2.1. Hydrops fetalis

Hydrops fetalis, characterized by an abnormal accumulation of fluid in multiple body areas, has been associated with several LSDs, including Type 2 GD [4]. While multiple disease processes are associated with hydrops, in over 25% of cases the cause is unknown. A portion of these undiagnosed cases may be due to LSDs that go unrecognized, leaving families unprepared regarding the risks for future pregnancies. Among patients with GD, cases involving hydrops tend to be perinatal lethal disorders and the pathophysiology is not well understood [6,7]. Generally, when hydrops is present in Type 2 GD, the fetus dies in utero, or is delivered prematurely and dies within several days of birth [7]. In cases of Type 2 GD without hydrops, fetuses generally reach full term [7].

2.2 Skin abnormalities

Newborns with Type 2 GD may present with congenital ichthyosis, an abnormal skin disorder resulting in shiny, almost cellophane-like skin. This is referred to as the collodion-baby phenotype [6,8]. The skin peels over the initial few weeks of life but then typically resolves while other symptoms worsen [6,9]. This pathology is thought to result from altered ratios of ceramides to glucosylceramides in the outermost layers of skin [10]. When severe, the skin must be treated aggressively with lubricants and fluids. Patients must be monitored vigilantly because of the risk for excessive loss of fluid and electrolytes.

2.3. Hepatosplenomegaly

Hepatosplenomegaly, enlargement of both the liver and spleen, is one of the characteristic signs observed among patients with all three types of GD [7]. Often a first diagnostic clue can be the discovery of an enlarged spleen in the newborn nursery. Untreated, the enlargement can be massive, with organs that extend to the pelvic brim, compromising feeding and breathing. However, some infants may not exhibit prominent organomegaly.

2.4. Thrombocytopenia and anemia

Thrombocytopenia is observed among all forms of GD and occurs in approximately 40% of patients with Type 2 GD [7], either transiently during the neonatal period or as the disease progresses. Anemia is also frequently observed in these patients [6].

2.5. Dysmorphology

Dysmorphic facial features, often associated with other specific LSDs but generally not GD, have been described in some infants with Type 2 GD, including low-set ears and a small, upturned nose with a flat nasal bridge [6,7]. Dysmorphic features often accompany the collodion-baby phenotype and might result from the presence of a thick membranous layer and decreased skin elasticity in utero.

2.6. Neurological Involvement

All patients with Type 2 GD experience a rapid neurological decline, but manifestations vary widely. Some patients present with arthrogyphosis (joint contractures), microcephaly (abnormally small head circumference) or hypokinesia (decreased bodily movement) [6,7]. More common neurologic signs include a hyperextended neck, spontaneous apnea, hypertonia, and poor suck and swallow reflexes [6-8]. The characteristic facies and neck extension observed are thought to be secondary to a cervico-facial dystonia. Strabismus is also commonly seen. Many patients go on to develop seizures, rigidity and opisthotonos as the disease progresses.

6.1. Failure to thrive and feeding difficulties

Failure to thrive is a common finding in patients with Type 2 GD and results from a combination of anorexia, nausea, hypotonia or hypertonia, vomiting and feeding difficulties [6]. Chewing difficulties, a weak suck, and/or problems with swallowing occur due to neurological involvement. In addition, the presence of abnormal neck tone and opisthotonos, trismus and/or the presence of laryngospasm can be contributing factors [24]. When the diagnosis is reached at an early stage, oral feeding may still be possible. A clinical evaluation of feeding should be performed by a speech pathologist, and infants should be monitored for weight gain, dehydration and/or signs of aspiration [25]. A video fluoroscopic evaluation of swallowing (modified barium scan) provides further information regarding the presence of aspiration, gastro-esophageal reflux and laryngeal penetration with different types of feedings [25] and can be used to adjust the type of bottle/nipple, formula thickening or recommend strict enteral feeding. It can also provide objective evidence for the extent of bulbar involvement [24,26]. The images can be used as an educational tool in discussions regarding the advantages and disadvantages of oral versus gavage feedings. In cases when it is decided to switch to enteral feedings, a nasogastric tube or gastric tube insertion with gastrostomy are two acceptable approaches. Decisions regarding the most appropriate approach should take into account potential anesthesia- related complications during a gastrostomy or gastric tube insertion procedure [27].

Assessment of macronutrient, micronutrient and fluid intake is important in these patients because their oral intake is usually low. An individualized nutrition plan should be constructed, considering the mode of feeding and energy requirements. Patients with Type 2 GD may not gain weight even with enteral or parenteral feeding because of increased resting energy expenditure [28].

