Berardinelli-Seip Congenital Lipodystrophy

[Includes: Brunzell Syndrome, BSCL Type 1 (BSCL1), BSCL Type 2 (BSCL2)]

Clinical Diagnosis

Three major criteria or two major criteria plus two or more minor criteria make a diagnosis of BSCL very likely.

Major criteria

• Lipoatrophy affecting the trunk, limbs, and face.  Generalized lipodystrophy is apparent at birth. In some individuals, the face may be normal at birth with lipoatrophy becoming apparent during the first months of life. Lipoatrophy gives an athletic appearance, especially because skeletal muscle hypertrophy is also present.

• Acromegaloid features.  These features include prognathism, prominent orbital ridges, enlarged hands and feet, clitoromegaly, enlarged external genitalia in the male, gigantism, muscular hypertrophy, and advanced bone age.

• Hepatomegaly.  Liver enlargement is secondary to fatty liver early on and to cirrhosis late in the disease course.

• Elevated serum concentration of triglycerides.  Serum concentration of triglycerides can be elevated up to 80 g/L, and is sometimes associated with hypercholesterolemia.

• Insulin resistance.   Elevated serum concentrations of insulin and C-peptide may occur starting in the first years of life. Overt clinical diabetes mellitus usually develops during the second decade. Its early clinical expression is acanthosis nigricans of the groin, neck, and axillae, which may have, in some cases, a verrucous appearance.

Minor criteria

• Hypertrophic cardiomyopathy.  This may be present in infancy or develop later in life.

• Psychomotor retardation or mild (IQ 50-70) to moderate (IQ 35-50) mental retardation.  Approximately 80% of individuals with mutations in BSCL2 have mild-to-moderate intellectual impairment, whereas only 10% of individuals with mutations in AGPAT2 have intellectual impairment.

• Hirsutism.  This manifests with low frontal and posterior hairline; hypertrichosis is apparently independent of hormonal stimulation.

• Precocious puberty in females.  In a series of 75 individuals with BSCL, three females underwent puberty before the age of seven years [Van Maldergem et al 2002].

• Bone cysts.  These occur in 8%-20% of affected individuals and have a polycystic appearance in x-rays. Located in the epiphyseal and metaphyseal regions of the long bones, bone cysts are often diagnosed during the second decade and are mostly observed in individuals with mutations in AGPAT2.

• Phlebomegaly.  Prominence of the veins of the lower and upper limbs is observed, in part because of the lack of subcutaneous fat.

Molecular Genetic Testing

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Genes.  Two genes are known to be associated with Berardinelli-Seip congenital lipodystrophy:

• AGPAT2: BSCL type 1

• BSCL2: BSCL type 2

The proportion of BSCL caused by mutations in each of the two genes is closely related to the population under study: BSCL2 disease-causing mutations accounted for the majority of cases in the Berardinelli-Seip study group [Van Maldergem et al 2002, Magré et al 2003], where affected individuals originated mostly from Europe, the Middle East, and sub-Saharan Africa; a study from Brazil draw similar conclusions (18/26) [Fu et al 2004]; likewise, in a small population sample (4) recently reported from Japan, three of four affected individuals were homozygous for a BSCL2 mutation [Ebihara et al 2004]. In contrast, a study conducted in the US reported AGPAT2 disease-causing mutations in the majority of affected individuals (26/45) [Agarwal et al 2003]. Of note, many individuals in this cohort are of African ancestry.

Other loci.  Magré et al (2003) found that 92/94 affected individuals harbor mutations that are either in BSCL2 or AGPAT2 or appear to be linked to their loci; Agarwal et al (2004) found this to be the case in 44/47 affected persons. The possibility of an additional locus is still a matter of debate since the failure to detect disease-causing mutations in one of these two genes and/or linkage to their loci may reflect either stringency of diagnostic criteria used for inclusion or locus heterogeneity.

Clinical uses

• Confirmatory diagnostic testing

• Carrier testing

• Prenatal diagnosis

Clinical testing

• BSCL2.  Sequence analysis of the BSCL2 nonsense mutation in exon 4 (a 5-base pair deletion) identified in the Lebanese population [Magré et al 2001] and mutations in individuals of European, Middle-Eastern, Asian, or Portuguese ancestry.

• AGPAT2.  Sequence analysis of the AGPAT2 gene may be used to detect mutations in individuals of African heritage.

