GD2/3 In-Depth

Gaucher Type 1, Type 2 and Type 3 — an important clarification

For the past 20+ years Gaucher Disease has been classified as Type 1, Type 2 and Type 3 (with some sub-groups identified within the Type 2 and Type 3 classifications). Because there is a great deal of overlap in terms of symptoms, severity and onset between Type 2 and Type 3, it has been difficult to clearly delineate between these two classifications of the disease. In other words, some patients simply fall in between Type 2 and Type 3. The following bullet points may help to clarify the current direction of classification within the research community.

• Gaucher Type 1 does not manifest any primary neurological symptoms
• Both Guacher Type 2 and Type 3 manifest neurological symptoms (affects the brain) and both are referred to as neuronopathic Gaucher Disease (NGD).
• Gaucher Type 2 manifests neurological symptoms (the brain is affected) and these patients present more severe neurological symptoms, and at an earlier age.
• Gaucher Type 3 manifests neurological symptoms (the brain is affected) and these patients present with less severe neurological symptoms, and often at a later age.
• Because of the overlap between Type 2 and Type 3, many in the research community are now referring to Gaucher Type 2 as “Acute Neuronopathic Gaucher Disease” (NGD) and to Gaucher Disease Type 3 as “Chronic Neuronopathic Gaucher Disease” (NGD).
• There is a long history of using the Type 2 and Type 3 classification within the Gaucher community, therefore this website will reference a) Neuronopathic Gaucher Disease (NGD) to indicate neurological (brain) involvement b) Will continue to use Type 2 to reference “Acute Neuronopathic Gaucher Disease” c) Will continue to use Type 3 to reference “Chronic Neuronopathic Gaucher Disease”.

Neuronopathic Forms of Gaucher Disease

Although easily stated, the distinction between Type 1, or non-neuronopathic Gaucher Disease, and Types 2 and 3, the neuronopathic variants, may be quite difficult in the clinical setting. This is particularly true in young children diagnosed in the first year or two of life since neuronopathic involvement may not be readily apparent, particularly in early Type 3. Classically, Type 2 Gaucher Disease has the earliest onset, within the first 3 to 6 months of life, and demise usually before 2 years of age. Type 3 is typically described as having somewhat later onset of visceral and central nervous system involvement, and a more protracted course with survival potentially into the 2nd to 4th decade. However, there is substantial overlap between Types 2 and 3, and clinically, these two variants may be difficult to distinguish very early in life, i.e. within the first 6 months. Indeed, this variation highlights the continuum of clinical involvement among the three variants early in life. However, differences between Types 2 and 3 Gaucher Disease occur in the rate of progression of the CNS involvement, and the earlier clinical onset and nature of neuronopathic involvement in Type 2 Gaucher Disease. Such distinctions very early in the Gaucher Disease course are clinically very challenging, but are of great importance in eventual prognosis since they impact the choices of therapy. The following discussion will focus on some potential distinctions between Types 2 and 3 Gaucher Disease, but the variation in the clinical course of each disorder must be clearly recognized.

Gaucher Disease Type 2 (Acute)

The presence of asymptomatic enlargement of the spleen with early neurologic involvement is a hallmark of Type 2 Gaucher Disease. Typically, patients with Type 2 Gaucher Disease fail to thrive in the first three months of life due to difficulties in swallowing. This is caused by neurologic involvement leading to uncoordinated movements of the pharynx. These abnormalities are termed bulbar involvement since they result from early damage to the part of the brain known as the brain stem. The progression of this bulbar involvement leads to increasing difficulties with swallowing and aspiration of food or secretion into the lungs. This can lead to recurrent bouts of pneumonia and/or periods of spasms of the muscles of the throat, known as laryngeal spasms, creating episodes of blueness, slowing of the heart rate, and, potentially, stopping of breathing or apnea. Some patients never experience these crises, but rather show a progressive deterioration of bulbar function. Concordant with these neurologic changes is increasing involvement of the spleen and liver, and an inability to consume sufficient calories in food to support normal growth. These characteristic neurologic and visceral abnormalities progress until demise around the age of 2 years. Death can occur from recurrent pneumonia, infections, and as a result of recurrent lung problems due to aspiration of secretions and food in combination with neurologic deterioration.

This description can be considered a stereotype and many patients with Type 2 Gaucher Disease have significant variation in their rates of progression and/or their degrees of visceral and central nervous system disease. What appears to be constant is the early involvement leading to bulbar abnormalities, and the progression of these signs and symptoms, together with involvement of the liver and spleen. Patients with Type 2 Gaucher Disease do not survive long enough to develop clinical bony involvement. As far as we know, the disease process of Type 2 Gaucher Disease does not cause pain to the affected child, except that accompanying pneumonia, fever or difficulty swallowing. Recently, an earlier onset variant of Type 2 Gaucher Disease with enlargement of the liver and spleen, and skin abnormalities (a collodion baby), and central nervous system involvement has been described as appearing at or shortly after birth. These children are very severely involved with rapidly progressing visceral and central nervous system disease. Only a few dozen of such patients are known worldwide, and are the most severe variant of Gaucher Disease.

