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Generalized Lipodystrophy

Berardinelli Seip Syndrome

Generalized lipodystrophy is a disorder characterized by loss of adipose tissue and, usually, metabolic disturbance due to deficiency of hormones derived from these tissues, most importantly leptin. Generalized lipodystrophy (GL) may be divided in congenital GL, also known as Berardinelli-Seip syndrome and acquired GL, referred to as Lawrence syndrome.


Presentation

Near-total lack of subcutaneous fat from birth is characteristic of congenital generalized lipodystrophy (CGL). One of the earliest symptoms of this condition is a well-defined musculature with prominent superficial veins. The infants and children show increased, insatiable appetite, often want to be breast-fed, or are looking for food. Tonsils and adenoids may be hyperplastic, hands and feet may be enlarged and umbilical hernias are common. Hepatomegaly and splenomegaly are frequently present from infancy leading to abdominal distention. Patients can also present with dermatological manifestations such as eruptive xanthomas, hirsutism and thick, curled scalp hair. Acanthosis nigricans occurs frequently in the adolescence. Children with CGL may attain more than 90% of adult growth within 10 years and an advanced bone age is detectable. Amenorrhea or irregular menstruation, clitoromegaly and infertility are frequently present in female patients. Hypertriglyceridemia, liver cirrhosis, diabetes mellitus, as well as cardiovascular complications are frequently observed. Severe hypertriglyceridaemia may cause recurrent pancreatitis. Acquired generalized lipodystrophy (AGL) causes variable extent of fat loss and is usually accompanied by diabetes mellitus, hepatic steatosis and fibrosis and hypertriglyceridemia.

