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VOLUME 3 4, NUMBER 4, FA LL 2016 181
FEATURE ARTICLE
Cardiac Manifestations of Congenital
Generalized Lipodystrophy
Vani P. Sanon,1 Yehuda Handelsman,2 Son V. Pham,1 and Robert Chilton1
Congenital generalized lipo-
dystrophy (CGL), also called
Berardinelli-Seip congenital li-
podystrophy, is a rare genetic disorder
characterized by loss of adipose tissue
and marked insulin resistance. A hall-
mark of this disorder is a low leptin
level, leading to a voracious appetite
in aected individuals. ere appear
to be ~300–500 cases of CGL world-
wide (1). Mutations in a variety of
genes can lead to the various subtypes
of congenital lipodystrophy (1). At
the cellular level, dysfunctional adipo-
cytes are unable to store triglycerides,
leading to high chylomicron levels.
e disorder is characterized by pro-
tean clinical manifestations, including
diabetes, pancreatitis, fatty liver, and
endothelial cell dysfunction (2).
Berardinelli (3) first described
CGL in a 2.5-year-old boy in Brazil
in 1954. Subsequently, in 1959,
Seip (4) described three more cases
in Norway. CGL has an autosomal
recessive pattern of inheritance. It
has multisystemic manifestations,
including muscular hypertrophy,
hypertrophic cardiomyopathy, hep-
atomegaly, steatohepatitis, acanthosis
nigricans, hypertriglyceridemia, and
diabetes (5). Aected patients develop
a hypertrophic “lipotoxic” cardio-
myopathy, with both diastolic and
systolic dysfunction, and have a pre-
dilection for cardiac dysrhythmias
and early sudden cardiac death (6).
In this article, we summarize the
literature on this rare genetic dis-
order, focusing on the translational
biology of the disease, its cardiac
manifestations, and novel treatment
considerations.
Genetics and Translational
Biology of CGL
CGL has four subclinical phenotypes
(CGL1, -2, -3, and -4) secondary to
mutations in the acylglycerol-3-phos-
phate-O-acyltransferase (AGPAT2)
gene, the gamma-3–linked gene lo-
cated at chromosome 11q13 (BSCL2),
caveolin-1 (CAV1), and RNA poly-
merase 1 and transcript release fac-
tor (PTRF), respectively (7–12)
(Figure 1). Agarwal et al. (9) report-
ed mutations in many genes, one of
which is the AGPAT2 gene found on
chromosome 9 in humans. is gene
has been found to code the protein lo-
cated in the endoplasmic reticulum,
aecting phospholipid biosynthesis.
■ IN BRIEF Congenital lipodystrophy is a rare genetic disorder characterized
by a near-complete absence of fat cells, hypoleptinemia leading to a voracious
appetite, and marked insulin resistance. This article focuses on the known car-
diovascular manifestations of patients with congenital lipodystrophy, including
cardiomyopathy, cardiac arrhythmias, and accelerated atherosclerosis arising
from a markedly deranged metabolic milieu. Future research that targets
leptin deciency (metreleptin) and apoC3 mRNA (antisense oligonucleotide)
could open a window for potential pharmacological treatment of this chal-
lenging disorder.
1Division of Cardiology, University of Texas
Health Science Center at San Antonio and
Audie L. Murphy VA Hospital, San Antonio,
TX
2Metabolic Institute of America, Tarzana, CA
Corresponding author: Robert Chilton,
chiltonr@gmail.com
DOI: 10.2337/cd16-0002
©2016 by the American Di abetes A ssoci ation .
Readers may us e this article as l ong as th e work
is properly cited , the use i s educ ation al and n ot
for prot, and the work is not altered . See http://
creativecomm ons.org/lice nses/by-nc-nd/3.0
for det ails .
182 CLINICAL.DIABETESJOURNALS.ORG
FEATURE ARTICLE
Severeal other mutations associated
with CGL have been described in the
literature (1).
At the cellular level, the dys-
functional adipocytes in CGL are
unable to store triglycerides. Figure
2 illustrates dierences between an
adipocyte of an obese individual
and one of a person with CGL. It
is noteworthy that, in obesity, the
enlarged adipocyte is no longer able
to store triglycerides and, in CGL,
the abnormal adipocyte is unable to
store triglycerides. Both conditions
lead to increased circulating levels
of free fatty acids (FFAs). It is well
known from numerous studies that
high levels of FFAs increase cardio-
vascular risk (13). Cardiovascular
interest in CGL comes, in part, from
the marked increase in circulating
FFAs found in this condition.
