Fabry disease

X-linked lysosomal storage disorder caused by mutations in α-galactosidase A gene with a prevalence of 1 per 117,000 live births.

Fabry disease; A lysosomal storage disease causing anhidrosis, fatigue, angiokeratomas, burning extremity pain and ocular involvement.

Second most common metabolic storage disease after Gaucher disease.

And X linked recessive defect in the GLA gene leading to the deficiency of Alpha-galactosidase A with subsequent accumulation of globotriaosylceramide (Gb3).

The accumulation of globotriaosylceramide (Gb3) occurs in a variety of cell types, which starts in utero in the most severe cases.

Accumulation of globotriaosylceramide (Gb3) leads to end organ damage most commonly in the heart with left ventricular wall thickening, arrhythmias, and fibrosis, the kidneys with glomerulosclerosis and proteinuria, and the central and peripheral nervous system with white matter changes, strokes, and  neuropathies.

Patients cannot metabolize globotriaosylceramide (Gb3) normally resulting in progressive lysosomal accumulation of Gb3 in vascular endothelium and smooth muscle cells.

Tissue deposits can occur in the brain, myocardium, dorsal root ganglia and the autonomic nervous system.

Enzyme deficiency leads to intracellular accumulation glycosphingolipids.

Cardiac manifestations include ventricular hypertrophy, progressive heart failure, and may mimic hypertrophic cardiomyopathy.

Manifests with dermatologic, neurologic, renal and cardiovascular manifestations.

Associated with infertility in affected males, with suspected accumulations of GB3 in Leydig cells and seminiferous tubules of the testes.

The accumulation of globotriaosylceramide (Gb3), if not treated can lead to premature death.

In  classic cases, symptoms begin in childhood and complications arise in adulthood.

Diagnostic delay in males is 14 years.

Hypohidrosis is a common clinical manifestation as is systemic hypertension, which is often do to coexistent renal failure.

The accumulation of globotriaoglyceramide in cardiomyocytes,  and endothelial cells,  and smooth muscle cells leads to myocardial  ischemia, valve abomalities, and myocardial wall thickening.

Patients may develop diastolic dysfunction and heart failure.

Arrhythmias and conduction system abnormalities commonly occur.

Echocardiographic findings suggest assessment of alpha galactosidase activity and genetic testing.

Echocardiography imaging is used for monitoring disease progression and treatment response.

Echocardiographic findings include bilateral ventricle wall thickening, bilateral biatrial enlargement, valvular thickening with regurgitation is common, dilatation of the aortic sinus and ascending aorta  have been have been described.

No echocardiogram findings, alone or in combination accommodation can confirm or rule out the diagnosis.

Strain imaging can assess the patterns of segmental longitudinal strain impairment involving the basal inferolateral wall.

Cardiac MRI imaging is an important tool for the assessment of cardiac involvement in patients with Fabry’s disease as well as for the evaluation of undifferentiated ventricular wall thickening.

Management include symptom-based interventions for heart and kidney disease and supportive care.

The management of Fabry disease typically involves a multidisciplinary approach with the coordination of several healthcare professionals, including geneticists, nephrologists, cardiologists, and neurologists. Here are the steps of the management of Fabry disease:

1. Enzyme replacement therapy (ERT): The primary treatment for Fabry disease is ERT, where the missing enzyme, alpha-galactosidase A, is replaced with a synthetic version. The FDA-approved ERTs for Fabry disease include agalsidase alpha and agalsidase beta, which are administered intravenously.

2. Pain relief: Patients with Fabry disease commonly experience episodes of pain, including acroparesthesias (burning, tingling, or shooting pain) in the hands and feet. Nerve pain medications such as gabapentin and pregabalin can help relieve symptoms.

3. Blood pressure control: Fabry disease can lead to hypertension, which increases the risk of cardiovascular complications such as stroke and heart attack. Blood pressure control is critical in Fabry disease management and can be achieved using medications such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

4. Kidney transplant: Patients with advanced Fabry disease and end-stage renal disease may benefit from a kidney transplant.

5. Genetic counseling: Genetic counseling is essential for families affected by Fabry disease to understand the inheritance pattern, assess the risk of the disease transmission to their children, and consider prenatal diagnosis options.

In summary, the management of Fabry disease requires a team approach, including ERT, pain relief, blood pressure control, kidney transplant, and genetic counseling.

Treatment options include enzyme replacement therapy.

Elfabrio delivers a functional version of GLA. 

It’s given by intravenous infusion every 2 weeks.

Evidence for safety, tolerability, and efficacy of Elfabrio stem from a comprehensive clinical program in more than 140 patients with up to 7.5 years of follow up treatment.

Elfabrio was non-inferior in safety and efficacy to agalsidase beta Fabrazyme.


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