6.2. Bulbar involvement and airway compromise

Brain stem degeneration leads to bulbar involvement, characterized by choking events, laryngeal spasm and apnea. These frightening episodes occur in a subset of patients and tend to occur with increased frequency as the disease progresses [29]. Laryngospasm can also lead to hypoxemia, which may accelerate the disease process. Treatment of gastro-esophageal reflux and strict enteral feeding can decrease the incidence of these events in early stages of the disease, but spontaneous episodes may occur as the disease worsens [29]. Excessive oral secretions may also contribute to respiratory symptoms, necessitating suction. Treatment with sublingually delivered ophthalmic atropine drops has been used with some success [30].

Whether to place a tracheotomy tube is one of the most challenging issues faced by physicians and families caring for children with Type 2 GD. A tracheostomy has been effectively used when the primary manifestation is laryngospasm and airway compromise. While in general patients with Type 2 GD who undergo tracheostomy placement tend to survive longer, consideration that this intervention may prolong suffering should be discussed with the family [31]. Extensive dialogue regarding realistic expectations is desirable prior to undertaking this measure. Parents should be counseled that the decision not to undergo tracheotomy can be very reasonable in many circumstances.

There is an increased risk for anesthesia-related complications due to increased secretions, gastro-esophageal reflux, poor control of laryngeal musculature and/or laryngeal spasm. These may be triggered by pre-anesthesia medications or manipulation of the airway [27]. Difficult airway access may require the need for smaller endotracheal tubes [27]. Pulmonary involvement in GD is another risk factor for anesthesia-related complications.

6.3. Neurological aspects

Neurological involvement can manifest as irritability and spasticity. Non-pharmacological treatments include gentle handling, maintaining a calm and familiar surrounding, physical therapy and proper positioning [32]. Pharmacological treatment with benzodiazepines can be useful for both irritability and spasticity. Caregivers should be educated about possible side effects including sedation, constipation, urinary retention, hypersalivation and weakness. Respiratory depression can be seen with benzodiazepine toxicity. Airway compromise due to bulbar involvement may limit their use. Other anti-spasticity drugs used include baclofen, dantrolene and tizanidine [33]. These medications can be offered in the setting of palliative therapy [32].

Seizures, sudden episodes of sensory disturbance, loss of consciousness, or convulsions, associated with abnormal electrical activity in the brain, can occur as the disease progresses. Electroencephalography (EEG) can identify abnormal brain activity in the absence of clinical signs. Findings on EEG may include slowing and disorganization of the background and/or epileptiform activity [Prows:1997bh; 33]. Myoclonic epilepsy and myclonus are often described although not universally, and are thought to be mainly of cortical origin [29,34].

Seizure control can be very challenging in patients with type 2 GD. Careful attention to the identification of treatable etiological factors such as hypoglycemia, hypocalcemia, hyponatremia, hypomagnesemia, hypoxia, intracranial hemorrhage, hyperammonemia, and/or infections is of critical importance. High quality neuroimaging and accurate EEG interpretation may help in optimizing patient care and outcomes [35]. Continuous EEG monitoring for the detection of subclinical seizures is recommended, but may not be possible due to the need for specialized training and access to equipment [36]. Periodic conventional EEG monitoring is more generally available. Antiepileptic treatment is generally guided by the particular epilepsy syndrome at presentation [37]. However, benzodiazepines are usually first-line therapy for status epilepticus although they can cause respiratory depression and/or cardiac dysrhythmia. Midazolam and lorazepam are the preferred agents. Second-line therapies include phenytoin and fosphenytoin. Phenytoin has been associated with local skin necrosis and hypotension. Both agents can cause cardiac dysrhythmias with more rapid administration. Phenobarbital is frequently used in infants, but carries the risk of hypotension, respiratory depression, and cardiac arrhythmia. Levetiracetam can also be considered. Valproate can be effective but patients must be monitored for potential side effects such as thrombocytopenia and hepatotoxicity [38].

6.4. Visceral and hematologic involvement

Visceral involvement presents as splenomegaly and is associated with anemia and thrombocytopenia. Liver enlargement is also seen, and can be accompanied by elevations in transaminases. Portal hypertension and liver dysfunction are rarely described in Type 2 GD, although neonatal cholestasis is occasionally seen and may precede other manifestations [39,40]. Splenectomies have been performed in these patients but are generally not recommended due to the risk of surgical complications. It is important to note that the absence of overt organomegaly is not sufficient to rule out the diagnosis of Type 2 GD.

The main hematological complication is a bleeding tendency secondary to the thrombocytopenia and abnormal platelet aggregation [41]. A decrease in clotting factors secondary to consumption by an enlarged spleen has also been described [42]. The complete blood cell count should be monitored regularly to identify the need for transfusions. Systemic disease can be minor or almost absent in comparison to the neurological deficits observed in patients with Type 2 GD.

