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Familial End Stage Hypertrophic Cardiomyopathy

Two brothers (patient A & patient B) with a morphological severe form of hypertrophic cardiomyopathy (HCM) and early onset are presented. Their mother died suddenly at the age of 28 years (see Pedigree). Post-mortem macroscopic analysis revealed HCM.

Myocardial Disease




Patient A was diagnosed with hypertrophic obstructive cardiomyopathy (HOCM) at the age of 9 months based on echocardiography measurements. The electrocardiogram (ECG) recorded left ventricular hypertrophy (LVH) voltage, repolarization disorders, short P-R interval and preexitation sign. Laboratory investigations showed increased plasma transaminases and creatine kinase (CK) levels. At the age of 14 years, he experienced a syncopal episode. His Holter monitoring revealed burst of non-sustained ventricular tachycardia (NSVT) and his LVWmax reached 30 mm. Electrophysiological study (EPS) provoked ventricular tachycardia (VT). An automatic cardioverter defribillator (ICD) was implanted and five discharges occurred during the following year. The evolution of HCM to the dilated hypokinetic form (end stage disease) was very fast. The patient died at the age of 17 years due to pump failure, while waiting heart transplantation (Figure 1).



Patient B, 5 years older than patient A, was diagnosed with HCM (non obstructive form) at the age of 9 years. Ten years later he experienced palpitation and a syncopal episode. Increased liver enzymes and CK plasma levels were observed. The ECG recorded bradycardia with repolarization changes, LVH by voltage and episodes of Mobitz I and II. His left ventricular function started gradually to deteriorate and at the same time bursts of NSVT were recorded in his 24h Holter monitoring. An ICD was implanted and one discharge was recorded. His condition gradually evolved to the dilated form. At the age of 22 years, he underwent successful heart transplantation (Figure 2).



Points to consider:

The two brothers’ final diagnosis of HCM substrate was clarified following further evaluation.
The National Transplantation committee was initially reluctant to approve the heart transplantation.
Finally, the permission was given and patient B is still alive and well 12 years after the transplantation.

Questions :

  • What is your differential diagnosis
  • Which tests do you recommend for further evaluation of those two patients?
  • Why the National Committee was reluctant to proceed to the heart transplantation?

Answers and results:

• PRKAG2 gene related  HCM disease
• Danon disease
• Mitochondrial disease



Which tests do you recommend for further evaluation of those two patients?
 
1. A skeletal muscular biopsy to search for vacuolar myopathy, and if it is present, to analyse the biopsy immunohistochemically with specific LAMP2 antibodies.
2. Direct molecular screening of the LAMP2 gene should be performed to confirm Danon’s disease.

To distinguish sarcomeric HCM from Danon’s disease is important, as the pathophysiology, clinical evolution, prognosis, mode of inheritance, and therefore genetic counselling are very different
As a first step, all patients with  HCM should be considered, whatever the familial context, except when it is a familial form with a male to male transmission (which excludes X linked disease). All of these patients should benefit from careful clinical and biological evaluation, including clinical muscular testing and determination of serum CK concentration, to search for additional features of Danon’s disease. Interestingly skeletal myopathy is mild in most cases (85%) but all male patients had increased serum CK concentration. Wolff-Parkinson-White syndrome was present in 35%, mild mental retardation was observed in 70%, and most patients had HCM and low ejection fraction. Women were less severely affected, with later onset cardiomyopathy.
As a second step, Danon’s disease can be reasonably excluded when HCM is isolated (without associated abnormalities). In contrast, in the presence of unusual clinical associations (especially HCM and clinical skeletal myopathy), the diagnosis of Danon’s disease should be discussed further. Other hereditary cardiac diseases should also be discussed (such as mitochondrial disease, glycogen storage disorders, and PRKAG2 gene related disease) because of overlapping clinical features (especially skeletal muscle disease and pre exitation syndrome).
As a third step, a skeletal muscular biopsy to search for vacuolar myopathy, and if it is present, to analyse the biopsy immunohistochemically with specific LAMP2 antibodies. Finally  direct molecular screening of the LAMP2 gene should be performed to confirm or exclude Danon’s disease.
However, molecular genetic screening is less invasive, possibly more efficient or sensitive (if mutations do not lead to a stop codon and the absence of the protein), and remains the criterion of reference in women (where the protein may be present because of one normal X chromosome).

OUR CASE

Skeletal muscle biopsy of patient B showed autophagic vacuoles and complete absence of LAMP2 protein (fig. 1). Molecular analysis in both patients revealed a mutation, a point deletion, c.716delT in exon 5, of the LAMP2 gene , setting the diagnosis of Danon disease (fig. 2)
Patient B also showed reduced plasma a-galactosidase activity with no features of Fabry’s disease. Mutation analysis of the alpha-galactosidase A gene, revealed a substitution already described, c.937G>T, which is however believed to be a non-disease-causing variant. 
 The causative mutation, c.716delT in exon 5, was reconfirmed in his brother’s DNA (pts A)who died while waiting for heart transplantation and also was found in his mother’s DNA (died suddenly – see pedigree)  which was extracted from the paraffin blocks.



Figure 1.
Lack of LAMP 2 immunostaining in muscle biopsies


Figure 2. LAMP2 mutation (c.716delT)






Patient B also showed reduced plasma a-galactosidase activity with no features of Fabry’s disease. Mutation analysis of the alpha-galactosidase A gene, revealed a substitution already described, c.937G>T, which is however believed to be a non-disease-causing variant. 
 The causative mutation, c.716delT in exon 5, was reconfirmed in his brother’s DNA (pts A) who died while waiting for heart transplantation and also was found in his mother’s DNA (died suddenly – see pedigree)  which was extracted from the paraffin blocks.

Conclusion:

In conclusion, physicians must be aware of Danon’s disease, a disease with variable phenotypic expression, which may mimic HCM but results in a very different clinical evolution, prognosis, mode of inheritance, and subsequently different genetic counselling.

Why the National Committee was reluctant to proceed to the heart transplantation?

Danon Cardiomyopathy is a multi-system disease. Mild peripheral muscle myopathy   and elevated liver enzymes  was the reason that members of the committee were reluctant to proceed to heart transplantation .
In our case the patient 10 years after the heart  transplantation is alive and well.

Notes to editor


Presented by : C. Ritsatos , C. Kotsiopoulou ,  A. Anastasakis, Unit of inherited Cardiovascular Diseases
1st Department of Cardiology, University of Athens, Hippokrateion Hospital

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.