Table 1. Molecular Genetic Testing Used in Berardinelli-Seip Congenital Lipodystrophy

Test Method	Mutations Detected	Mutation Detection Frequency  1		Test Availability
		Ethnic Heritage of Affected Individual	Prevalent Mutation
Sequence analysis	BSCL2 5-base pair deletion in exon 4	Lebanese	100%	Clinical
	BSCL2 mutations	European	20%
		Asian	Unknown
		Portuguese	80%
	AGPAT2 mutations	African or African-American  2 , Portuguese, other Caucasians	80%, 95%, 100%	Clinical

1. Proportion of affected individuals with a mutation(s) as classified by gene and population group
2. Nearly all individuals of African origin with BSCL type 1 have the mutation IVS-2A>G in exon 4

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Genetically Related (Allelic) Disorders

AGPAT2. No other phenotypes are associated with mutations in AGPAT2, assuming that Brunzell syndrome is classic BSCL with one of its late complications, i.e. bone cysts.

BSCL2. Heterozygous missense mutations in BSCL2 have been identified in BSCL2-related neurologic disorders, a spectrum of conditions that includes: Charcot-Marie-Tooth disease type 2, distal hereditary motor neuropathy type V, spastic paraplegia 17, and Silver syndrome. The clinical features of these BSCL2-related neurologic disorders include:

• Onset of symptoms ranging from the first to the seventh decade (6-66 years, mean 19 years)

• Slow disease progression

• Upper motor neuron involvement: gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses

• Lower motor neuron involvement: amyotrophy (wasting) of the peroneal muscles and the small muscles of the hand (particularly the thenar and dorsalis interosseus I muscles) that is frequently unilateral

• Usually normal sensation except for pallesthesia (i.e., abnormal vibration sense)

• Pes cavus and other foot deformities

Natural History

Berardinelli-Seip congenital lipodystrophy (BSCL) is mostly diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Hepatomegaly secondary to hepatic steatosis occurs in virtually all individuals with BSCL. Skeletal muscle hypertrophy occurs in all affected individuals.

Affected individuals develop insulin resistance and about 25%-35% of individuals develop diabetes mellitus between ages 15 and 20 years. Diabetes mellitus can be difficult to control.

Hypertrophic cardiomyopathy is reported in 20%-25% of individuals and is a significant cause of morbidity from cardiac failure and early mortality around age 30 years. Affected individuals have died as early as age 19 months of complications of cardiomyopathy.

Intellectual impairment is common, especially in individuals with mutations in BSCL2. Intrafamilial variability, including variability in intellectual impairment, exists.

Neonatal or infantile presentation.  Severe forms of BSCL may have prenatal onset with intrauterine growth retardation. Presentation in the first months of life includes failure to thrive (or conversely gigantism), hepatomegaly, lipoatrophy, facial dysmorphia, enlarged tongue, or developmental delay. All affected individuals demonstrate lipoatrophy in the first year of life.

Juvenile presentation.  Diabetes mellitus manifest by weight loss, polydipsia, polyuria, or asthenia is frequently the presenting finding in the second decade.

Adult presentation.  BSCL presents on occasion in early adulthood with diabetes mellitus. Individuals may first be seen in the plastic surgery clinic seeking cosmetic improvement of facial lipoatrophy or in the cardiology clinic or gastroenterology clinic for manifestations such as hypertrophic cardiomyopathy or hepatomegaly. Some women present with oligomenorrhea, amenorrhea, or features of polycystic ovary syndrome.

Genotype-Phenotype Correlations

Approximately 80% of individuals with mutations in BSCL2 have mild-to-moderate intellectual impairment, whereas only 10% of individuals with mutations in AGPAT2 have intellectual impairment.

No correlation exists between the site and type of BSCL2 mutation and intellectual impairment [Van Maldergem et al 2002]. Furthermore, related and unrelated individuals with the same mutation may be discordant for intellectual impairment.

Individuals with BSCL2 mutations have increased prevalence of cardiomyopathy.

There appears to be no relationship between the site and type of AGPAT2 mutations and severity of lipodystrophy or metabolic complications.

Penetrance

Penetrance is complete.

Nomenclature

• Berardinelli-Seip syndrome is named after Berardinelli who reported the first affected individuals from Brazil in 1954. The syndrome was confirmed in 1959 in Norway by Seip, whose patients originated from the county of Rogaland. In the European literature, the terms Seip syndrome, generalized lipodystrophy, congenital generalized lipodystrophy, or total lipodystrophy have been used.

