Gaucher Symptoms & Diagnosis

Diagnosing Gaucher Disease

Gaucher Disease has been described in individuals of various ethnic backgrounds. The diagnosis should be suspected in patients of all ages who present with the following signs and symptoms, in the absence of an alternative explanation: enlarged liver and spleen (hepatosplenomegaly), low blood counts (anemia and thrombocytopenia), and bone problems (osteonecrosis, fracture, pain). Gaucher Disease can also be associated with heart and lung problems (interstitial lung disease, pulmonary hypertension). Rarely, Gaucher Disease can present in the newborn with skin changes, in addition to hepatosplenomegaly and eventual neurologic complications. Findings noted in this lethal form of Gaucher Disease have included non-immune hydrops fetalis, collodion or ichthyosiform skin abnormalities.

The majority of patients with Gaucher Disease, including a vast majority of affected individuals of Ashkenazi Jewish ancestry, do not have primary neurologic problems (Type 1). Secondary complications can arise because of bone or clotting abnormalities that lead to compression of the spinal cord or nerve. Certain forms of Gaucher Disease may be associated with primary central nervous system involvement; there should be heightened index of suspicion in patients presenting with the features outlined in the “Neuronopathic Gaucher Disease” section below.

Gaucher Disease can be diagnosed by a blood test that is available through specialized laboratories, in the appropriate setting or clinical context this test may obviate the need for invasive studies such as a bone marrow or liver biopsy as components of the initial diagnostic workup.

Neuronopathic Gaucher Disease
(“Acute” – Type 2 and “Chronic” – Type 3)

Neuronopathic Gaucher Disease (NGD) can be defined as the presence of neurological involvement in a patient with biochemically proven Gaucher Disease, for which there is no explanation other than Gaucher Disease. Gaucher Disease may or may not be associated with primary central nervous system involvement. With the availability of enzyme replacement therapy, there is a need to establish its effectiveness in the treatment of patients with Gaucher Disease and neurologic complications. The variability in clinical presentation of patients with Gaucher Disease and neurologic involvement necessitates a change in the ways that patients have been classified previously, i.e. acute severe (Type 2) and subacute or chronic form (Type 3). It is hoped that a uniform classification will facilitate exchange of clinical information among the various treating physicians involved in the care of these patients. (See further explanation of this topic in GD2/3 In-Depth.)

Proposed minimum criteria for the diagnosis of Gaucher Disease:

1. Confirmed acid beta-glucosidase (glucocerbrosidase) deficiency
2. The presence of the N370S mutation excludes Types 2 or 3, however the absence of the N370S mutation does not imply Type 2 or 3.

High-risk group:

1. Supranuclear gaze palsy with slow saccades with or without the following: a. cognitive problems, b. gait disturbances, c. myoclonic seizures.
2. Positive family history; previously affected sibling diagnosed with NGD.

In the European Consensus Paper (ECP), additional factors:

1. High risk genotypes: L444P/L444P, D409H/D409H, and L444P/D409H.

Acute versus chronic forms: The following findings would be consistent with an acute course:

1. Onset before age one year
2. Progressive brainstem signs (feeding problems, laryngeal spasms, apneic episodes) within the first two to four months of age
3. Minimal gains in developmental milestones or signs of regression
4. Rapidly progressive course of CNS findings

NGD is a continuum between the acute (Type 2) and the chronic (Type 3) form of neuronopathic Gaucher Disease. An intermediate form of NGD has been described. This is characterized by a relatively late age of onset but eventually rapidly progressive neurological disease. In the early stages these patients may be erroneously labeled as having Type 3 or chronic NGD.

It is recognized that a severe form of Gaucher Disease associated with non-immune hydrops fetalis with or without overt collodion or ichthyosiform skin abnormalities exists. It is felt that this congenital (conatal) lethal form should be considered in a class of its own. Similarly, patients homozygous for the D409H mutation have a unique phenotype, including oculomotor apraxia, bilateral corneal opacification, and splenomegaly. There also is progressive thickening and calcification of the mitral and aortic valves associated with clinically significant regurgitation, which is not typically found in the other Gaucher Disease subtypes.