CAUSES OF HYPERTROPHIC CARDIOMYOPATHY

Fabry Disease:Cardiology

This document is designed to provide information on the potential causes of unexplained hypertrophic cardiomyopathy (HCM) that are independent of hypertension.

• Amyloidosis

• Neuromuscular diseases

• Glycogen storage diseases

• Lysosomal storage diseases

• Malformation syndromes

• Mitochondrial diseases

• Newborn of a diabetic mother

• Chronic use of some drugs

Figure adapted from: ELLIOTT, PM. et al. Eur Heart J 2014; 35(39): 2733–79.

Sarcomeric protein gene mutation ~40-60%

Unknown ~25-30%

Other genetic and non-genetic causes ~5-10%

Patients≥30 years

of age*†

with LVHwall thickness

≥13mm*

Test for Fabry

disease

*ELLIOTT, PM. et al. Eur Heart J 2014; 35(39): 2733–79.†BECK, M. et al. In: Mehta, A. et al (eds). Fabry disease: perspectives from 5 years of FOS. Oxford: Oxford PharmaGenesis; 2006.

Shire International GmbH, Zählerweg 10, 6300 Zug, Switzerland Prepared and funded by Shire | INTSP/C-ANPROM/FAB/16/0006mDate of Preparation: June 2016

References1. ELLIOTT, PM. et al. Eur Heart J 2016; 37: 164–173. 2. BANYPERSAD, SM. et al. J Am Heart Assoc 2012; 1(2): e000364. 3. MAYO CLINIC. Diseases and conditions: Amyloidosis. Accessed 17/02/2016. 4. JENSEN, MK. and BUNDGAARD, H. Circulation 2012; 125(13): 1591–3. 5. FRIEDRICH, FW. et al. Hum Mol Genet 2012; 21(14): 3237–54. 6. HARTMANNOVA, H. et al. Circ Cardiovasc Genet 2013; 6(6): 543–51. 7. ELLIOTT, PM. et al. Eur Heart J 2014; 35(39): 2733–79. 8. HIRSHHORN, R. In: Scriver C, et al. 2001; 3389–420. 9. BOUCEK, D. et al. Genet Med 2011; 13(6): 563–8. 10. BARBEY, F. et al. Curr Med Chem Cardiovasc Hematol Agents 2004; 2(4): 277–86. 11. SPADA, M. et al. Am J Hum Genet 2006; 79(1): 31–40. 12. LANEY, DA and FERNHOFF, PM. J Genet Couns 2008; 17(1): 79–83. 13. LINHART, A. et al. Eur Heart J 2007; 28(10): 1228–35. 14. VAN DER BURGT, I. Orphanet J Rare Dis 2007; 2: 4. 15. SARKOZY, A. et al. Orphanet J Rare Dis 2008; 3: 13. 16. ABE, Y. et al. Am J Med Genet A 2012; 158A(5): 1083–94. 17. LIANG, C. et al. Biochim Biophys Acta 2014; 1840(4): 1360–7. 18. REMES, AM. et al. J Neurol Neurosurg Psychiatry 2003; 74(8): 1158–9.

Condition DescriptionAmyloidosis A multisystem disease, accounting for approximately 2% of HCM cases1 caused by extracellular and/or intracellular

deposition of insoluble abnormal amyloid fibrils.2 The specific cause depends on the type of amyloidosis; the most common type, amyloid light-chain (AL) amyloidosis occurs when the bone marrow produces abnormal antibodies, which are deposited as amyloid.3 The incidence is uncertain, but AL amyloidosis has an estimated prevalence of 6–10 in 1,000,000 individuals in the UK and US.2 The most common form of hereditary amyloidosis is variant transthyretin amyloidosis (ATTR), caused by mutations in the transthyretin gene.2 Although the prevalence of ATTR amyloidosis is unknown, it is almost certainly underdiagnosed.2 ATTR can also occur due to wild-type TTR deposits, known as wild-type ATTR, the prevalence of which remains to be ascertained.2

Neuromuscular diseases

Friedreich’s ataxia (FA) An autosomal recessive inherited neuromuscular disease that causes progressive damage to the nervous system.4 A substantial proportion of patients with FA also develop a cardiomyopathy that usually presents as left ventricular hypertrophy (LVH).4 FA is a rare disease, affecting between 0.1–4.7 in 100,000 individuals in the US.4