Accelerated Growth
  • In addition to hepatomegaly, accelerated growth, muscle hypertrophy, lack of adipose tissue, hirsutism and hypertriglyceridemia, which are the characteristics of the syndrome, these brothers demonstrated bilateral, symmetrical, renal medullary hyperechogenicity[ncbi.nlm.nih.gov]
  • E. : Generalized lipoatrophy, hepatic cirrhosis, disturbed carbohydrate metabolism and accelerated growth (lipoatrophic diabetes). Amer. J. Med. 28 , 973–985 (1960).[link.springer.com]
  • Complications include hypertrophic cardiomyopathy, a fatty liver with hepatic dysfunction, muscular hypertrophy, a number of endocrine disturbances (accelerated growth in infancy, precocious puberty etc .) and bone cysts with spontaneous fractures.[orpha.net]
Infertility
  • Amenorrhea or irregular menstruation, clitoromegaly and infertility are frequently present in female patients. Hypertriglyceridemia, liver cirrhosis, diabetes mellitus, as well as cardiovascular complications are frequently observed.[symptoma.com]
Splenomegaly
  • Common clinical features are acanthosis nigricans, hepatomegaly with or without splenomegaly and high stature. Acromegaloid features, cardiomyopathy and mental retardation can also be present.[ncbi.nlm.nih.gov]
  • Symptoms Absence of body fat Prominent superficial veins Acromegaloid features Increased appetite Hepatomegaly Splenomegaly Cirrhosis Intellectual disability Diabetes Diagnosis Patient history Blood test- assesses glucose lipid, liver enzyme and uric[raredr.com]
  • Hepatomegaly and splenomegaly are frequently present from infancy leading to abdominal distention. Patients can also present with dermatological manifestations such as eruptive xanthomas, hirsutism and thick, curled scalp hair.[symptoma.com]
  • Some individuals may also have an abnormally enlarged spleen (splenomegaly). Hepatomegaly is often noticed during infancy.[rarediseases.org]
  • Splenomegaly and phlebomegaly (mostly in the extremities) is a feature. [7] There is also slight increase in the size of the external genitalia - the penis and the clitoris - since childhood. [4] Women may have hirsutism, oligomenorrhea, and polycystic[ijdvl.com]
Overeating
  • Visualize more of the conditions you see in practice with over 3500 illustrations, of which over 1,400 are new: 1,039 clinical images, 398 pathology slides, and 152 schematics.[books.google.com]
  • HbA1c and triglyceride changes over time significantly differed between GLD and PLD.[ncbi.nlm.nih.gov]
  • These guidelines have stimulated generation of similar recommendations from all over the world, particularly Europe, Canada, Australia and Asia.[books.google.com]
  • Over the course of the next couple of months, life went on as usual, Alani flourished as any infant would and we watched her grow only different in appearance from her other siblings.[rareundiagnosed.org]
Increased Appetite
  • Subjects with generalized lipodystrophy and reduced leptin levels often have an increased appetite leading to hyperphagia.[ncbi.nlm.nih.gov]
  • Symptoms Absence of body fat Prominent superficial veins Acromegaloid features Increased appetite Hepatomegaly Splenomegaly Cirrhosis Intellectual disability Diabetes Diagnosis Patient history Blood test- assesses glucose lipid, liver enzyme and uric[raredr.com]
  • Infants and children have a markedly increased appetite and have been described as voracious eaters. In individuals with CGL, fat deposits build up in areas of the body such as the muscles and liver.[rarediseases.org]
  • Hypermetabolism is an important feature and is associated with increased appetite; there is ingestion of large amounts of calories and profuse sweating. There may be hyperthermia.[ijdvl.com]
Hypertension
  • His younger brother, a 37-year-old Caucasian male developed generalized lipodystrophy around 2 years of age and was diagnosed with diabetes, hypertriglyceridemia, fatty liver, and hypertension at 36 years of age.[ncbi.nlm.nih.gov]
  • Common cardiovascular alterations related to this syndrome are cardiac hypertrophy and arterial hypertension.[ncbi.nlm.nih.gov]
  • One had pulmonary hypertension. We conclude that generalized lipodystrophy is a serious disease with cardiac affection leading to cardiac dysfunction and early death.[ncbi.nlm.nih.gov]
  • Compared with controls, CGL patients had higher blood pressure (systolic, 131.1 vs. 106.3 mmHg, P 0.05; diastolic, 85.0 vs. 68.2 mmHg, P 0.05) and 10 patients met criteria for arterial hypertension and concentric left ventricular hypertrophy (LVM index[ncbi.nlm.nih.gov]
Hepatomegaly
  • The diagnosis is made on the basis of lack of body fat, muscular hypertrophy, acanthosis nigricans, hirsutism, hepatomegaly with fatty liver, hyperlipidemia and hyperglycemia with insulin resistance.[ncbi.nlm.nih.gov]