Cardiac Manifestations of CGL
e cardiac manifestations of CGL
were described as early as 1959 (4). A
variety of cardiac issues have been de-
scribed, ranging from dilated cardio-
myopathy to hypertrophic cardiomy-
opathy and severe biventricular heart
failure. In addition, patients have
been noted to have both brady- and
tachyarrhythmias, particularly long
QT syndrome and sudden cardiac
death. Following is a summary of
the literature on CGL as it pertains
to the heart; ~200 cases of CGL (or
Berardinelli-Seip syndrome) have
been reported (14,15).
Rajab et al. (16) described the
cardiac manifestations of CGL4.
Patients with CGL4 have a wide
variety of clinical manifestations,
including cardiac dysrhythmias, joint
involvement, skeletal and smooth
muscle hypertrophy, and myopa-
thies. Individuals with CGL4 are
described to have mutations in the
PT R F - C AVIN gene, which in turn
interferes with the functioning of
CAV1 and CAV3 , manifesting as
lipodystrophy or myopathy, respec-
tively (17). At the cardiac physiology
level, these mutations adversely aect
the functioning of various ion chan-
nels in the heart, including the nodal
pacemaker channel hyperpolariza-
tion-activated cyclic nucleotide-gated
potassium channel 4 (HCN4 ), volt-
age-gated Na+ channel (Nav1.5,
SCN5A), and the L-type Ca2+ chan-
nels (C ACN A1C ), leading to various
dysrhythmias. Mutations in HCN4
can cause sinus node dysfunction/sick
sinus syndrome, whereas mutations
in SCN5A, CAV3, and CAC NA1C
are linked to sudden cardiac death,
ventricular tachycardia, and long QT
syndromes (LQT3, -8, and -9) (17)
(Figure 3).
Rajab et al. (16) described 11
cases of CGL, of which 6 experi-
enced sudden cardiac death at an
early age. ey reported the case of
a 14-year-old boy with CGL who
was found to have had multiple epi-
sodes of palpitations and syncope
secondary to both ventricular and
supraventricular tachycardia, as well
as sinus bradycardia. Electrocardio-
gram (ECG) revealed a prolonged
corrected QT of ~ 450–480 ms, for
indicating long QT syndrome. Long
QT syndrome is a congenital disor-
der characterized by ECG evidence of
a prolonged QT interval, which may
lead to ventricular tachyarrhythmias,
■ FIGURE 1. Subtypes of congenital lipodystrophy. Adapted from Ref. 1.
■ FIGURE 2. An adipocyte in an obese individual is contrasted with a dysfunctional
adipocyte in congenital lipodystrophy. It is noteworthy that in obesity, the enlarged
adipocyte is no longer able to store triglycerides, and in CGL, the abnormal adipo-
cyte is unable to store triglycerides. Both conditions lead to increased circulating
FFAs. TRG, triglycerides.
VOLUME 3 4, NUMBER 4, FA LL 2016 183
s a n o n e t a l .
FEATURE ARTICLE
syncope, cardiac arrest, or sudden
cardiac death. Another patient was
noted to have syncope, with a cardiac
loop recorder revealing supraven-
tricular and ventricular tachycardia
and frequent ventricular extrasysto-
les; eventually, at the age of 13 years,
this patient sustained cardiac arrest
secondary to ventricular brillation
that was refractory to debrillation.
Another ve patients reported by
Rajab et al. sustained sudden cardiac
death in their teens. Postmortem
examinations of these children were
precluded because they lived in rural
areas of Oman.
Shastry et al. (18) described ve
patients with CGL4, associated with
mutations in the PTRF gene. Two
of these patients showed catechol-
aminergic polymorphic ventricular
tachycardia on exercise treadmill
testing, three had normal left ven-
tricular (LV) size and function on
transthoracic echocardiography, and
one had hypertension.
Rahman et al. (19) described
CGL in two Pakistani children.
From the cardiac standpoint, both
children demonstrated echocardio-
graphic evidence of LV hypertrophy,
although LV function was found to
be normal. One child had a small
patent foramen ovale, and the other
had a small secundum atrial septal
defect. Electrocardiography of the
aected children showed a right bun-
dle branch pattern.
Bjornstad et al. (6) reported
the cardiac manifestations of CGL
in seven patients. ere were four
deaths in their case series, in patients
ranging in age from 24 to 37 years,
with a mean age of death of 32
years. Biventricular hypertrophy
and dysfunction with pulmonary
hypertension was also described.
