than 6% have been reported . Furthermore, CGL1 is not only associated with abnormal lipid storage but also with considerable metabolic disturbances. This can be explained by the fact that adipose tissue plays an important role in endocrine processes and secretes a variety of hormones. One of those hormones is leptin, a proinflammatory adipokine and regulator of appetite and energy expenditure . Unsurprisingly though, metabolic complications start to arise soon after birth in those affected by congenital generalized lipodystrophy:
- Insulin resistance and hyperinsulinemia may be detected in affected infants and children, while diabetes mellitus rarely manifests before puberty. CGL1 patients suffer from ketosis-resistant diabetes mellitus . Furthermore, about three out of four patients affected by CGL1 develop hypertriglyceridemia during late childhood or adolescence. It has been speculated that enhanced lipolysis and defective energy storage contribute to the development of this type of dyslipidemia, but further research is necessary to understand how these processes are related to each other .
- Insulin resistance has also been related to hyperandrogenism  and hyperandrogenism interferes with ovary function in women suffering from congenital generalized lipodystrophy . Additionally, irregular luteinizing hormone
stimulation presumably contributes to anovulation and infertility in affected females .
Affected families may benefit from genetic counseling. Those with a positive family history of hereditary diseases should be informed about the risks inherent in consanguineous marriage, and in case CGL1 has been diagnosed in family members, genetic analyses may help to assess the precise risk for any couple to engender a child homozygous for AGPAT2 mutations.
The term congenital generalized lipodystrophy refers to a heterogeneous group of disorders, all of which are inherited in an autosomal recessive manner. In general, individuals suffering from congenital generalized lipodystrophy lack adipose tissue from birth and are prone to metabolic disease. Most patients develop severe insulin resistance and diabetes mellitus, hypertriglyceridemia, hepatic steatosis, polycystic ovary syndrome, acanthosis nigricans and
hypertension . There are four types of congenital generalized lipodystrophy, which differ with regards to their etiology, but largely coincide clinically:
- CGL1 results from mutations in the AGPAT2 gene and will be discussed in this article.
- Congenital generalized lipodystrophy type 2 is associated with mutations of the BSCL2 gene.
- Congenital generalized lipodystrophy type 3 is caused by sequence anomalies within the CAV1 gene.
- Congenital generalized lipodystrophy type 4 develops due to mutations of the CAVIN1 or PTRF gene.
Alternative denominations of CGL1 include Berardinelli-Seip syndrome, Berardinelli-Seip congenital lipodystrophy type 1, and AGPAT2-related Brunzell syndrome.
Congenital generalized lipodystrophy type 1 (CGL1) is an inherited disease associated with anomalies of fat storage and metabolism affecting the whole body. In detail, children who inherit defective allels of a gene named AGPAT2 from both their parents will suffer from CGL1. A near-total absence of body fat and extreme muscularity are characteristic of the disease and usually apparent at birth. Furthermore, affected individuals may show umbilical prominence or even have umbilical hernia due to an enlarged liver. These observations can be explained by the fact that functional adipose tissue can only be formed by those disposing of at least one "healthy" AGPAT2 gene. In CGL1 patients, however, adipose tissue is largely missing and lipids are stored in muscles and liver.
Because adipose tissue plays an important role in endocrine processes and secretes a variety of hormones, CGL1 predisposes for metabolic complications such as insulin resistance, hyperinsulinemia, and diabetes mellitus as well as hypertriglyceridemia. In turn, these conditions render CGL1 patients prone to cardiovascular disease and interfere with fertility. Acanthosis nigricans and eruptive xanthomas may result from CGL1, but also irregular menstruation, amenorrhea, polycystic ovary syndrome and pancreatitis.
In order to decrease the risk of such potentially life-threatening complications, metabolic anomalies as described above have to be corrected. Recombinant analogs of human leptin, i.e., of one of those hormones secreted by normal adipose tissue, as well as antidiabetic and lipid-lowering drugs are applied to this end. In some cases, patients require high doses of insulin to sufficiently lower blood glucose concentrations. Still, treatment shouldn't rely on medication alone and needs to be complemented by an appropriate diet. Those suffering from CGL1 are recommended to restrict fat and carbohydrate intake in order to maintain blood lipid levels within desirable ranges and to avoid complications due to fluctuations in energy supply that cannot be compensated.
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