Congenital generalized lipodystrophy type 4 (CGL4) is a rare metabolic disorder inherited in an autosomal recessive pattern. It has been related to mutations of the PTRF or CAVIN1 gene. Affected individuals are greatly lacking body fat, and this condition may be apparent at birth or develop during childhood. Congenital myopathy is another hallmark of this type of the disease. Despite recent advances in CGL4 therapy - recombinant analogs of human leptin have been proven highly effective to control metabolic complications of the disease - life quality and expectancy of CGL4 patients remain decreased.
The near-total absence of body fat is characteristic of congenital generalized lipodystrophies and is apparent at birth in the majority of cases and most types of the disease . Less frequently, it is only 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 . And indeed, the rare variant CGL4 has been associated with rather late-onset, progressive loss of body fat . Mechanical adipose tissue may be spared. With regards to the patients' general appearance, acromegaly-like large hands and feet may be noted.
Hepatomegaly and splenomegaly may be found during the postnatal examination and may provoke umbilical prominence or even an 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 CGL4 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, CGL4-associated diabetes mellitus doesn't generally cause asthenia, weight loss, polyuria, or polydipsia until the second decade of life.
By the time CGL4 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.
Contrary to other types of congenital generalized lipodystrophy, CGL4 may be associated with pyloric stenosis, osteopenia, atlanto-axial instability, distal metaphyseal deformation and joint stiffness  .
[…] frequency of infection infections, recurrent Predisposition to infections Susceptibility to infection [ more ] 0002719 Scoliosis 0002650 Skeletal muscle hypertrophy Increased skeletal muscle cells 0003712 Spinal rigidity Reduced spine movement 0003306 Splenomegaly [rarediseases.info.nih.gov]
Entire Body System
- Recurrent Infection
infections Frequent infections Frequent, severe infections Increased frequency of infection infections, recurrent Predisposition to infections Susceptibility to infection [ more ] 0002719 Scoliosis 0002650 Skeletal muscle hypertrophy Increased skeletal [rarediseases.info.nih.gov]
- Poor Feeding
[…] difficulties Feeding problems Poor feeding [ more ] 0011968 Flexion contracture Flexed joint that cannot be straightened 0001371 Generalized muscle weakness 0003324 Hepatic steatosis Fatty infiltration of liver Fatty liver [ more ] 0001397 Hepatomegaly [rarediseases.info.nih.gov]
He was diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) at age 8 years, had poor compliance with medications, and died suddenly at age 15.3 years. [utsouthwestern.pure.elsevier.com]
She received several course of anti-arrhythmic treatments for catecholaminergic polymorphic ventricular tachycardia and rapid atrial fibrillation. An implantable cardioverter defibrillator was also placed. [ncbi.nlm.nih.gov]
The ECG showed an incomplete right bundle branch block, a frequent atrial ectopic beat in the holter, ventricular tachycardia, and a mild hypertrophy of the left ventricle in the ECO. [abstracts.eurospe.org]
Predisposition to infections Susceptibility to infection [ more ] 0002719 Scoliosis 0002650 Skeletal muscle hypertrophy Increased skeletal muscle cells 0003712 Spinal rigidity Reduced spine movement 0003306 Splenomegaly Increased spleen size 0001744 Tachycardia [rarediseases.info.nih.gov]
- Proximal Muscle Weakness
] 0001544 Proximal muscle weakness Weakness in muscles of upper arms and upper legs 0003701 Pyloric stenosis 0002021 Recurrent infections Frequent infections Frequent, severe infections Increased frequency of infection infections, recurrent Predisposition [rarediseases.info.nih.gov]
Physical examination weight: 31.7 kg (50-75p), Height: 143.5 cm (75-90p), dysmorphic appearance, whole body subcutaneous fat tissue deficiency, axial muscle weakness, lumbar lordosis, hypertrophy appearance in muscles, hip, knee and ankle joints had limitation [abstracts.eurospe.org]
Lordosis and thoracolumbar scoliosis. Mild umbilical hernia. Tanner A3 B2 P refused. Neurological review showed normal neurology with no signs of muscle weakness. Cardiac and orthopaedic review is pending. [endocrine-abstracts.org]
[…] examination showed normal cranial nerves, normal tone, mild axial weakness, with difficulty in sitting from supine position, but normal strength limb muscles, hypertrophic buttock and lower limb muscles (Figure 1 ), reduced lower limb tendon reflexes, lumbar lordosis [bmcmedgenet.biomedcentral.com]
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 CGL4.
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  . Findings implying concomitant myopathy are to be expected in CGL4 patients, but not in individuals affected by other types of congenital generalized lipodystrophy . In detail, biochemical analyses typically yield the following results :
- Creatine kinase increased
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 CGL4 patients, a near total absence of body fat 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. Lytic lesions along the long bones, a condition that predisposes for pathological fractures and that is frequently observed in patients suffering from congenital generalized lipodystrophy type 1, are not usually observed in people affected by CGL4. By contrast, images obtained by means of radiography and computer tomography may reveal osteopenia .
Genetic analyses have to be conducted to identify the causal mutation of the PTRF gene.
There is no causal therapy for CGL4. 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 CGL4 and decrease the life expectancy of affected individuals . CGL4 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 .
CGL4 results from sequence anomalies within PTRF gene and encodes for polymerase 1 and transcript release factor. This protein plays a key role in rRNA transcription regulation, favoring the dissociation of transcription complexes and promoting the reinitiation of polymerase 1 on rRNA transcripts. The PTRF gene may also be called CAVIN1 gene and its gene product is referred to as caveolae-associated protein 1. Regardless of its role in rRNA transcription regulation, it is thought to be involved in the formation of caveolae in the plasma membrane.
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.
As for CGL4, about 20 cases have been described in literature only . Most cases have been reported in Oman, Japan and Mexico, but people of other ethnic groups have also been affected  .
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, CGL4 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. CGL4 patients suffer from ketosis-resistant diabetes mellitus . Furthermore, about three out of four patients affected by CGL4 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 CGL4 has been diagnosed in family members, genetic analyses may help to assess the precise risk for any couple to engender a child homozygous for PTRF 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:
- Congenital generalized lipodystrophy type 1 results from mutations in the AGPAT2 gene.
- 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.
- CGL4 develops due to mutations of the CAVIN1 or PTRF gene and will be discussed in this article.
CGL4 has also been called Berardinelli-Seip congenital lipodystrophy with muscular dystrophy.
Congenital generalized lipodystrophy type 2 (CGL4) 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 PTRF from both their parents will suffer from CGL4. A near-total absence of body fat may be apparent at birth or develop during childhood. Furthermore, affected children 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" PTRF gene. In CGL4 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, CGL4 predisposes for metabolic complications such as insulin resistance, hyperinsulinemia, and diabetes mellitus as well as hypertriglyceridemia. In turn, these conditions render CGL4 patients prone to cardiovascular disease and interfere with fertility. Acanthosis nigricans and eruptive xanthomas may result from CGL4, 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 CGL4 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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