Echocardiographically, the thick-
ened myocardium showed evidence
of vacuolization or intramyocardial
channels. Moreover, on histopatho-
logical assessment of endomyocardial
biopsies, diuse interstitial deposition
of collagen was noted in addition to
marked subendocardial brosis. ere
was no disarray in terms of myocyte
arrangement; however, the myocytes
were hypertrophic, with increases in
the diameters of the nuclei and bers.
Rheuban et al. (20) described the
cardiac manifestations of total gener-
alized lipodystrophy in four patients.
These patients were between the
ages of 16 and 23 years, and echo-
cardiography revealed symmetric
hypertrophic cardiomyopathy and
preserved systolic function. Autopsy
of one patient showed hypertrophy of
the myocardial bers.
Klar et al. (21) described a case
of CGL in a 13-year-old girl who
was found on echocardiography to
have asymmetric septal hypertrophy
without evidence of outow tract
obstruction. Marked myocardial
hypertrophy in a 6-month-old child
with insulin resistance and CGL
was described by Gener et al. (22).
Viegas et al. (23) described the cardio-
vascular manifestations of a woman
with total generalized lipodystrophy
who presented with decompensated
heart failure. Transthoracic echocar-
diography revealed severe concentric
LV hypertrophy with hyperdynamic
LV function and advanced diastolic
dysfunction with a restrictive mitral
inow pattern. Cardiac MRI con-
rmed LV hypertrophy. e patient
underwent diuresis and was started
on calcium channel blockers, with
marked clinical improvement.
Cardiac Imaging in CGL
Lupsa et al. (24) described the echocar-
diographic features of 25 patients with
CGL; 18 had an increased LV mass, 4
had LV dysfunction, 1 had a patent
ductus arteriosus, 1 had concentric
remodeling, and 1 had moderate LV
dysfunction and dilation. Nelson et
al. (25) used MRI and localized pho-
ton spectroscopy to demonstrate that
patients with CGL had a myocardial
triglyceride content that was three-
fold higher than in control subjects
(0.6–0.2 vs. 0.2–0.1%, P = 0.004).
In addition, patients with CGL were
found to have increased LV mass in-
dex, LV concentricity, and LV hyper-
trophy independent of blood pressure.
Interestingly, this group described
MRI evidence of pericardial fat in
CGL patients that was in contrast to
previous autopsy studies showing an
absence of pericardial fat (26).
Cardiac Autopsy Findings
in CGL
Autopsy studies from Bjornstad’s
CGL group (6) revealed “moderate-
ly symmetrically enlarged heart with
■ FIGURE 3. CGL4 (PTRF mutation) has been associated with cardiac arrhyth-
mias. Rajab et al. (16) characterized patients with fatal cardiac arrhythmias and long
QT syndrome and reported patients with sudden death in the teenage years. The
treatment of these patients is best evaluated by an electrophysiologist because of the
complexity related to polymorphic ventricular tachycardia seen in CGL4 patients.
CGL2 patients also are at increased risk, and avoidance of exercise might be consid-
ered, but this remains unclear. Napolitano and Priori (33) reported on the diagnosis
and treatment of patients with catecholaminergic polymorphic ventricular tachycar-
dia, which has been seen in lipodystrophy.
184 CLINICAL.DIABETESJOURNALS.ORG
FEATURE ARTICLE
normal cusps.” e histopathological
examination showed “mild thickening
of the smaller intramural coronary ar-
teries with intimal brosis, as well as
a moderate subendocardial collagen
deposition. Larger intramural arter-
ies were normal, and the epicardial
branches revealed only sparse focal
intimal brosis. e myocytes were
slightly hypertrophic and normally
arranged. e content of perivascular
and subepicardial fat was decreased.”
One case in particular was described
as having concentric hypertrophy
with the posterior wall and the inter-
ventricular septum, both measuring
up to 16 mm, whereas another case
had asymmetrical septal hypertrophy.
Haque et al. (27) described the
autopsy findings of two patients
with familial partial lipodystrophy,
Dunnigan variety. e rst case was
of a white female who died at the age
of 66 years. e heart was enlarged
(weight 670 g vs. normal weight of
250–300 g in adult women). e
authors reported nding old myo-
cardial scars, but no new infarct was
apparent. Moderate to severe ath-
erosclerosis of the coronary arteries,
proximal aorta, and carotid arteries
was noted.
