[CRT-FORUM] 49E 4-year-old girl with dilated cardiomyopathy. Dr. Perez Riera

[CRT-INFO]

Dear Dr. Alexandre Cezimbra
I think that familial dilated cardiomyopathies (FDCMs) account for about 35%
of idiopathic DCMs, yet clinicians under-appreciate their prevalence. Among
the inherited cardiomyopathies, FDCMs account for the greatest burden of HF
and its associated morbidities. Genetic testing can help to identify family
members who are likely to develop FDCMs and should have regular heart exams,
so that treatment can be started early. Genetic testing can also help to
identify family members who are unlikely to develop FDCMs and do not need
regular heart exams.  In cases where the cause of DCM is unknown, or
"idiopathic" DCM. About 30% to 50% of patients with idiopathic DCM have a
family history of the disease in one or more relatives. These patients are
considered to have FDCM. It is caused by defective genes that affect the
function of the heart muscle. Several FDCM genes are currently known,
whereas others are still under investigation. FDCMs has been linked to
defects (called mutations) in any one of several genes, including TNNT2,
TNNI3, TPM1, MYBPC3, MYH7, and ACTC. Detection of a disease-causing mutation
in any of these genes therefore allows diagnosis of FDCMs. Such a
diagnostic test is referred to as a “genetic test.” Importantly, genetic
testing cannot only confirm a clinical diagnosis, but can also detect a
predisposition for FDCMs in individuals who don’t yet have symptoms. In
addition, genetic testing can show that DCM is familial, even if the patient
doesn’t have or is not aware of a family history of the condition. Once the
specific mutation causing FDCMs in one family is known (the “familial
mutation”), genetic testing can easily identify both  presymptomatic or
affected family members (who have the familial mutation) and unaffected
family members (who do not have the familial mutation). Unaffected family
members no longer have to worry about developing the disease or passing it
on to their children and do not need to undergo the rigorous and costly
heart exams recommended for DCM patients. Presymptomatic or affected family
members, on the other hand, know that they have to remain vigilant for
symptoms of the disease (1).
Transmission patters of FDCM forms
1)    Autosomal Dominant: The disease is genetically heterogeneous, but
the most common form of its transmission is an autosomal dominant pattern.
Several of the mutant genes linked to autosomal dominant DCM encode the same
contractile sarcomeric proteins that are responsible for hypertrophic
cardiomyopathy, including alpha-cardiac actin; alpha-tropomyosin; cardiac
troponin T, I, and C; and beta- and alpha-myosin heavy chain. Research to
determine further disease loci is ongoing.

2)    Autosomal recessive: as found, for example, in TNNI3 gene (Cardiac
troponinI CMD2A). TNNI3 is the first recessive gene identified for DCM. It
is on chromosome 19q13.4. The OMIN number is 611880(2).

3)    X-Linked FDCM. (XLDC) or XLDCM is a clinical phenotype of
dystrophinopathy characterized by preferential myocardial involvement
without any overt signs of skeletal myopathy. It is a FDCM that presents
with severe CHF in young males with symptoms occurred between ages 15 and 21
years. Progressive CHF develop gradually over a period of approximately 10
years. A significant portion of XLDC-patients carry mutations in the
dystrophin gene.  Alström syndrome, X-linked, is also found.(3).

4)    Mitochondrial (mt) DNA/RNA mutations mitochondrial inheritance of
the disease is also found.(3). Mahjoub et al.(4) identified a novel
heteroplasmic mitochondrial DNA (mtDNA) (m.4322dupC) mutation in tRNA gene
associated with isolated DCM as maternal trait. Recently, Van Hove et al.
identified a 6-week-old child presented with hypotonia, myopathy, and a
rapidly worsening DCM with severe atrial and ventricular arrhythmias and
pulmonary hypertension, which proved fatal at age 3 months. Biochemical
analysis showed a combined deficiency of the enzymatic activities of
complexes I and IV and T14709C mutation in the mitochondrial tRNA glutamic
acid gene(5).

Inherited DCM is a genetically and phenotypically very heterogeneous
disease. DCM is caused by mutations in multiple genes encoding proteins that
are involved in force generation, force transmission, energy production and
several signalling pathways. Additionally, the mutation could occur in
mitochondrial DNA and mitochondrial tRNA. Many individuals with DCM do not
even consider that they may have an inherited form of the condition until
they begin to analyze their family history. FDCM is clinically and
diagnostically the same as other forms of DCM, so careful attention to
family history is essential. It is important to recognize that if a person
with DCM has just one affected relative, this could suggest a diagnosis of
FDCM.
Criteria for FDCM: One individual diagnosed with idiopathic DCM in a family,
with at least: One relative also diagnosed with idiopathic DCM or one
first-degree relative with an unexplained SD under the age of 35 years.
Occasionally, FDCM is not limited to problems with the pumping function of
the heart. Additional complications may also be present, such as dromotropic
disturbances that cause bradychardia and syncope, arrhythmia and potentially
SD, or conditions involving other muscles in the body that cause muscle
weakness. It is important to consider these other features of FDCM when
evaluating your family history. If the patient is suspected to have a FDCM,
his/her relatives could be at risk for DCM. A detailed pedigree provides
important clues about whether FDCM is present in a family. Among affected
relatives, symptoms can be quite variable. For example, age of onset of
symptoms can be anywhere from infancy to the 70s, even within the same
family. Physician or a genetic counselor can help construct the family
pedigree and analyze it for inheritance patterns. Most of the time, FDCM
follows an autosomal dominant inheritance pattern, although other patterns,
such as recessive and sex-linked, have been reported as well. In autosomal
dominant inheritance, men and women are equally affected, and first-degree
relatives (parents, siblings, and children) of a patient with FDCM have a
50% chance of inheriting FDCM. Often, several generations are affected.
References
1)    Burkett EL, Hershberger RE (2005) Clinical and genetic Issues in
familial dilated cardiomyopathy. J. Am. Coll. Cardiol. 45:969-981.
2)    Murphy RT, Mogensen J, Shaw A, Kubo T, Hughes S, McKenna WJ. Novel
mutation in cardiac troponin I in recessive idiopathic dilated
cardiomyopathyLancet.2004; 363:371-372.
3)    Schonberger J, Seidman CE. Many roads lead to a broken heart: the
genetics of dilated cardiomyopathy. Am J Hum Genet. 2001; 69: 249-260.
4)    Mahjoub S, Sternberg D, Boussaada R, Filaut S, Gmira F, Mechmech R,
Jardel C, Arab SB. A novel mitochondrial DNA tRNAIle (m.4322dupC) mutation
associated with idiopathic dilated cardiomyopathy. Diagn Mol Pathol. 2007;
16: 238-242.
5)    Van Hove JL, Freehauf C, Miyamoto S, Vladutiu GD, Pancrudo J,
Bonilla E, Lovell MA, Mierau GW, Thomas JA, Shanske S. Infantile
cardiomyopathy caused by the T14709C mutation in the mitochondrial tRNA
glutamic acid gene. Eur J Pediatr. 2008 Jul;167:771-776.

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

> I would like to congratulate everyone for this outstanding symposium 
> and add that this genetic screening would be important for the future 
> retatives of this pedriatic patient, being altogether useless for 
> herself, since, so far, we can not treat sick genes.
> Sincerely,
> Alexandre Cezimbra M.D.
> <cezimbra at cardiol.br>
-- 
Dr. Sergio Dubner
President of Scientific Committee

Dr. Edgardo Schapachnik
President of Steering Committee