  • In addition to hepatomegaly, accelerated growth, muscle hypertrophy, lack of adipose tissue, hirsutism and hypertriglyceridemia, which are the characteristics of the syndrome, these brothers demonstrated bilateral, symmetrical, renal medullary hyperechogenicity[ncbi.nlm.nih.gov]
  • The diagnosis is made on the basis of loss of body fat, muscular hypertrophy, acanthosis nigricans, hirsutism, hepatomegaly with fatty liver, hyperlipidemia and hyperglycemia with insulin resistance.[ncbi.nlm.nih.gov]
  • RESULTS: Generalized lipodystrophy, acanthosis nigricans, muscular hypertrophy, severe hypertriglyceridemia, and hepatomegaly were features in all three patients.[ncbi.nlm.nih.gov]
  • We report a case of α 14 years old mediterranean female, affected by SBLD with a lack of subcutaneous fat, hyperlipidemia and hepatomegaly, impaired glucose tolerance and acanthosis nigricans.[moh-it.pure.elsevier.com]
Hepatosplenomegaly
  • Abnormalities of lipid and carbohydrate metabolism, hepatosplenomegaly, acanthosis nigricans, and hirsutism were not found.[ncbi.nlm.nih.gov]
  • A 4-month-old Taiwanese female infant had hepatosplenomegaly and low body weight gain despite a voracious appetite.[ncbi.nlm.nih.gov]
  • We report two siblings of Hispanic origin who displayed characteristic features of CGL such as generalized loss of subcutaneous fat from birth, acanthosis nigricans, acromegaloid habitus, umbilical prominence, hepatosplenomegaly, hypoleptinemia, dyslipidemia[ncbi.nlm.nih.gov]
  • The clinical phenotype, viz. lack of subcutaneous fat, hepatosplenomegaly, cardiomegaly, and advanced bone age was also documented. The patient was found to be insulin resistant and diabetes mellitus was diagnosed by age 13 years.[ncbi.nlm.nih.gov]
  • On examination, she had generalized loss of subcutaneous fat, with prominent subcutaneous veins; there was severe acanthosis nigricans involving all flexures, generalized hyperpigmentation, curly scalp hair, a protuberant abdomen with hepatosplenomegaly[ijdvl.com]
Advanced Bone Age
  • It is characterized by a lack of adipose tissue throughout the body from birth, muscular hypertrophy, advanced bone age, fatty liver, and insulin resistance.[ncbi.nlm.nih.gov]
  • The clinical phenotype, viz. lack of subcutaneous fat, hepatosplenomegaly, cardiomegaly, and advanced bone age was also documented. The patient was found to be insulin resistant and diabetes mellitus was diagnosed by age 13 years.[ncbi.nlm.nih.gov]
  • Advanced bone age and linear growth and skeletal muscle prominence can be seen during childhood. Severe dyslipidaemia, hepatomegaly and non-alcoholic steatohepatitis are almost always noted.[dnatesting.uchicago.edu]
  • Children with CGL may attain more than 90% of adult growth within 10 years and an advanced bone age is detectable. Amenorrhea or irregular menstruation, clitoromegaly and infertility are frequently present in female patients.[symptoma.com]
  • bone age Have a belly that sticks out (protrudes) Have highly developed muscles (prominent musculature) Go through puberty early (precocious sexual development) Have mental retardation Have dark, velvety skin patches ( acanthosis nigricans ) Generalized[medicinenet.com]
Large Hand
  • Affected individuals tend to have prominent bones above the eyes ( orbital ridges ), large hands and feet, and a prominent belly button (umbilicus).[ghr.nlm.nih.gov]
  • Continued Adults with CGL have large hands and feet and a strong, square jawbone because their hormone balance is off and they keep growing. They could have larger than usual sex organs (clitoris, or penis and testicles).[webmd.com]
Hirsutism
  • The diagnosis is made on the basis of lack of body fat, muscular hypertrophy, acanthosis nigricans, hirsutism, hepatomegaly with fatty liver, hyperlipidemia and hyperglycemia with insulin resistance.[ncbi.nlm.nih.gov]
  • In addition to hepatomegaly, accelerated growth, muscle hypertrophy, lack of adipose tissue, hirsutism and hypertriglyceridemia, which are the characteristics of the syndrome, these brothers demonstrated bilateral, symmetrical, renal medullary hyperechogenicity[ncbi.nlm.nih.gov]
  • The diagnosis is made on the basis of loss of body fat, muscular hypertrophy, acanthosis nigricans, hirsutism, hepatomegaly with fatty liver, hyperlipidemia and hyperglycemia with insulin resistance.[ncbi.nlm.nih.gov]
  • Abnormalities of lipid and carbohydrate metabolism, hepatosplenomegaly, acanthosis nigricans, and hirsutism were not found.[ncbi.nlm.nih.gov]
  • Patients can also present with dermatological manifestations such as eruptive xanthomas, hirsutism and thick, curled scalp hair. Acanthosis nigricans occurs frequently in the adolescence.[symptoma.com]
Hypertrichosis
