Danon Disease

CLINICAL CHARACTERISTICS

Danon disease is a multisystem condition with predominant involvement of the heart, skeletal muscles, and retina, with overlying cognitive dysfunction. Males are typically more severely affected than females. Males usually present with childhood onset concentric hypertrophic cardiomyopathy that is progressive and often requires heart transplantation. Rarely, hypertrophic cardiomyopathy can evolve to resemble dilated cardiomyopathy. Most affected males also have cardiac conduction abnormalities. Skeletal muscle weakness may lead to delayed acquisition of motor milestones. Learning disability and intellectual disability, most often in the mild range, are common. Additionally, affected males can develop retinopathy with subsequent visual impairment. The clinical features in females are broader and more variable. Females are more likely to have dilated cardiomyopathy, with a smaller proportion requiring heart transplantation compared to affected males. Cardiac conduction abnormalities, skeletal muscle weakness, mild cognitive impairment, and pigmentary retinopathy are variably seen in affected females.

DIAGNOSIS/TESTING: The diagnosis of Danon disease is established in a proband (male or female) with suggestive findings and/or a hemizygous (in males) or a heterozygous (in females) pathogenic variant in identified by molecular genetic testing.

MANAGEMENT

While the age of onset and progression of disease are typically later and slower in females, the management approach in males and females is similar. Standard treatment guidelines for hypertrophic cardiomyopathy and heart failure; consideration of ablation therapy in those with cardiac pre-excitation and arrhythmia; physical therapy for skeletal muscle weakness; standard treatment for developmental delay / intellectual disability; use of low vision aids for those with retinopathy. Electrocardiography at least annually with echocardiography and cardiac MRI at least every one to two years; ambulatory arrhythmia monitoring as needed based on symptoms; annual assessment of strength and for neurologic changes; monitoring of developmental progress, educational needs, and behavior at each visit with formal developmental assessments every three to five years during childhood; ophthalmology evaluation at least every three to five years. Avoidance of dehydration or over-diuresis in those with heart failure; in the presence of significant cardiac hypertrophy with obstruction and/or symptomatic arrhythmia, consideration of instituting the guidelines for physical exertion for individuals with sarcomeric hypertrophic cardiomyopathy. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance. Management should be guided by the degree of overt disease in the pregnant woman and per guidelines for pregnant women with hypertrophic or dilated cardiomyopathy, depending on their condition.

GENETIC COUNSELING

Danon disease is inherited in an X-linked manner. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who have a pathogenic variant in will transmit the pathogenic variant to all of their daughters and none of their sons. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and may have features of Danon disease. Once the causative pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing for Danon disease for a pregnancy at increased risk are possible.