Type 1 (GD1)
GD1, also known as “adult type” or chronic, non-neuronopathic form, usually presents with splenomegaly (from minimal enlarge ment detected incidentally to massive enlargement extending across the midline to the right lower quadrant) and bleeding tendencies, mainly mucosal bleeding (i.e., epistaxis, ecchymosis, menorrhagia) or bleeding after surgery, dental procedures, or postpartum. Massive hepatomegaly may occur in splenectomized patients; but predominant hepatomegaly suggests a primary hepatic comorbidity. Hypersplenism manifests as thrombocytopenia followed by anemia and then leukopenia. An elevated platelet count is seen in splenectomized patients. The younger the age, the more severe the clinical course, and in young children, there is often linear growth retardation. The bleeding tendency is exacerbated by platelet dysfunction, a coagulopathy (probably due to low level activation of the coagulation pathway); and in Ashkenazi Jewish patients, an association with partial deficiency of Factor XI is common.
Bone involvement is common and may be asymptomatic or extensive and debilitating; the skeletal complications tend to develop later in the course of the disease, and they are far more severe in splenectomized patients or among untreated patients with severe mutations, who do not have access to GD-specific therapies. Bone crisis is an acute onset of excruciating pain, usually above or below the knee, commonly accompanied by swelling and redness, with or without systemic signs of inflammation including fever, leukocytosis and elevated erythrocyte sedimentation rate (ESR) or c-reactive protein (CRP). These bone crises are commonly mistaken for acute osteomyelitis, particularly before GD has been diagnosed, and many patients undergo surgical drainage to exclude infection, which, not infrequently, leads to bacterial contamination. Bone crises were traditionally related to reduction in blood flow (“aseptic infarction”), and hence to lack or reduced tracer uptake in bone scintigraphy, when performed within a few hours from the onset of pain, unlike the expected increased uptake during infection). However, magnetic resonance imaging (MRI) studies done during the acute events reveal that at least in some cases there is evidence of subperiosteal bleeding. Bone crises by themselves are predictors for osteonecrosis (avascular necrosis; AVN) in the future; AVN usually develops in the hip joints (unilateral or bilateral; Fig. 1) but also in other large joints including the knees and shoulders. Pathological fractures may occur in the ribs and vertebrae due to osteoporosis. Devastating bone complications have become much rarer since the introduction of ERT, in part due to the fact that splenectomy is no longer indicated.
Fig1. BILATERAL OSTEONECROSIS OF THE HIP JOINT. Bilateral osteonecrosis (AVN) in a 48-year-old woman with Gaucher disease (GD)1; the AVN occurred sequentially within 3 years after splenectomy, two decades earlier, in the pre-ERT era.
Lung involvement usually arises due to interstitial infiltration by pathological/alveolar macrophages, but intravascular shunts and pulmonary hypertension may occur. While symptomatic lung disease is rare (mainly splenectomized previously untreated patients, and in GD3), pulmonary function tests commonly show airways obstruction, with reduced expiratory flow, reduction in lung volumes and alveolar-capillary diffusion abnormality.
Fatigue is a frequent symptom which does not necessarily correlate with overall disease severity nor with anemia, but still impacts significantly on QOL. It has been related to underlying inflammation, possibly ER-stress, and it is not always responsive to ERT or SRT, but theoretically might improve with PCs.
Types 2 (GD2) and 3 (GD3)
Neuronopathic GD (nGD) includes GD2, known as the “acute infantile” type, and GD3—the sub-acute juvenile neuronopathic type, represent the more severe GD forms, which also demonstrate diverse phenotypes. The distinction between “milder” GD2 and very severe GD3 may be challenging in young children. A common and pathognomonic sign is oculomotor apraxia, or supra-nuclear gaze palsy, predominantly horizontal, which in GD2 becomes a fixed convergent squint early in the course of the disease. Its universal absence in GD1 supports our preference to keep the classification of GD to three distinct forms.
GD2 is subdivided into a classic form (a fatal disease presenting during early infancy with survival of up to 2 to 3 years without complete life support), and a neonatal form (presenting at birth with hydrops fetalis, ichthyosis and death within 48 hours). GD3 has three sub-types: GD3a with a dominant neurological disease and relatively minor visceral involvement, GD3b with minimal neurological symptoms and massive visceral and skeletal disease, and more recently GD3c, the cardiac variant, with severe calcifications of the left heart valves and aorta, leading to death during late child hood to early adulthood, without significant visceral or neurological abnormalities.
The definitions of the exact form of nGD are based on clinical symptoms, and may not be based on the molecular diagnosis. With the launch of clinical trials specific for nGD, it became important to establish well-defined criteria to allow uniform patients’ recruitment.
GD2
Patients with GD2 typically present with severe, progressive neurological deficits in the first weeks of life. Stridor and apnea are common, necessitating tracheostomy by age 2 years; swallowing dysfunction, aspiration (requiring percutaneous endoscopic gastronomy [PEG] feeding), opisthotonos, progressive myoclonic epilepsy, and failure to achieve gait are other symptoms.
GD3
This nGD form is more heterogeneous; the gaze palsy (sometimes hard to notice at an early age) may be the isolated neurological finding (GD3b) or be part of dominantly neurological abnormalities including motor and coordination deficits (ataxia), epilepsy (generalized seizures or myoclonic), stridor, dysarthria, cognitive impairments and more—GD3a. Most GD3 patients do not deteriorate rapidly. The most common genotype is homozygosity of L444P, and it is also the most frequent type of GD in Asia. A rather typical and very debilitating symptom is thoracic kyphosis (usually without scoliosis) and with no evidence of vertebral body collapse, usually developing between the age of 6 to 16 years. In GD3b, all the visceral and hematological manifestations that were described in GD1 are also present but usually with more severe prevalence of lung involvement.