• Brunzell syndrome (OMIM 272500) is the association of bone cysts and lipoatrophic diabetes mellitus described in five affected African-Americans from the same sibship. Originally Brunzell syndrome was thought to be a separate entity, but it is now generally recognized that bone cysts represent a rare complication of Berardinelli-Seip congenital lipodystrophy. Furthermore, Fu et al (2004) identified mutations in AGPAT2 in three sibs with Brunzell syndrome.

• After onset of diabetes mellitus, some have termed individuals with BSCL as having "lipoatrophic diabetes."

• Lawrence syndrome is synonymous with acquired generalized lipodystrophy.

Prevalence

More than one hundred cases of BSCL have been reported in the medical literature (see Suggested Readings).

Prevalence estimates:

• One per 12 million in USA [Garg 2000]

• One per million in Norway

• One per 200,000 in Lebanon

• One per 500,000 in Portugal

Individuals with mutations in AGPAT2 typically originate from sub-Saharan Africa and the Maghreb (Morocco, Algeria, Tunisia) and occasionally from Middle Eastern countries (e.g., Turkey) and northern Europe [Van Maldergem et al 2002].

Individuals with mutations in BSCL2 include whites of varying ethnicities (Norway, United Kingdom, Portugal and its former colonies, Mediterranean countries) and Middle-Eastern Arabs [Van Maldergem et al 2002].

In Infancy

• SHORT syndrome (OMIM 269880)

• Neonatal progeroid syndrome (OMIM 264090)

• Neurometabolic lysosomal storage disorder: Gaucher type 2, Krabbe disease

• Russell diencephalic syndrome

• Leprechaunism: Donohue syndrome (OMIM 246200)

In Childhood

• Familial partial Dunnigan-Koëberling lipodystrophy (OMIM 151660)

• Rabson-Mendenhall (OMIM 262190)

• Insulin-dependent diabetes mellitus

• Acquired generalized lipodystrophy (Lawrence syndrome) [Misra & Garg 2003]. Three subtypes exist.

• Mandibuloacral dysplasia (MAD) caused by LAMNA and ZMPSTE24 mutations

• Hutchinson-Gilford progeria syndrome

In Adulthood

• Acquired partial lipodystrophy (Barraquer-Simons syndrome)

• Lipodystrophy associated with human immunodeficiency virus infection

• Partial lipodystrophy with C3 nephritic factor

• Acquired generalized lipodystrophy (Lawrence syndrome)

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Berardinelli-Seip congenital lipodystrophy (BSCL), the following clinical evaluations are recommended:

• Assessment of pubertal status according to Tanner's charts

• Neurological examination

• Search for signs of liver dysfunction

• Search for evidence of hypertrophic cardiomyopathy

• Search for evidence of possible orthopedic problems (reduced hip mobility, genu valgum)

• Complete ophthalmological examination, including slit lamp examination

• Testing of IQ with age-appropriate scales

The following additional investigations are recommended:

• Complete blood count

• Serum concentration of electrolytes, insulin, AST, alanine transaminase, urea, creatinine, C-peptide, triglycerides, cholesterol

• Serum proteins and electrophoresis

• Oral glucose tolerance test. When appropriate: clamp glucose homeostasis study

• When appropriate: GH, IgG, A, M, E, C3 nephritic factor, CH50, C3, C4, apolipoproteins, hypothalamo-pituitary dynamic tests

• Echocardiogram

• Liver ultrasound examination

• Renal ultrasound examination to evaluate for kidney size

• Skeletal survey, especially long bones; search for bone cysts and evaluation of bone age maturation

• Dual energy x-ray absorptiometry (DEXA) scan for assessment of bone density to evaluate for osteopenia

Treatment of Manifestations

• Restriction of total fat intake between 20% and 30% of total dietary energy is often sufficient to maintain normal triglyceride serum concentration.

• Fibric acid derivatives and n-3 polyunsaturated fatty acids derived from fish oils can be tried for the treatment of extreme hypertriglyceridemia.

• Leptin treatment has proven successful in controlling both hypertriglyceridemia and diabetes mellitus [Garg et al 1999, Simha et al 2002], but its availability outside of clinical trials is limited.

• Management of diabetes mellitus does not differ from that of childhood-onset diabetes mellitus.

• Special education is required for individuals with psychomotor retardation or mental retardation.