Accelerated Atherosclerosis
in CGL
Atherosclerotic and vascular disease in
patients with CGL may stem from a
number of metabolic derangements.
Marked elevations in triglyceride and
insulin levels with low HDL choles-
terol levels have been well document-
ed to be associated with increased ath-
erosclerosis, and people with CGL t
this metabolic prole (28). In addi-
tion, fatty liver, which is frequently
associated with lipodystrophy, is also
known to be associated with an in-
creased risk for cardiovascular disease
(CVD) (29).
e National Institutes of Health
(NIH) and FHA101 trials were
open-label, single-arm, U.S. Food
and Drug Administration regulatory
trials that focused on the long-term
safety and ecacy of metreleptin for
the treatment of patients with CGL
(30,31). Goldens (31) described the
burden of atherosclerotic and CVD
in this small cohort of CGL patients:
72 patients with CGL in the NIH tri-
als and 28 patients with CGL in the
FHA101 trial. In the NIH trials, two
patients (2.8%) had a medical history
of coronary artery disease (CAD),
and four patients (5.6%) had cardio-
myopathy (two with hypertrophic
cardiomyopathy, one with cardio-
myopathy, and one with decreased
ejection fraction). In the FHA101
trial, seven (28%) of 25 patients
had CVD (four with CAD, one
with aortic atherosclerosis, one with
myocardial infarction, and one with
ischemic cardiomyopathy). Needless
to say, older patients with CGL may
accrue a higher risk for atherosclerotic
cardiovascular events over time. e
FHA101 trial had a high proportion
of adults with CGL in contrast to
the NIH trials, in which more than
half of the patients were <18 years of
age, which likely explains the higher
proportion of CVD in the FHA101
cohort. However, further studies and
longer-term follow-up of individuals
with CGL are needed to better under-
■ FIGURE 4. The cardiac manifestations of CGL are wide-ranging. Involvement
of the cardiovascular system is very apparent, ranging from sudden death to likely
increased atherosclerotic risk.
TABLE 1. Treatment Considerations in Lipodystrophy
●Diagnosis can lead to major anxiety for patients and their families.
●Cosmetic surgery to address fat loss can be considered with caution.
●Dietary considerations: high-carbohydrate, low-fat diet
❍Improves marked chylomicronemia but may increase VLDL cholesterol
■Fibric acid agents and peroxisome proliferator–activated receptor
agents may be helpful but are untested
■Fish oil supplementation should be considered
●There are special cardiovascular concerns with CGL4 because of
arrhythmia risk:
❍Avoid strenguous exercise
❍Possible role for β-blockers
❍Electrophysiology consultation should be given strong consideration
●Newest consideration: metreleptin
❍Leads to improved metabolic parameters
❍Glucose, triglyercides, fat ty organ disease
VOLUME 3 4, NUMBER 4, FA LL 2016 185
s a n o n e t a l .
FEATURE ARTICLE
stand these patients’ predilection for
atherosclerotic vascular disease.
Conclusion
CGL is a rare genetic disorder with
unusual cardiac manifestations
(Figure 4). Cardiac involvement
may include electrophysiological ab-
normalities resulting from long QT
syndrome and a predisposition to
tachyarrhythmias, including cate-
cholaminergic polymorphic ventric-
ulartachycardia and sudden cardiac
death. Patients with CGL may devel-
op heart failure and advanced diastolic
dysfunction from marked LV hyper-
trophy that may be either symmet-
rical or asymmetrical. Histologically,
the absence of rearrangement of
myocardial bers in CGL dierenti-
ates this condition from hypertrophic
cardiomyopathy. In addition, because
of increased circulating FFAs and low
HDL cholesterol levels, such patients
may develop accelerated atherosclero-
sis. Patients with this rare genetic dis-
order require cardiac care focused on
the diagnosis and treatment of heart
failure, appropriate screening and
management of rhythm disorders,
and aggressive treatment of dyslipid-
emia (Table 1). Since leptin deciency
is a key abnormality in lipodystrophy,
leptin replacement has been found to
ameliorate insulin resistance, hyper-
glycemia, hypertriglyceridemia, and
hepatic steatosis (32). Future direc-
tions for treatment could include
novel pharmacological therapies that
target leptin deciency (metreleptin)
and hypertriglyceridemia via inhibi-
tion of apoC3 mRNA (antisense oli-
gonucleotide) (32–34).
Duality of Interest
No potential con icts of interest relevant to
this article were reported.
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