Danon disease

Description

Denon disease is a condition characterized by weakening of the heart muscle (cardiomyopathy); weakening of the muscles used for movement, called skeletal muscles, (myopathy); and intellectual disability. Males with Danon disease usually develop the condition earlier than females and are more severely affected. Signs and symptoms begin in childhood or adolescence in most affected males and in early adulthood in most affected females. Affected males, on average, live to age 19, while affected females live to an average age of 34.

Cardiomyopathy is the most common symptom of Danon disease and occurs in all males with the condition. Most affected men have hypertrophic cardiomyopathy, which is a thickening of the heart muscle that may make it harder for the heart to pump blood. Other affected males have dilated cardiomyopathy, which is a condition that weakens and enlarges the heart, preventing it from pumping blood efficiently. Some affected men with hypertrophic cardiomyopathy later develop dilated cardiomyopathy. Either type of cardiomyopathy can lead to heart failure and premature death. Most women with Danon disease also develop cardiomyopathy; of the women who have this feature, about half have hypertrophic cardiomyopathy, and the other half have dilated cardiomyopathy.

Affected individuals can have other heart-related signs and symptoms, including a sensation of fluttering or pounding in the chest (palpitations), an abnormal heartbeat (arrhythmia), or chest pain. Many affected individuals have abnormalities of the electrical signals that control the heartbeat (conduction abnormalities). People with Danon disease are often affected by a specific conduction abnormality known as cardiac preexcitation. The type of cardiac preexcitation most often seen in people with Danon disease is called the Wolff-Parkinson-White syndrome pattern.

Skeletal myopathy occurs in most men with Danon disease and about half of affected women. The weakness typically occurs in the muscles of the upper arms, shoulders, neck, and upper thighs. Many males with Danon disease have elevated levels of an enzyme called creatine kinase in their blood, which often indicates muscle disease.

Most men with Danon disease, but only a small percentage of affected women, have intellectual disability. If present, the disability is usually mild.

There can be other signs and symptoms of the condition in addition to the three characteristic features. Several affected individuals have had gastrointestinal disease, breathing problems, or visual abnormalities.

Synonyms

• Antopol disease
• glycogen storage cardiomyopathy
• glycogen storage disease type IIB
• GSD IIB
• lysosomal glycogen storage disease without acid maltase deficiency
• pseudo glycogenosis II
• vacuolar cardiomyopathy and myopathy, X-linked

Signs & Symptoms

Symptoms of Danon disease vary from person to person and depend on gender. Boys usually show early signs of muscle problems (difficulty sitting or walking), and motor skills may be awkward or delayed. Intellectual disability is usually noticed by parents and/or teachers and can be quite mild. The development of heart disease can lead to further fatigue and shortness of breath. Visual complaints are also prevalent with serious color vision disturbances and near-complete loss of retinal pigment in some patients.

In general, young girls may have no symptoms and will report normal muscle strength and have normal intellect. As females age, symptoms of heart disease can begin to develop, and many adult women will experience arrhythmias and may develop progressive heart failure and be considered for cardiac transplantation. Muscle symptoms are reported by some girls and women, but overt findings of frank muscle weakness are usually absent. Visual complaints may also be reported in women and can be an early feature of the disease, although manifestations are less severe than in men.

Clinical researchers believe that the skeletal muscle involvement in Danon disease preferentially involves the muscles of the back, shoulder, upper legs and the neck muscles. These are the proximal muscles; that is, those closest to the center of the body. Symptoms of weakness in these muscles can include back pain and difficulty raising one’s arms over the head, getting out of a chair or walking up steps. In a young boy, these problems may be suggested by problems meeting motor milestones (sitting, crawling, and walking, running). An experienced neurologist can recognize the extent of muscle disease by performing a physical examination. Increasingly it is apparent that for some patients the muscle disease progresses over time and some older males may require assistance devices (walkers, wheelchairs).

The diseased heart muscle (cardiomyopathy) can lead to a thickened, stiff heart (hypertrophic cardiomyopathy) or to an enlarged heart (dilated cardiomyopathy). Hypertrophic cardiomyopathy is more common in males (approximately 90% hypertrophic and 10% dilated), whereas females are more apt to show features of dilated cardiomyopathy (approximately 50% hypertrophic and 50% dilated). Sometimes the cardiomyopathy can be the first sign of disease in male children. In both instances, problems with heart function and symptoms of heart failure (shortness of breath, fatigue, fluid gain) can occur. Death from heart disease seems to more occur frequently in males, especially as they reach the second and third decades of life. Heart transplantation has been performed successfully and can greatly improve symptoms and extend life. Implantable cardiac defibrillators are used to manage heart arrhythmias and should probably be considered when arrhythmia and cardiomyopathy develop.

