Left ventricular noncompaction associated with hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome

doi:10.4236/health.2010.23029

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Vol.2, No.3, 200-203 (2010) Health

doi:10.4236/health.2010.23029

Left ventricular noncompaction associated with

hypertrophic cardiomyopathy and

Wolff-Parkinson-White syndrome

Luis Alday1, Eduardo Moreyra1, Eva Bruno2, Norma Rossi3, Hector Maisuls2

1Divisions of Pediatric Cardiology and Cardiology, Sanatorio Allende, Córdoba, Argentina; [email protected]

2Division of Cardiology, Children’s Hospital, Cordoba, Argentina

3Division of Genetics, Private Hospital, Cordoba, Argentina

Received 14 October 2009; revised 10 December 2009; accepted 14 December 2009.

ABSTRACT

We report a 35-year-old female patient with hy-

pertrophic cardiomyopathy, left ventricular non-

compaction, and Wolff-Parkinson-White EKG patt-

ern. Several other family members present the

same clinical condition. We speculate that this

phenotype is related to the genotypes PRKAG2

and LAMP2 represented by mutations of the

genes encoding AMP-activated protein kinase

(PRKAG2) and lysosome associated membrane

protein 2 (LAMP2 ).

Keywords: Left Ventricular Noncompaction;

Hypertrophic Cardiomyopathy;

Wolff-Parkinson-White Syndrome

1. INTRODUCTION

Left ventricular noncompaction (LVNC) is the result

from the a rrest in m yocardi al dev elopm ent w ith pe rsist ent

sinusoid tracts interspersed with prominent muscular

trabeculae. Affected patients usually develop congestive

heart failure associated with arrhythmias and systemic

thromboembolism.W e report a proband with mental retar-

dation and peculiar somatic findings, associated LVNC

and hypertrophic cardiomyopathy (HCM). Other family

members were also involved, all of them, the proband

included, had Wolff-Parkinson-White (WPW) syndrome,

suggesting a relationship regarding the etiology of this

LVNC - HCM phenotype overlapping.

2. CASE REPORT

The proband is a 35-year-old female who had been fol-

lowed since infancy. She was referred to us for a heart

murmur and congestive heart failure. Clinical examina-

tion at presentation was compatible with moderate to

severe mitral regurgitation. There was cardiomegaly and

signs of pulmonary venous hypertension on the chest

X-ray. The EKG showed a WPW pattern with extremely

high voltage. Cineangi ography reveal ed a hypercontractile

left ventricle without outflow tract obstruction, moderate

to severe mitral regurgitation, and a never-seen-before

cont our wh ich made i t rese mble a “porcu pine ” since there

were heavy trabeculations leaving thin spaces between

them as if they were wheel spokes radiating from the

center to the periphery of the ventricular cavity. On the

basis of the a n gi o gra phic findings this pat i ent’s heart was

called a “spongy” heart because was thought to be the

result of persistence of embryonic myocardium [1].

The patient was treated for heart failure until early

childhood. There was clinical i mprovement with decreasi ng

mitral regurgitation as judged by auscultation. She re-

mained symptom free for several years and she had

non-obstructive HCM with mild mitral insufficiency

upon echocardiographic examination. She continued

regular follo w- up visits and the echocardiograms showed

progression to a dilated stage. Eight years ago she was

admitted with pulmonary edema and frequent ventricular

extrasystoles. Following treatment she was in NYHA

functional class II and was discharged. Occasional re-

missions occurred caused by treatment non-com pliance.

Presently, she is in functional class III and has slight

mental retardation. She has lower than normal stature, a

short neck, low posterior hairline, and a high palate.

Clinical genetics evaluation suggests the diagnosis of

Noonan syndrome. Cardiovascular examination shows, a

mitral regurgitation murmur and gallop rhythm. Chest

x-ray a nd E KG pr ese nt e d s e ve re ca r di omegaly wi th si g ns

of pulmonary venous hypertension and WPW pattern,

respectively. Color Doppler-echocardiography demon-

strated hypertrophic and dilated left ventr icle with promi-

nent cavitary trabeculae compatible with the diagnosis of

LVNC (LVNC: C ratio > 2.0), poor contractility, moderate

mitral regur gitation, and pericardial ef fusion (Figur e 1(a)).

L. Alday et al. / HEALTH 2 (2010) 200-203

201

(a)

(b)

Figure 1. (a) Echocardiographic four-chamber view of the proband; There is hypertrophic cardiom yopathy (H CM)

and left ventricular noncompaction (LVNC) with heavy trabeculations in the left ventricular (LV) cavity. The inter-

ventricular septum (IVS): LV posterior wall (PW) ratio is 1.4:1.0. The noncompacted (NC): compacted (C) ratio is

>2.0. The LV end d iasto lic (ED ) dia meter is 6. 0 and the e jection frac tion (E F) 23 %. Peri cardia l ef fusio n is pr esent ; (b)

Color-Doppler echocardiographic four-chamber view of the proband’s sister. There is also HCM and LVNC. The

color i n the LV c avity d eline ates t he heav y trab eculae . The NC: C r atio > 2.0. T here i s conce ntric LV hypert rophy w ith

a prominent septal bulge. The IVS: PW ratio is 1.8:1.0. The LVED diameter and the EF are 4.9 mm and 56% re-

spectively.

