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Clinical Analysis of Children’s Gaucher Disease
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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
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 incoordinate 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 colloidin 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 world-wide, and are the most severe variant of Gaucher disease.
GAUCHER DISEASE TYPE 3
Gaucher disease Type 3 has been divided into two variants, termed Types 3b and 3a. 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 likely to be substantially diminished, and is dictated by the degree of involvement of the liver and spleen, and lungs.
These children usually do not experience the progressivity of bulbar involvement, the laryngeal spasm, nor the feeding difficulties of Type 2 patients, but may have more progressive involvement of the lungs.In contrast, Gaucher disease Type 3a 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.
GAUCHER DISEASE TYPE 4 (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. Moreover, because of its rarity the spectrum of its clinical punctuation has not yet been fully described. These patients can develop enough cardiac disease to require surgery for valve replacement.
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 was thought to be predictive of neurologic involvement by Gaucher disease although it could not distinguish between Types 2 and 3. However, a number of patients with this genotype may have completely normal neurologic development, including the absence of eye movement abnormalities, but, without therapy develop very severe visceral and lung disease. Thus, it appears that this genotype is consistent with a severe Gaucher disease course, but is not entirely predictive of central nervous system involvement. 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 Types 2 and 3 involvement of the liver and spleen has been effective with either enzyme therapy or bone marrow transplantation. These two modalities of therapy effectively diminish the size of the liver and spleen, and normalize the hematologic abnormalities. However, the same cannot be said with assurity about 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. With bone marrow transplantation in Type 2 Gaucher disease, it is expected that this will not provide a highly effective therapy for the central nervous system involvement and these children will have substantial non-reversible central nervous system disease at the time of the transplant. Thus, the care of patients with Type 2 Gaucher disease at this time is primarily supportive.
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 also may be prevented, and thus, a high quality of life can be achieved. The effect of enzyme therapy on the central nervous system involvement is equivocal. 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. While this may be the case, long-term studies will be required to see if substantial changes can be achieved in the eventual progression of the central nervous system involvement. Such studies are currently underway, but will require many years for resolution. In the interim, enzyme therapy and/or bone marrow transplantation should be considered as life-saving interventions that can lead to higher quality of life for such affected individual and families.
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