The extent of intellectual disability in affected males has been described in some epidemiological studies. Most boys will be mildly affected cognitively, usually allowing them to achieve the ability to read, hold jobs, form relationships and live independently. Furthermore, providing education and learning support may help some boys improve their intellectual functioning. In women, intellect appears to be normal, although very little information in the literature addresses this question.

Less prevalent symptoms might also include liver and lung involvement, although these have not been studied extensively and might be secondary to muscle involvement (e.g., serum liver enzyme elevation and respiratory muscle weakness). Some speculation also exists on psychiatric disease, with some case reports detailing depression, psychosis, suicidal ideation and attention-deficit hyperactivity disorder in Danon disease patients. However, it is unclear if psychiatric episodes are related to Danon disease.

Males with Danon disease typically have abnormalities on certain laboratory tests. The creatine kinase (CPK) level in the blood is often elevated and reflects ongoing muscle damage. The CPK is usually elevated in males but is usually normal in females who have Danon disease. Abnormalities in liver enzyme tests are common in males; in some boys, these are mistakenly interpreted as a sign of primary liver disease rather than a reflection of skeletal muscle dysfunction; frank liver dysfunction has not been well-described in Danon disease. The electrocardiogram (ECG), which measures electrical impulses made by the heart, is often abnormal. This abnormality in conduction and electrical impulse is also known as an arrhythmia. Frequently, an arrhythmia called Wolff-Parkinson-White syndrome, or a pre-excitation syndrome will be seen on the ECG. An examination of the retina by an experienced eye doctor (ophthalmologist) will often detect changes in the pigment of the retina. This can be a useful sign in women, as the retinal changes appear to precede other symptoms of the disease in some females.

causes

Danon disease is caused by mutations in the LAMP2 gene, which contains instructions for the production of an enzyme called lysosomal associated membrane protein-2 (LAMP-2). This enzyme is thought to assist with the transportation of cellular material into the lysosomes of the cell, where the materials are normally broken down and recycled. Mutations in the LAMP2 gene impair this process, leading to an abnormal accumulation of material that eventually inhibits function and leads to Danon disease.

Every human cell contains two sex chromosomes. Males have one X chromosome and one Y chromosome in each of their cells. Females have two X chromosomes. Danon disease is a genetic condition located on the X chromosome. A mutated gene on the lone X chromosome in males is sufficient to cause a severe form of Danon disease. Because girls have two X chromosomes and a non-mutated gene on the additional X chromosome may reduce the severity of the disease, Danon disease is often less severe in girls.

Diagnosis

Because Danon disease is rare and unfamiliar to most physicians, diagnosis is difficult and takes substantial time. The diagnosis is suggested based on a family history compatible with X-linked dominant inheritance and symptoms in affected relatives (cardiomyopathy, skeletal myopathy, intellectual disability, Wolff-Parkinson White, etc.). Skeletal muscle biopsy is done in some males to determine the cause of muscle weakness. If, while examining the biopsy materials, glycogen buildup and/or empty spaces appear in the cells of the muscle tissue (vacuolization), Danon disease must be considered. This also holds true for the analysis of a heart biopsy. A muscle biopsy that yields evidence of glycogen build-up and empty spaces in the muscle cells are key signs and indications that a diagnosis of Danon disease is a high probability.

It is important to recognize that, in early stages of Danon disease, and probably also in women, the muscle biopsy can be non-specific. Thus, a normal or non-specific muscle biopsy does not exclude Danon disease. If other features of Danon disease are present, a non-diagnostic muscle biopsy should not discourage more definitive genetic testing. Patients who appear to have Pompe disease (based on muscle biopsy for instance) but have normal acid maltase activity, should be evaluated for Danon disease. Unexplained hypertrophic cardiomyopathy in males is probably due to Danon disease in some people.

Antibodies to the LAMP-2 protein are available and tissue staining (of a muscle biopsy) for the absence of LAMP-2 protein is another potential, but not widely available, diagnostic approach. LAMP-2 antibody testing is likely to be normal in women with Danon disease and if done should be interpreted with caution due to the possibility of a false-negative result.

Genetic testing of the LAMP2 gene is currently the gold standard for diagnosis and is available in specialized genetics laboratories. Most genetic variants causing Danon disease predict reduced levels or even absence of the LAMP2 gene product, the LAMP-2 protein. Although the sensitivity of LAMP2 genetic testing is not known at this time, it is the best that is available. The noninvasive nature of DNA-based testing and the inclusion of LAMP2 gene testing in hypertrophic cardiomyopathy genetic diagnostic panels favor this method as the most common route to diagnosis.

TYPE OF DOCTOR DEPARTMENT:-Cardiovascular