Neurological Manifestations in Fabry Disease - An Overview

Introduction

Fabry disease is a rare genetic disorder caused by the deficiency of an enzyme called alpha-galactosidase A. This enzyme is essential for breaking down a particular type of fat. The lack of this enzyme results in globotriaosylceramide (Gb3) buildup in various organs, including the nervous system. This article explores how this accumulation impacts the nervous system and gives rise to neurological emergencies.

What Is Fabry Disease?

Fabry disease is a rare genetic condition characterized by insufficient production of a critical enzyme known as alpha-galactosidase A (alpha-GAL) in the body. This enzyme is crucial in breaking down sphingolipids, a fat-like substance, preventing their accumulation in the blood vessels and tissues. This disorder falls under the category of lysosomal storage disorders. When alpha-GAL enzymes are not functioning properly, harmful levels of sphingolipids build up in the blood vessels and tissues, impacting various organs like the heart, kidneys, brain, central nervous system, and skin.

Also known as Anderson-Fabry disease, Fabry’s disease, and alpha-galactosidase-A deficiency, this condition reflects the challenges posed by a deficiency in alpha-GAL enzymes, leading to the accumulation of sphingolipids and affecting multiple aspects of health.

How Do Neurological Emergencies Manifest in Fabry Disease?

Fabry disease affects the peripheral nervous systems (nerves outside the brain and spinal cord) and the central nervous systems (brain and spinal cord). It happens because globotriaosylceramide builds up in specific cells, causing nerve issues. This can lead to neurological problems, especially related to blood vessel issues in the brain (cerebral vasculopathy), making strokes more likely. While the abnormal substance buildup does not dramatically change how Fabry disease normally progresses, some people might experience mild cognitive issues. The exact cause of blood vessel problems in Fabry disease is not completely understood, but it appears to be linked to issues in the cells lining the vessels due to a lack of a specific enzyme. This can lead to blood vessel blockages, similar to what happens in conditions like atherosclerosis. Involvement of the peripheral nervous system can lead to changes in how the automatic bodily functions work, like those related to the heart, and can cause nerve pain and other neurological challenges.

What Are the Common Neurological Complications of Fabry Disease?

1. Central Nervous System Presentations:

• Ischemia: This refers to a condition with reduced blood supply to a particular part of the body, in this case, the brain. The inadequate blood flow can lead to oxygen and nutrient deprivation, causing damage to the brain tissue.

• Acute Cerebral Infarction: A sudden obstruction of blood flow to a part of the brain, resulting in the death of brain cells. This can lead to neurological deficits depending on the affected area.

• Posterior Circulation Infarcts: These are infarctions in the back part of the brain, affecting areas such as the cerebellum and brainstem. Symptoms may include dizziness, coordination difficulty, and vision or speech problems.

• Anterior Circulation Infarcts: Infarctions in the front part of the brain potentially cause weakness on one side of the body, speech difficulties, or visual disturbances.

• Lacunar Infarcts: Small strokes specifically occur in the brain's small, deep blood vessels. These can result in localized neurological symptoms.

• Watershed Infarcts: Strokes that occur in brain areas with vulnerable blood supply between two major arteries. This can lead to a specific pattern of neurological deficits.

• Chronic Small Vessel Ischemia: Long-term reduced blood supply to the small blood vessels in the brain. This chronic condition can contribute to ongoing damage and progressive neurological symptoms.

• Cerebral Hemorrhage: Bleeding within the brain tissue. Hemorrhages can induce abrupt and intense neurological symptoms, the nature of which depends on the location and extent of the bleeding.

• Primary Hypertensive Hemorrhages: Hemorrhages in the brain due to high blood pressure. Uncontrolled hypertension can lead to vessel damage and subsequent bleeding.

• Complications of Basilar Dolichoectasia: Basilar dolichoectasia is an abnormal dilation and elongation of the basilar artery, a major blood vessel in the brainstem. Complications may include compression of surrounding structures, leading to neurological symptoms.

• Brainstem Compression: Pressure on the brain stem, a crucial part of the brain involved in various functions, including breathing and heart rate regulation.

• Brainstem Infarction: Tissue damage in the brainstem due to a lack of blood supply. The brainstem controls essential functions such as breathing, heartbeat, and consciousness.

• Rupture and Subarachnoid Hemorrhage: Bursting of blood vessels with bleeding into the space surrounding the brain. Subarachnoid bleeding can cause a sudden, severe headache and other neurological symptoms.

1. Peripheral Nervous System:

• Acroparesthesia: This refers to abnormal sensations, such as tingling or burning, in the extremities, particularly the hands and feet. These sensations can be chronic and debilitating.

1. Autonomic Nervous System:

• Gastrointestinal Autonomic Dysfunction: Involvement of the autonomic (sympathetic) nervous system, leading to dysfunction in the gastrointestinal system. This can manifest as issues with digestion, bowel movements, and other gastrointestinal functions.

What Is the Diagnosis of Fabry Disease?

• Enzyme Assay: A blood test measures the activity of the alpha-GAL enzyme, which is crucial for diagnosing Fabry disease. Results showing one percent or lower activity levels indicate the presence of the disease. It is a reliable test for men and those assigned males at birth (AMAB) but less suited for women and those assigned females at birth (AFAB).

• Genetic Testing: Since men and AFAB individuals with Fabry disease may have normal enzyme levels, genetic testing (DNA sequencing) is employed to identify GLA gene mutations, ensuring a more accurate diagnosis.

• Newborn Screenings: Some states conduct newborn screenings to detect Fabry disease and other lysosomal storage disorders early in life.

What Treatment Options Are Available for Fabry Disease?

As of now, there is currently no cure for Fabry's disease, but medications can help manage symptoms, particularly pain and stomach issues. Two treatments aim to slow down the accumulation of fatty substances, preventing complications like heart problems and kidney disease:

• Enzyme Replacement Therapy: This involves receiving a lab-made enzyme through intravenous (IV) infusion every two weeks. Available replacement enzymes include agalsidase beta and pegunigalsidase alfa. These enzymes substitute for the missing alpha-GAL enzyme, preventing the buildup of fatty substances. Infusions may be done in an infusion center or at home, and precautions like antihistamines may be taken to prevent allergic reactions.

• Oral Chaperone Therapy: Chaperones are small molecules that fix faulty alpha-GAL enzymes. The mended enzymes can then break down fatty substances. With oral chaperone therapy, patients take a pill every other day to stabilize the faulty enzyme. This treatment is based on the specific genetic mutation in the GLA gene, and its effectiveness varies from person to person.

Conclusion

In conclusion, Fabry disease, a rare genetic disorder stemming from alpha-galactosidase A deficiency, accumulates sphingolipids, particularly in the nervous system, leading to various neurological emergencies. The impact on both the central and peripheral nervous systems manifests in complications such as strokes, infarctions, and autonomic dysfunction. Diagnosis involves enzyme assays, genetic testing, and newborn screenings. While there is no cure, symptom management and prevention of complications are achieved through enzyme replacement therapy and oral chaperone therapy.