[CRT-FORUM] 43E 4-year-old girl with dilated cardiomyopathy. Dr. Perez Riera

[CRT-INFO]

Dear all: I insist that genetic screening is very important in this case
report.
Example: Mutations in the PRKAG2 gene that encodes the gamma2 regulatory
subunit of AMP-activated protein kinase have been shown to cause autosomal
dominant WPW syndrome associated with HCM. PRKAG2 mutations are responsible
for a diverse phenotype and not only the familial form of the WPW syndrome.
Familial occurrence of pseudo appearance of atrial hypertrophy, sinus
dysfunction, sinus bradycardia, supraventricular extrasystole, short PR
interval, RBBB and occasionally left anterior fascicular block, and should
raise suspicion of a mutant PRKAG2 gene. Mutations in this gene are
associated with familial ventricular WPW, HCM, and SA and AV conduction
disturbances. Clinico-pathologic and experimental data suggest the
hypothesis of a glycogen storage disease. PRKAG2 mutations do not cause HCM
but rather lead to a novel myocardial metabolic storage disease, in which
hypertrophy, ventricular WPW and conduction system defects coexist(1).
Sternick et al(2) studied two large families and found a total of 20
affected individuals showing a combination of sinus bradycardia, short PR
interval, RBBB, intra and infrahisian conduction disturbances often
requiring a pacemaker, and atrial tachyarrhythmias. Three individuals died
suddenly at a young age. No patient had the WPW syndrome, and 10% had
myocardial hypertrophy. The authors performed screening of the exons and
exon-intron boundaries of PRKAG2 that revealed a missense mutation
(Arg302Gln) in the affected individuals from both families. This mutation
had been associated with the familial form of the WPW syndrome and with a
high prevalence of LVH. Besides WPW syndrome and HCM, PRKAG2 mutations are
responsible also for a diverse phenotypes. PRKAG2 gene mutation should be
suspected with familial occurrence of RBBB, sinus bradycardia, and short PR
interval(3).
Another entity is Danon disease: it is clinically characterized by the
triad;
1) HCM or dilatation of all cardiac chambers with impaired systolic and
diastolic function
2) Proximal myopathy
3) Mental retardation.
Myopathy and mental retardation can be absent, It is a dominant X-linked
disorder. It is due to mutation in gene for lysosome-associated membrane
protein 2 (LAMP 2). The LAMP 2 gene is located on Xq24, and its mutation
causes primary deficiency of LAMP 2 and myocyte hypertrophy by accumulations
of vacuoles containing glycogen. Danon disease is an under-recognized and
frequently fatal condition, treatable by heart transplantation.
Investigation of the primary molecular defect is important for cardiac
surveillance and genetic counseling(4)

References

1) Arad M, Benson DW, Perez-Atayde AR, McKenna WJ, Sparks EA, Kanter
RJ, McGarry K, Seidman JG, Seidman CE. Constitutively active AMP kinase
mutations cause glycogen storage disease mimicking hypertrophic
cardiomyopathy. J Clin Invest. 2002 Feb;109:357-362.

2) Sternick EB, Oliva A, Magalhães LP, Gerken LM, Hong K, Santana O,
Brugada P, Brugada J, Brugada R. Familial pseudo-Wolff-Parkinson-White
syndrome. J Cardiovasc Electrophysiol. 2006 Jul; 17:724-732.

3) Hong K, Oliva A, Cheng XS, Brugada P, Brugada J, Sternick EB,
Brugada R. Same genotype and different phenotypes in a family with PRKAG2
gene mutation. Zhonghua Xin Xue Guan Bing Za Zhi. 2007 Jun; 35: 552-554.

4) Di Blasi C, Jarre L, Blasevich F, Dassi P, Mora M. Danon disease: a
novel LAMP2 mutation affecting the pre-mRNA splicing and causing aberrant
transcripts and partial protein expression. Neuromuscul Disord. 2008
Dec;18:962-966.

All the best for all
Andrés Ricardo Pérez Riera MD
Chief of electrovectorcardiographic sector. ABC’s Medical School, ABC
Foundation, Santo André, São Paulo, Brazil Riera at uol.com.br

-- 
Dr. Sergio Dubner
President of Scientific Committee

Dr. Edgardo Schapachnik
President of Steering Committee