  • Abstract Congenital generalized lipodystrophy (CGL) is a rare disease, the main symptoms of which are a reduction of systemic subcutaneous fat, characteristic facial features, hypertrichosis, and insulin-resistant diabetes.[ncbi.nlm.nih.gov]
  • Hypermetabolism, hyperhidrosis, loss of subcutaneous fat, muscular hypertrophy, acanthosis nigricans, hypertrichosis, and marked hypertriglyceridemia were also noted. Liver histology revealed fatty change and portal-to-portal bridging fibrosis.[ncbi.nlm.nih.gov]
  • […] flexural areas and generalized hypertrichosis since birth.[ijpd.in]
  • Minor features include hypertrophic cardiomyopathy, mental retardation, hypertrichosis, bone cysts, precocious puberty (in females), and phlebomegaly. Both the siblings had hypertrichosis and phlebomegaly.[idoj.in]
  • On examination there was apparent loss of subcutaneous fat (Figure 1) generalized hypertrichosis, but scalp hair was abundant and curly (Figure 2). Mild acanthosis nigricans was present in the axillae (Figure 3).[jpma.org.pk]
Xanthoma
  • We report a 3-month-old Taiwanese boy with initial presentation of a lack of subcutaneous fat, prominent musculature, generalized eruptive xanthomas, and extreme hypertriglyceridemia.[ncbi.nlm.nih.gov]
  • Patients can also present with dermatological manifestations such as eruptive xanthomas, hirsutism and thick, curled scalp hair. Acanthosis nigricans occurs frequently in the adolescence.[symptoma.com]
  • Most affected individuals also have high levels of fats called triglycerides circulating in the bloodstream (hypertriglyceridemia), which can lead to the development of small yellow deposits of fat under the skin called eruptive xanthomas and inflammation[ghr.nlm.nih.gov]
Absence of Subcutaneous Fat
  • […] of subcutaneous fat. [8] CGL3 patients have serum creatine kinase concentrations much higher than normal (2.5 to 10 times the normal limit).[en.wikipedia.org]
  • Case Reports Case 1 A 13-month-old female child, born out of nonconsanguineous marriage, was brought to our department with complaints of abnormal facial features, almost complete generalized absence of subcutaneous fat, muscular hypertrophy, generalized[ijpd.in]
  • Biopsy of the skin showed an absence of subcutaneous fat. Hyper-insulinaemia was noted 148.2 IU/ml (normal 3-35 IU/ml). She was treated with pimozide 2 rug once daily for about a year.[jpma.org.pk]
Cutaneous Manifestation
  • The patient had several cutaneous manifestations, including severe acanthosis nigricans, generalized hyperpigmentation, curly scalp hair, prominent subcutaneous veins, and enlarged clitoris. She also had associated celiac disease.[ncbi.nlm.nih.gov]
  • The patient had several cutaneous manifestations.[ijdvl.com]
  • We report BSCL type 2 in two siblings with several cutaneous manifestations like acanthosis nigricans, hypertrichosis, prominent subcutaneous veins, and increased lanugo hair.[idoj.in]
Hunger
  • Tell your doctor right away if you experience shakiness, sweating, headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, fast heartbeat, or a jittery feeling because these may be signs of low blood sugar (hypoglycemia).[myalept.com]
Clitoromegaly
  • Amenorrhea or irregular menstruation, clitoromegaly and infertility are frequently present in female patients. Hypertriglyceridemia, liver cirrhosis, diabetes mellitus, as well as cardiovascular complications are frequently observed.[symptoma.com]
  • Affected females may have an enlarged clitoris (clitoromegaly), an increased amount of body hair (hirsutism), irregular menstrual periods, and multiple cysts on the ovaries , which may be related to hormonal changes.[ghr.nlm.nih.gov]
  • In addition, acanthosis nigricans, enlargement of both breasts (Tanner Stage 3) and clitoromegaly were found [Figure 1] and [Figure 2]. Her height was 84 cm, weight 8 kg (above 98 percentile of the WHO growth chart).[ijpd.in]
  • In women, clitoromegaly and polycystic ovary syndrome can develop. This impairs fertility for women, and only a few documented cases of successful pregnancies in women with CGL exist.[en.wikipedia.org]
Amenorrhea
  • Amenorrhea or irregular menstruation, clitoromegaly and infertility are frequently present in female patients. Hypertriglyceridemia, liver cirrhosis, diabetes mellitus, as well as cardiovascular complications are frequently observed.[symptoma.com]
Irregular Menstruation
  • Amenorrhea or irregular menstruation, clitoromegaly and infertility are frequently present in female patients. Hypertriglyceridemia, liver cirrhosis, diabetes mellitus, as well as cardiovascular complications are frequently observed.[symptoma.com]
Kidney Failure
  • The proband, a 23-year-old Caucasian male was reported to have generalized lipodystrophy at 3 weeks of age, developed diabetes, hypertriglyceridemia, hypertension and liver problems and died with complications of cirrhosis, and kidney failure.[ncbi.nlm.nih.gov]