Surveillance

• Screening for glycosuria as a manifestation of diabetes mellitus

• Follow-up in a diabetes clinic every six months to monitor for possible retinal, peripheral nerve, and renal complications

• Yearly echocardiogram and ultrasound examination

Agents/Circumstances to Avoid

Other drugs, including fenfluramine, have no proven efficacy and should be avoided.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Berardinelli-Seip congenital lipodystrophy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic, although an increased frequency of diabetes mellitus is suggested.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic, although an increased frequency of diabetes mellitus is suggested.

Offspring of a proband.  The offspring of an individual with BSCL are obligate heterozygotes (carriers) for a disease-causing mutation.

• Pregnancies have been described in individuals with BSCL type 1 [Van Maldergem et al 2002].

• Many individuals with BSCL type 2 (BSCL2) do not reproduce.

Other family members of a proband.  Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

• BSCL1.  Carrier testing for mutations in the AGPAT2 gene is available on a clinical basis once the mutations have been identified fin the family.

• BSCL2.  Carrier testing is available on a clinical basis for mutations in the BSCL2 gene once the mutations have been identified in the family.

Related Genetic Counseling Issues

Differentiation between BSCL type 1 and BSCL type 2 may be useful for purposes of genetic counseling, particularly if the affected individual is too young for mental development to have been clearly characterized. However, because AGPAT2 molecular genetic testing is currently performed on a research basis only, it may not be possible in many instances.

Family planning.  The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only and the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for BSCL caused by BSCL2 or AGPAT2 mutations is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

AGPAT2

Normal allelic variants: The AGPAT2 gene consists of six exons spanning less than 20 kb.

Pathologic allelic variants: Homozygous or compound heterozygous AGPAT2 mutations are associated with BSCL. Agarwal et al (2002) identified various AGPAT2 mutations in 11 pedigrees, including a deletion resulting in a frameshift mutation and premature termination codon, nonsense mutations, splice site mutations, missense mutations, and single-amino acid deletions. Magré et al (2003) also reported various mutations in 38 individuals from 30 pedigrees. (For more information, see Table A: locus-specific databases and HGMD above.)

Normal gene product: The AGPAT2 protein, 1-acyl-sn-glycerol-3-phosphate acyltransferase beta (also known as lysophosphatidic acid acyltransferase beta (LPAAT) has 278 amino acids and belongs to the family of acyltransferases. The AGPAT2 enzyme catalyzes an essential reaction in the biosynthetic pathway of glycerophospholipids and triacylglycerol [Agarwal et al 2002].

Abnormal gene product: Mutations in AGPAT2 may cause congenital lipodystrophy by inhibiting/reducing triacylglycerol synthesis and storage in adipocytes. It is also likely that reduced AGPAT2 activity could increase tissue levels of lysophosphatidic acid, which may negatively affect adipocyte functions [Agarwal et al 2002].

BSCL2

Normal allelic variants: The BSCL2 gene consists of 11 exons spanning at least 14 kb. The putative translation initiation codon is located in the second exon.

Pathologic allelic variants: Homozygous or compound heterozygous BSCL2 mutations are associated with BSCL. Magré et al (2001) identified several different mutations in BSCL2 among 44 individuals, including microdeletions, small insertions and deletions, and five nucleotide substitutions. The majority of mutations resulted in a frameshift or a premature stop codon. (For more information, see Table A: locus-specific databases and HGMD above.)

Normal gene product: The BSCL2 gene encodes a 398-amino acid protein, seipin. Seipin has at least two hydrophobic amino acid stretches, indicating that it could be a transmembrane protein. The function of seipin is unknown [Magré et al 2001].

Abnormal gene product: The majority of BSCL2 variants are null mutations that are predicted to result in severe disruption of the protein function.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Readings

Author Notes

Dr. Van Maldergem is a pediatrician with 15 years' experience in clinical genetics. He is the coordinator of the Berardinelli-Seip study group (created in 1993) and organizer of the first international conference on lipodystrophies (Brussels, 1997).

Revision History

• 23 August 2007 (cd) Revision: sequence analysis and prenatal diagnosis for BSCL type 1 available on a clinical basis

• 21 December 2005 (me) Comprehensive update posted to live Web site

• 3 August 2004 (lvm) Revision: Genetically Related Disorders

• 8 September 2003 (me) Review posted to live Web site

• 24 April 2003 (lvm) Original submission