Introduction

Cells are the single, fundamental and biological units of all living organisms, and are the building blocks of life responsible for different processes. The stomach, kidney, heart, and lungs are all well-known organs in the human body, and everything in the body is made up of tissues, which are then made up of cells. Sometimes, things go wrong in cells, and can affect the human body so much that it results in a disease or a deficiency. This is what happens in Gaucher disease and this article will explore the risk of neurological involvement in type 2 and type 3 Gaucher disease.

Overview of Gaucher disease

Definition and genetic basis

Gaucher disease is a rare lysosomal storage disease characterised by the inability to break down fats, which causes it to build up in the body in areas including the spleen, bone marrow and the liver.¹ Put simply, cells also have smaller parts within them to carry out the cell’s job, called organelles. A particular organelle, the lysosome, contains enzymes to break down large molecules such as carbohydrates and fats. However, certain people can inherit recessive genes from both their parents, causing a deficiency in an important enzyme found in lysosomes, called ‘glucocerebrosidase’. This means the lysosome will not be able to function effectively or even at all.¹

Classification

There are three types of Gaucher disease, varying in the presence and severity of neurological involvement:

• Type 1 (Non-neuropathic): The most common form, predominantly affecting adults, with symptoms including hepatosplenomegaly, bone disease, anaemia, and thrombocytopenia. Neurological involvement is absent in this type
• Type 2 (Acute Infantile Neuronopathic): The most severe form, usually presenting in infants and begins to show from 0 - 6 months of life. It is an extreme case where the life expectancy of the infant is significantly reduced (less than two years old). It mainly involves severe damage to the brain along with an enlarged spleen and liver, with no present cure for it
• Type 3 (Chronic Neuronopathic): Commonly arises in growing children as they go through puberty. Despite symptoms, life expectancy reaches adulthood but leaves the individual vulnerable to a worsening condition¹

Importance of understanding neurological complications

The neurological complications associated with Type 2 and Type 3 are profound, and are named neuronopathic forms. Understanding these complications is crucial for developing effective treatments and improving patient outcomes. Current research focuses on elucidating the mechanisms behind neuronal damage and exploring potential therapeutic avenues.

Pathophysiology of neurological complications in Gaucher disease

Genetic mutations and enzyme deficiencies

Genetic mutations can be thought of as mistakes in DNA which can cause problems with health. Humans have DNA which are essentially instructions or the blueprint for the body to make certain proteins which affect processes in the body including what we look like. However, genetic mutations can occur in important features of the body such as our ability to break down fats.

The main recessive mutation responsible for Gaucher disease is found in the GBA1 gene.² It contains instructions for making an enzyme (a protein) called glucocerebrosidase, which is responsible for breaking down large molecules into glucose and ceramide. When there are at least 300 mutations in the GBA1 gene, it can lead to a lack of the enzyme which causes a build-up of glucose and ceramide, leading to the development of the symptoms seen on the surface.²

Accumulation of glucosylsphingosine in the brain

Along with the dangerous build-up of glucose and ceramide, there is another build-up of a product that causes devastating effects on neurological health. Glucosylsphingosine, a byproduct of impaired glucocerebroside breakdown, accumulates in the brain, which can start even from conception and then further accumulate as the individual grows. It can cause the death of brain cells as research shows that it changes the shape of brain cells and can cause a decrease in new brain cells forming.² However, it is still unknown how more glucosylsphingosine contributes to Type 2 Gaucher disease.

Impact on central nervous system functioning

The brain acquires damage from Type 2 Gaucher disease, causing brainstem degeneration. However, the exact process of how the central nervous system is affected by Type 2 Gaucher disease is still unknown.² It is worth considering that a build-up of glucose and ceramide can cause cell death and degeneration, and can be seen in the death of brain cells in certain areas.² Unfortunately, the connections between brain cells are also impacted, an essential feature of the nervous system in healthy individuals.²

Neurological manifestations in Type 2 and Type 3 Gaucher disease

Type 2 Gaucher disease

Neurological symptoms in Type 2 Gaucher disease manifest early, often within the first six months of life. These symptoms include:⁴

• Bulbar signs: Damage in the brainstem can affect the control of muscles responsible for everyday actions such as speaking and chewing. Symptoms include speech that sounds unclear and continuous, difficulty chewing and drooling
• Pyramidal signs: Damage in the brain can affect the control of muscles responsible for voluntary movements. Symptoms include weak muscles, stiff legs and unusually large reflexes
• Cognitive impairment: Damage in the brain can affect an individual’s mental processes. Symptoms include difficulty in memorisation, concentration and problem-solving

Type 3 Gaucher disease

The onset of neurological symptoms usually occurs from childhood into adolescence:⁴

• Oculomotor apraxia: Individuals will experience trouble with their vision, including difficulty moving eyes in a controlled manner, eye jerks and difficulty reading
• Seizures: A symptom that arises due to inappropriate levels or firing of electrical signals in the brain. They may experience body jerks, dizziness and in extreme cases, a loss of consciousness
• Progressive myoclonic epilepsy: This type of epilepsy gets worse as the condition progresses, mostly affecting the muscles when episodes occur. Symptoms include muscle jerks, seizures and a decline in mental/cognitive function and processes

Diagnosis of neurological involvement

Clinical evaluation and patient history

A thorough clinical evaluation, including a detailed patient history can be acquired by investigating if the patient has parents who have a recessive mutation. This means both parents must have the recessive mutation for the person to have Gaucher disease, which can be examined using molecular genetic testing.⁴ 

Laboratory tests and Imaging

Diagnosis is supported by measuring the levels of glucosylceramidase or investigating any possible mutations within the GBA1 gene of an individual.⁴

Treatment and management of neurological complications

There are several treatments available for those who suffer with Type 2 and Type 3 Gaucher disease:⁴

• Enzyme replacement therapy: Administered intravenously, ERT helps break down fats in the body
• Substrate reduction therapy: Oral medications help reduce the build-up of fats
• Seizure management: Regular health check-ups and ensuring a healthy lifestyle can aid in reducing seizures
• Gene therapy: It is possible to try and correct a person’s gene mutations that contribute to Type 2 and Type 3 Gaucher disease

Summary

Type 2 and Type 3 Gaucher disease are severe, life-limiting conditions that profoundly affect the nervous system. The mutations cause a build-up of fats and manifest as severe symptoms including brain damage. Neurological damage has a great impact on the quality of life and life expectancy of sufferers, as epilepsy and seizures are common. Further research must be conducted to understand the mechanisms of how brain damage occurs. There is potential for gene therapy and gene counselling to have a role in further understanding the disease as it will tackle the root cause.