Workup

Diagnosis of this disease is mainly based on clinical features and generalized lipodystrophy should be included in the differential diagnosis of lean individuals presenting with early-onset diabetes mellitus, hypertriglyceridemia, nonalcoholic steatohepatitis (NASH), acanthosis nigricans and polycystic ovary syndrome. Laboratory studies are used to examine for associated conditions like metabolic disorders and autoimmune diseases. Fasting blood glucose, lipid profile, liver enzymes, uric acid, creatinine and urinalysis should be obtained. Tests may also be conducted for antinuclear antibodies, and anticardiolipin antibodies. For congenital lipodystrophy, genetic workup may be needed.

Hypertriglyceridemia
  • As this uncommon allele has been reported to be related to high plasma triglyceride levels, this association could be relevant in explaining in part the hypertriglyceridemia observed in these patients.[ncbi.nlm.nih.gov]
  • KEYWORDS: Congenital generalized lipodystrophy; Diabetes; Hypertriglyceridemia; PPARG[ncbi.nlm.nih.gov]
  • His younger brother, a 37-year-old Caucasian male developed generalized lipodystrophy around 2 years of age and was diagnosed with diabetes, hypertriglyceridemia, fatty liver, and hypertension at 36 years of age.[ncbi.nlm.nih.gov]
  • Fibrates and extended release niacin may be used for controlling hypertriglyceridemia. Ezetimibe may be opted for patients who cannot tolerate statins.[symptoma.com]
  • Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly[ncbi.nlm.nih.gov]

Treatment

A general approach includes lifestyle modification like diet, exercise, and nutritional therapy. Patients with this disease are recommended to have 25% of daily calories from fat. 75% of the calories should be provided by protein and carbohydrates [1]. Exercise may be helpful in improving the metabolic parameters. Resistance training is found to enhance total lean mass and to decrease total fat accumulation. Exercise is also helpful in increasing peripheral insulin sensitivity and HDL cholesterol levels. Patients with concurrent diabetes mellitus may be suggested oral anti-diabetic drugs such as metformin for managing this associated condition. Thiazolidinediones also may be helpful in improving insulin resistance, hyperinsulinemia, and hypertriglyceridemia. Treatment guidelines for dyslipidemia in lipodystrophy are similar to that of coronary artery disease. Lifestyle modification is the first step in this regard. Statins are given for hypercholesterolemia. Fibrates and extended release niacin may be used for controlling hypertriglyceridemia. Ezetimibe may be opted for patients who cannot tolerate statins. In February 2014, the Food and Drug Administration (FDA) approved metreleptin (Myalept), a recombinant leptin analog, for the treatment of generalized forms of lipodystrophy in children and adults [1] [2] [3] [4] [5].

Prognosis

Mortality and morbidity associated with the disease depend on the organs involved and the extent of involvement. In congenital forms most of the patients survive to young adulthood or early middle age.

Etiology

Congenital generalized lipodystrophy is caused by an autosomal recessive mutation. There are four subtypes of CGL due to compound mutations in four genes, 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT2), Berardinelli-Seip congenital lipodystrophy 2 (BSCL2), caveolin 1 (CAV1), and polymerase I and transcript release factor (PTRF). In some patients one or more as-yet-unidentified genes cause the disorder. Acquired generalized lipodystrophy may be caused by medications, autoimmunity or may be idiopathic. Panniculitis-associated forms of AGL occur [6].

Epidemiology

Both acquired and inherited types of this disease are rare. The incidence of CGL is 1:1.000,000 and found to be equal in male and female. The highest frequency of congenital generalized lipodystrophy is reported from Brazil [7]. AGL is more common than the inherited form and the female to male ratio is 3:1.

