Gaucher Disease Type III - Symptoms, Diagnosis, and Treatment

Introduction

Gaucher disease is an inherited lysosomal storage disorder where fat metabolism gets affected, leading to its accumulation. Gaucher disease is a multisystem disorder, and its effects can be seen in the cells of various organs. Based on the age of onset, clinical presentation, and disease severity, Gaucher disease is classified into three types, Type 1, Type 2, and Type 3. Type 1 exhibits systemic defects involving various body organs, whereas Type 2 and 3 exhibit neural defects in addition to systemic defects, with Type 2 being severe. All three subtypes share the same defect but have different onsets and progression rates. Therefore, they help in determining treatment approaches.

What Is Gaucher’s Type 3 Disease?

Type III is also called juvenile or chronic neuronopathic Gaucher disease. It is a recessive inherited condition. The disease's symptoms include progressive encephalopathy, organomegaly, bone involvement, cytopenia, and others.

What Is the Incidence?

The disease affects all ethnicities but is most common among Asians. Although the age of onset is below 10 years, neurological symptoms develop within the first two years of life.

What Are the Subtypes of Gaucher III?

1. Subtype 3A Gaucher Disease: It is characterized by mild visceral involvement but rapidly progressive neurological manifestations.

2. Subtype 3B Gaucher Disease: It is characterized by severe visceral disease with skeletal manifestation but slowly progressive nervous tissue involvement.

3. Subtype 3C Gaucher Disease: It is a rare variant characterized by cardiovascular involvement with the hardening (calcifying) of heart valves. The other organs involved are the eyes, bones, and mild enlargement of the spleen.

What Is the Cause?

The mutations in the GBA gene cause Gaucher disease. The gene aids in enzyme production called beta- glucocerebrosidase. This enzyme breaks down a fatty substance called glucocerebroside into glucose and fat (sphingolipids). The enzyme functions are disrupted, resulting in toxic levels of glucocerebroside and other substances, thus leading to tissue and organ damage. The functioning of the brain, bones, and other organ systems is hindered.

What Are the Symptoms?

Symptoms vary from person to person and range from mild to life-threatening conditions.

• The symptoms associated with organs and blood are:

  • Anemia: Buildup of lipids in the bone marrow that destroy red blood cells, which carry oxygen throughout the body. Having few red blood cells leads to anemia.

  • Enlarged Organs: The spleen and liver get enlarged due to fat build-up. The disorder causes a tender and enlarged belly. In addition, an enlarged spleen destroys platelets, leading to a low platelet count and bleeding disorders.

  • Bleeding Disorders: Easy bruising and prolonged bleeding after minor injuries or surgery. Blood fails to clot. Fatigue can be seen due to anemia.

  • Lung Involvement: Fats accumulated in the lungs cause breathing difficulties.

  • Bone Involvement: When bones are deprived of blood, there is a lack of nutrients and oxygen, leading to fracture. Arthritis, joint pain, and joint damage may be seen. The damaged bone progresses into osteonecrosis. Reduced calcium fulfillment can also lead to osteoporosis, thus, affecting the skeletal structure.

• Symptoms of Brain and Brain Stem:

  • Cognitive difficulties.

  • Eye problems (when moving eye side to side).

  • Problem with motor skills and coordination.

  • Seizures, muscle spasms, and jerky movements are seen.

  • Behavioral changes.

• Symptoms of Subtype 3A:

  • Neurological manifestations are oculomotor apraxia, cerebellar ataxia, spasticity, and progressive myoclonic epilepsy refractory to treatment.

• Symptoms of Subtype 3B:

  • Hepatosplenomegaly, growth retardation, and bony symptoms. Horizontal supranuclear gaze palsy is a major neurologic sign.

• Symptoms of Subtype 3B:

  • Heart valves and ascending aortic calcifications, fibrosis, supranuclear gaze palsy, mild hepatosplenomegaly, corneal opacities, bone disease, hydrocephalus, and skeletal anomalies.

How Is Gaucher’s Disease Diagnosed?

• The diagnosis occurs several years after the onset of the first symptoms.

• A physical examination is carried out on the abdomen to detect hepatosplenomegaly. In addition, the child’s growth milestones are assessed.

• Medical history is taken.

• Gcase Activity:

  • The diagnosis is confirmed by assessing gcase (glucocerebrosidase) activity in total leukocytes, mononuclear cells, or fibroblasts. The enzyme activity is reduced to less than 10 %.

  • Dried blood can also be used to detect enzyme activity.

  • Flow cytometry is also used to analyze monocytes.

• Bone Marrow Aspirations:

  • It is not essential but can be used in isolated cases of thrombocytopenia and splenomegaly to confirm the diagnosis.

• Lab Tests:

  • Blood samples are assessed to determine the enzyme responsible for the disease. Genetic analysis is done.

  • Liver function test to detect abnormalities.

  • C-reactive protein level to detect bone involvement.

  • Serum calcium and vitamin D level are assessed as the level have to be maintained.

  • Disease biomarkers help in assessing treatment efficacy. The common biomarkers are chitotriosidase, CCL18, and glucosyl sphingosine. They show elevated levels in the presence of disease.

• Imaging Tests:

  • Dual-energy X-ray absorptiometry (DXA) low-level X-ray measures bone density.

  • Magnetic resonance imaging (MRI) is used to detect spleen or liver enlargement and bone marrow involvement.

  • Computed tomography (CT) scan is used to assess organ volumes.

  • Bone densitometry is used to diagnose osteoporosis.

  • Bone scintigraphy is used to locate bone lesions.

• Prenatal screening and testing with genetic counseling may be considered.

What Is the Treatment Methodology?

There is no treatment available to cure the disease. However, medication provided aid in managing symptoms. This treatment is provided throughout life.

• Enzyme Replacement Therapy (ERT)-

  • This technique replaces defective enzymes with artificial enzymes. Enzyme therapy is an outpatient procedure; the enzyme is given through veins.

• Miglustat (Zavesca) - Oral medication interferes with fat production that builds up in tissues.

• Eliglustat (Cerdelga) - Inhibits fat production in people with Gaucher disease.

• Osteoporosis drugs help in bone strengthening. In severe conditions, patients may require orthopedic surgery to treat cancers.

• Bone marrow transplant.

• Splenectomy

• Liver transplant.

• Patients may require spinal surgery if kyphosis develops.

• Psychological support is essential.

• The treatment provided improves the quality of life. If severe symptoms are not present, patients with Gaucher type III live in their 20’s and 30s. Neurological symptoms may manifest after several years after systemic involvement. Even in Gaucher type I, there may be a manifestation of neurological symptoms later.

What Is the Prognosis?

In ERT failure, the treatment does not restrict neural damage and improves brain function. As a result, children with type 3 are often ill and require assistance with basic functions.

The prognosis for subtype 3a and subtype 3c is poor, as the rate of progression is fast, and the functioning of the brain and heart is impaired.

What Are the Complications?

• There is a known link between Parkinson's disease and Gaucher’s disease.

• Delayed puberty.

• Brain damage.

• Increased pancreatic cancer and lymphoma risk.

Conclusion

It is important to diagnose the disease early and seek appropriate treatment. Because the symptoms vary so greatly, it is critical to assess all organ damage and complications that arise. Treatment and management of symptoms are effective when a complete diagnosis is made.