L. Alday et al. / HEALTH 2 (2010) 200-203

202

III

Unaffected status

Hypertrophic Cardiomyopathy

Hypertrophic Cardiomyopat hy and Left Ventricular Noncompaction

Unknown clinical status

1 2 345

1 2 3 4 5 6 78 910 11 12 13 14 15 16

1 2 34 56 7

Figure 2. Pedigree of the kindred with hypertrophic cardiomyopathy (HCM), Wolff-Parkinson-White syndrome (WPW),

and left ventricular noncompaction (LVNC) inherited as a Mendelian autosomal dominant trait.The proband is pointed by

the ar row. I4: Pr oband’s grandmother with unknown clinical statu s. II7 and 8: Proband’s mother and aunt both of them with

HCM and WPW. III4: Proband’s sister with HCM, WPW, and LVNC.

The better resolution of the new echocardiographic

technology allowed confirmation of the initial cinean-

giography. An updated family tree (Figure 2) showed an

interesting family pattern where the proposita had a

37-year-old sister also with non-obstructive HCM with

non-compaction and normal left ventricular function

(Figure 1(b)). External features and mental status were

normal. She also had a WPW pattern on the EKG with

normal voltage. She had occasional episodes of su-

praventricular tachycardia. Both the mother and her

identical twin had HCM, WPW, and atrial fibrillation.

They might have had also LVNC but could not be con-

firmed. They died one year apart at the ages of 59 and 60

years due to congestive heart failure and stroke, respec-

tively. The mother’s sister had no descendants. The twins

had 3 siblings and half- siblings each with no history of

HCM. The maternal grandmother died suddenly at a

young age of unspecified causes.

3. DISCUSSION

LVNC was a poorly recognized entity that began to gain

interest from the medical community in the 90’ s. Recently ,

it has become clear that is more pre valent than previ ously

recognized [2]. H owever, its etiology remained unknow n

until recently, when molecular genetic studies showed

that mutations of cytoskeletal genes like those encoding

taffazin (TAZ) and alpha-dystrobrevin (DTNA) causing

Barth syndrome were associated with LVNC [3]. More

recently , it was found that LV NC was also associated with

mutations of sarcomeric genes shared by patients with

HCM and dilated cardiomyopathy, like the alpha-cardiac

actin gene (ACTC), beta-myosin heavy chain (MYH7),

and cardiac troponin T (TNNT2) [4,5]. Cases of patients

sharing both the LVNC and HCM phenotypes have been

published rece ntly but there was no m ention of a mutation

[6,7].

The patient reported here, had other family members

with the same disease, and all had the associated WPW

syndrome. Such overlapping phenotype suggests a strong

genetic association.

WPW syndrome is infrequently associated with HCM.

It has been found in patients with HCM phenotypes with

mutations of the genes encoding AMP-activated protein

kinase (PRKAG2) and lysosome associated membrane

protein 2 (LAMP2). PRKAG2 is an important enzyme

involved in th e production of cellular energy and its mu-

tations might cause HCM, WPW syndrome, conduction

disorders requiring pacing, skeletal myopathy, and gly-

cogen storage disease [8]. About 30% of affected indi-

viduals have atrial fibrillation or supraventricular tachy-

cardia. This clinical pattern was seen in three of the fam-

ily members of our proposita.

LAMP-2, an X-linked gene, encodes proteins that

regulate the integrity and function of lysosomes. Muta-

tions of this gene cause Danon disease characterized by

HCM, WPW syndrome, skeletal myopathy and mental

retardation. Female carriers present later in life with less

severe disease than in males [9].

L. Alday et al. / HEALTH 2 (2010) 200-203

203

In the family under discussion, the proband and the

sister had a phenotype of HCM, WPW syndrome, and

LVNC. The proband had also somatic features suggestive

of Noonan syndrome and mental retardation. The dis-

eased mother and her twin, with normal external pheno-

type, had ha d HCM, WPW syndr ome, an d late onset at rial

fibrillation, but LVNC could not be confirmed.

The members of this family had features shared with

patients affected with the PRKG2 and LAMP-2 mutations.

It is then possible that any of the two might be the in-

volved gene. There are no systematic molecular genetic

studies available showing the association of these genes

with the H CM, WPW and LVNC phenotypes.

The complex overlapping phenotypes of HCM with

WPW syndrome and LVNC seen in this fam ily is possibly

due to a previously not described mutation which should

be studied further.

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