Sex distribution
Age distribution

Pathophysiology

Congenital generalized lipodystrophy is classified in type 1 to 4, depending on the clinical manifestations and the etiological mutations. Type 1 (CGL1) is caused by a mutation of 1-acylglycerol-3-phosphate-O-acyltransferase 2 gene (AGPAT2). AGPAT2 plays an important role in functioning of adipocyte tissue and also in the synthesis of triacylglycerol in adipose tissue [8]. Mutation of this gene affects the metabolically important tissues like fat tissue in subcutaneous regions, bone marrow, intramuscular, intraabdominal and intrathoracic regions. Type 2 (CGL2) occurs due to mutations of Berardinelli-Seip Congenital Lipodystrophy 2 gene (BSCL2). BSCL2 is involved in the coding of the protein seipin, which is implicated in the differentiation of adipose tissue and lipid droplet formation [9]. Caveolin 1 (CAV1) mutations, and Polymerase I and transcript release factor (PTRF) mutations are associated with CGL3, and CGL4, respectively. In some patients one or more as-yet-unidentified genes lead to CGL.

AGL may be caused by nucleoside reverse transcriptase inhibitors. It may result in abnormal proliferation of mitochondria, known as mitochondrial toxicity [10]. Protease inhibitors are also implicated in the disruption of adipocyte differentiation and also in increased production of cytokines. Drug-induced lipodystrophy may also include increased lipolysis. Enhanced lipolysis along with deficiency of subcutaneous fat, indirectly lead to metabolic disturbances like insulin resistance and dyslipidemia.

Prevention

There are no guidelines for prevention.

Summary

Generalized lipodystrophies are a group of disorders characterized by loss of adipose tissue and, usually, metabolic disturbance and may be divided in congenital GL, also known as Berardinelli-Seip syndrome and acquired GL, referred to as Lawrence syndrome. Congenital generalized lipodystrophy was first reported by Berardinelli in 1954 and Seip in 1959, and to date, approximately 300 cases have been described in the literature.

Patient Information

Lipodystrophy refers to a heterogeneous group of disorders that result in fat loss. Generalized lipodystrophy (GL) may be categorized as congenital GL, also known as Berardinelli-Seip syndrome and acquired GL, referred to as Lawrence syndrome. Loss of fat leads to metabolic complications, the severity of which depends on the extent of the loss. Location of fat loss may vary and patients usually have very little fat and appear muscular. In most of these patients the condition leads to serious problems like insulin resistance, high cholesterol, diabetes mellitus and fatty liver disease.

Clinical features with a family history of lipodystrophy and associated conditions are often used in diagnosis of the disease. Associated conditions may include diabetes mellitus, high levels of triglycerides or cholesterol, fatty liver, dark, velvety patches of skin and polycystic ovary syndrome. The treatment strategy includes alleviating the disturbances due to changes in fat distribution. Lifestyle modifications with diet, nutrition therapy and exercise are important steps in the treatment of the condition. Medications are given for controlling diabetes mellitus, high levels of cholesterol and triglycerides. Myalept is a recombinant leptin analog for the treatment of generalized forms of lipodystrophy in children and adults.

References

Article

  1. Meehan CA, Cochran E, Kassai A, Brown RJ, Gorden P. Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. Expert review of clinical pharmacology. 2016;9(1):59-68. doi:10.1586/17512433.2016.1096772.
  2. Oral EA, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346(8):570–578.
  3. Javor ED, et al. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes. 2005;54(7):1994–2002.
  4. Chong AY, et al. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia. 2010;53(1):27–35.
  5. Diker-Cohen T, et al. Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol Metab. 2015;100(5):1802–1810.
  6. Peters MS, Winkelmann RK. Localized lipoatrophy (atrophic connective tissue disease panniculitis). Arch Dermatol. 1980 Dec;116(12):1363-8.
  7. Gomes KB, et al. Mutations in the Seipin and AGPAT2 genes clustering in consanguineous families with Berardinelli-Seip congenital lipodystrophy from two separate geographical regions of Brazil. J.Clin.Endocrinol.Metab. 2004;89:357–361.
  8. Agarwal AK, et al. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat.Genet. 2002;31:21–23.
  9. Boutet E, et al. Seipin deficiency alters fatty acid Delta 9 desaturation and lipid droplet formation in Berardinelli-Seip congenital lipodystrophy. Biochimie. 2009;91:796–803.
  10. Divi RL, et al. Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long-term to zidovudine. Environ. Mol. Mutagen. 2007;48:179–189.

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Last updated: 2018-06-21 21:37