Gaucher Disease Type 3 (Chronic)

Gaucher Disease Type 3 has been divided into two variants, termed Types 3b and 3a but this division is no longer considered useful since a lot of overlap exists. Type 3b has earlier onset of massive livers and spleens. They can also experience direct involvement of the lungs and rapidly progressive bony disease. The central nervous system involvement can include abnormal eye movement and slowing of development. These children are usually quite ill and require substantial nutritional support for growth. The neurologic involvement appears to be slowly progressive or static, and can remain as isolated eye movement abnormalities until quite late in life. The life expectancy without therapeutic intervention is substantially diminished, and is dictated by the degree of involvement of the liver, spleen, and lungs.

These children usually do not experience the progressivity of bulbar involvement, laryngeal spasm, nor the feeding difficulties of Type 2 patients, but may have more progressive involvement of the lungs. In contrast, Gaucher Disease Type 3b has onset in the late teens to early twenties with a more rapidly progressive deterioration of central nervous system function and relatively lesser involvement of the visceral organs. Importantly, combined variants with features of both Types 3a and 3b are known, and careful clinical follow-up of such patients must be a part of standard care. The variation in Type 3 is greater than that in Type 2 and equal in scope to that observed in Type 1 Gaucher Disease.

Patients Homozygotes For The D409h Mutation (also referred to as Type 3c)

In the past few years, a new variant of Gaucher Disease has been described to involve the central nervous system. This variant has a unique phenotype that involves the eyes with cataracts, the central nervous system with hydrocephalus, and the heart with cardiac valvular calcification. The liver and splenic disease can be relatively mild, but the cardiac manifestations are quite severe. This variant was originally described in Japan, but has now been described in the Arabs, Spain, and in the United States. This variant appears rare, but with its description increased recognition of Gaucher Disease is sure to occur. These patients can develop enough cardiac disease to require surgery for valve replacement or even hydrocephalus (enlargement of the water cavities in the brain).

Genotype/Phenotype Correlations in Neuronopathic Variants

A development of a relationship between the Type of mutation that causes Gaucher Disease and the degree of clinical severity and/or neurologic involvement is very important for developing a therapeutic plan. However, such genotype/phenotype correlations are becoming increasingly difficult to firmly establish due to the greater variation among patients and to the impact that some therapeutic interventions may have on Gaucher Disease course. The L444P/L444P genotype is the most common in NGD and is thought to be predictive of neurologic involvement. However, a few patients with this genotype may have completely normal neurologic development, including the absence of eye movement abnormalities, but, without therapy develop very severe visceral disease. Thus, it appears that this genotype is consistent with a severe systemic Gaucher Disease course, while neurologic involvement may be minimal to severe. Follow-up and careful clinical documentation of young children with Gaucher Disease is critical to provision of accurate information to affected families and to potential prognosis. Currently, no substitutes are available for high quality clinical care by knowledgeable physicians who can provide the family with prognostic guidance. Also, affected siblings are usually never identically involved, and sometimes can have substantial differences in the degree of involvement by Gaucher Disease. However, if one child in a family has a specific Type of Gaucher Disease, the next child will also have a similar clinical phenotype. Consequently, the medical caregivers need to provide prognoses based upon the clinical course in their individual patients so that informed decisions about the clinical course can be made in those affected families.

Therapy of Neuronopathic Gaucher Disease

Treatment of Gaucher Disease Type 3 involvement of the liver and spleen has been very effective with enzyme therapy. Bone marrow (also called hematopoietic stem cell) transplantation has been used in a few patients. These two modalities of therapy effectively diminish the size of the liver and spleen, and normalize the hematologic abnormalities. However, they have no benefit to the central nervous system disease. In few, well-documented cases of intravenous enzyme therapy in Type 2 Gaucher Disease, no substantial impact was made on the reversal of central nervous system involvement and it is no longer recommended for this form of Gaucher Disease. Thus, the care of patients with Type 2 Gaucher Disease at this time is primarily supportive. A few patients with NGD (mostly Type 3) have been treated with bone marrow transplantation. If this intervention results in complete engraftment, the systemic Gaucher Disease is cured but there is no evidence for a therapeutic effect on the neurological aspects of the disease. Because of this and because of the risks of the procedure, bone marrow transplantation is not generally recommended for NGD.

Similar to Gaucher Disease Type 2, the visceral involvement in Type 3 Gaucher Disease is effectively treated by enzyme therapy or bone marrow transplantation. Because of the severe involvement of the visceral organs and the rapid progression, enzyme therapy provides the most available modality of therapy for these visceral manifestations. Indeed, children with early onset rapidly progressing Type 3 Gaucher Disease should be treated early and with significant doses of enzyme to reverse the visceral involvement of their disease process. If instituted early, the bony progression may be prevented, and thus, a high quality of life can be achieved. As stated above, intravenous enzyme infusions do not seem to have an effect on the primary neurological manifestations of NGD. The slowness of central nervous system progression in some patients, and the difficulty in documenting the primary involvement of the brain in these patients make such studies quite difficult. For example, many of these patients have severe visceral involvement and are chronically ill and, therefore, tend to be developmentally slower. This could reflect their chronic disease or their central nervous system involvement. Upon therapy, with of the visceral symptoms, patients feel better, do better, learn faster, and appear to have improved central nervous system function. Enzyme therapy should be considered as life-saving interventions that can lead to higher quality of life for such affected individual with chronic NGD (Type 3).