Four and a half LIM domains protein 1 (FHL1) mutations

Three novel variants in the FHL1 gene have been identified in HCM patients; one which is associated with muscle weakness (c.459C>A) and three which are associated with isolated HCM (c.134delA, c.827G>C, and C.647_648 ins.T).5,6 The exact prevalence of FHL1 gene mutations are unknown although, with the exception of FA, HCM is a rare manifestation of neuromuscular disease.7

Glycogen storage disorders

Pompe disease An autosomal recessively inherited metabolic disorder, which affects the acid alpha-glucosidase gene that codes for the enzyme acid alpha-glucosidase.8 Infantile Pompe disease is characterized by prominent involvement of cardiac, smooth, and skeletal muscle leading to severe hypotonia and cardio-respiratory failure.8 The incidence of Pompe disease may vary in different ethnic groups. The highest frequency of infantile-onset disease may be among African-American (1 in 14,000) and Chinese (1 in 40,000–50,000) individuals.8

Danon disease A rare X-linked dominant metabolic disorder, caused by a primary deficiency in lysosome-associated membrane protein-2 (LAMP-2).9 The pathophysiology is not well understood but all men and many women will develop hypertrophic cardiomyopathy, Wolff-Parkinson-White syndrome, skeletal myopathy and mental retardation.9 The exact prevalence is unknown, although LAMP-2 mutations were noted in 1% of cases of HCM.9

Lysosomal storage disorders

Fabry disease An X-linked disorder, caused by mutations of the alpha-galactosidase A gene.10 Fabry disease is a rare disease, affecting approximately 1 in 20,000–40,000 individuals.11,12 Cardiac involvement is common in Fabry disease and LVH is the most frequent sign of cardiac involvement in untreated patients, affecting 33% of women and 53% of men.13

Malformation syndromes

Noonan syndrome (NS) NS is a genetic mutation disorder (which can affect a number of different genes), characterized by short stature, typical face dysmorphology and congenital heart defects.14 NS may be sporadic or inherited in an autosomal dominant pattern.14 The incidence of NS is estimated to be between 1 in 1,000 and 1 in 2,500 live births.14

LEOPARD syndrome (LS) LS is a multiple congenital condition, normally caused by mutations in the protein tyrosine phosphatase, non-receptor type 11 gene.15 It is mainly characterized by skin facial, and cardiac anomalies. LS may be sporadic or inherited in an autosomal dominant pattern.15 The exact prevalence is unknown, although approximately 200 patients have been reported worldwide.15

Costello syndrome A congenital anomaly syndrome caused by germline mutations in HRAS proto-oncogene (small G-protein in the Ras subfamily).16 Costello syndrome is characterized by a distinctive facial appearance, heart defects, and intellectual disability.16 Costello syndrome is a rare condition, with an estimated prevalence of 1 in 1,290,000 individuals in Japan.16

Cardiofaciocutaneous (CFC) syndrome

A congenital anomaly syndrome caused by mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2).16 CFC is characterized by a distinctive facial appearance, heart defects, and intellectual disability.16 CFC is a rare condition with an estimated prevalence of 1 in 810,000 individuals in Japan.16

Mitochondrial diseases

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)

MELAS is a progressive neurodegenerative disorder, most commonly caused by a tRNA point mutation, the m.3243A>G mutation.17 The estimated minimum population prevalence of mitochondrial disease is 9.2–16.5 in 100,000 individuals.17 The minimal m.3243A>G mutational prevalence is estimated to be over 16 in 100,000 individuals in Finland.13

Myoclonic epilepsy with ragged-red fibers (MERRF)

MERRF is a progressive neurodegenerative disorder, associated with a tRNA point mutations, usually m.8344A>G.17 The estimated minimum population prevalence of mitochondrial disease is 9.2–16.5 in 100,000 individuals.17 The 8344A>G mutational prevalence is estimated to be 0–1.5 in 100,000 individuals in Finland.18

Newborn of diabetic mother Transient ventricular hypertrophy is seen in infants of mothers with diabetes, even after good diabetic control during pregnancy.7

Chronic use of some drugs Chronic use of some drugs, including anabolic steroids, immunosuppressant drugs (tacrolimus and hydroxychloroquine), can cause LVH although they rarely result in a left ventricular wall thickness ≥15 mm.7