Pulmonary involvement with interstitial lung disease is a common finding primarily resulting from recurrent aspirations [6] or from the infiltration of alveolar, interstitial, perivascular, and peribronchial spaces by lipid-laden macrophages [43]. Chest X-ray may show diffuse interstitial infiltration in both lung fields, and a ground glass pattern can be seen on chest CT. On lung biopsy, Gaucher cells can be seen [43]. Periodic monitoring of pulmonary involvement should include examination for evidence of respiratory distress, oxygen saturation measurements, and chest X-rays. Such testing can identify the need for supportive treatment with oxygen and/or antibiotics if there is evidence for aspiration pneumonia. Fever may be a sign of a pulmonary infection, but can also be present in the absence of infection due to inflammation, possibly mediated by activated glucosylceramide-laden macrophages [6]. Prolonged, unexplained fever has been associated with a worsening disease course [29].

7.1. Enzyme replacement and substrate reduction

Enzyme replacement therapy (ERT) can ameliorate the visceromegaly and hematologic abnormalities in patients with Type 2 GD [28,44]. It is not clear whether ERT impacts pulmonary involvement, although when the primary cause of pulmonary involvement is recurrent aspirations secondary to neurological deterioration, ERT is not beneficial [28,44]. The recombinant enzyme does not cross the blood-brain barrier and there is no evidence that ERT has reversed, stabilized, or slowed the progression of neurological involvement [45]. Siblings were described where one received ERT after diagnosis at 7 months, and the subsequent sibling was treated from birth. While the sibling treated pre-symptomatically survived 6 months longer, the final outcome was the same [45]. It has been debated whether it is ethical to treat Type 2 GD patients with ERT because it is a very costly and inconvenient therapy that may only prolong suffering [46]. It is generally accepted that ERT should be discussed with families presenting both its potential merits and the limitations. Some physicians feel that ERT is not indicated for patients with Type 2 GD, although in recent years many infants have been started on the therapy [45]. It is sometimes deemed appropriate to treat with ERT until it is clear that the patient does not have Type 3 GD. In addition, it is reasonable to consider therapy for Type 2 GD patients in situations where it could be palliative, for example if reduction of organomegaly would alleviate pain, avoid surgery or facilitate other necessary interventions such as gastric tube placement.

Alternative methods of enzyme delivery have been investigated to treat the neurological deterioration in GD. Intraventricular delivery via a reservoir was attempted without success [47]. An animal study evaluated convection-enhanced delivery (CED) to restore GCase levels in the brains of rats and primates [48]. Enzymatic assays showed significant increases in GCase activity in the white matter, cortex, and pons of treated animals, and immunohistochemical staining confirmed GCase localization in neurons of the cortex [48]. One patient with Type 2 GD was treated with GCase via CED, and while successful delivery of enzyme was documented, there was continued disease progression [49]. Intravascular delivery after disruption of the blood-brain barrier has been investigated but not attempted in these patients [50].

Substrate reduction therapy with Miglustat, an inhibitor of glucosylceramide synthase, was not shown to be beneficial for neurological manifestations in Type 3 GD [51]. This treatment is not indicated for Type 2 GD.

7.2. Bone marrow and hematopoietic stem cell transplantation

Full engraftment of a hematopoietic stem cell transplantation (HSCT) has been performed in patients with Type 1 GD resulting in complete hematologic correction [52,53]. Ringden et al described four Swedish patients with Type 3 GD who underwent bone marrow transplantation between the ages of 2-9 years old [54]. Two patients had no cognitive decline at follow-up ten years later [54]. However, both developed epilepsy 14 and 22 years after allo-HSCT [55]. Thus, the procedure does not prevent development of neurological damage although it might affect the extent or rate of neurological deterioration. Published reports regarding the results of bone marrow transplantation in patients with Type 2GD are not available. The risks involved in transplanting a seriously ill infant must be seriously considered, given the strong possibility of continued neurological deterioration. Moreover, end-of-life issues may need to be addressed in distant centers, away from the support of home and family.

9.1. Substrate reduction therapy

Inhibitors of glucosylceramide synthase have been explored as a means to attenuate glucosylceramide production and accumulation in various organs. The currently available therapy is not beneficial in neuropathic GD (Type 2 and 3) [51]. A novel glucosylceramide synthase inhibitor decreased substrate accumulation in the brains of a mouse model for neuronopathic GD [58]. This treatment modality might be beneficial for neuronopathic GD if given pre-symptomatically and before significant accumulation of substrate in the brain occurs, perhaps through newborn screening programs [59].

9.2. Chaperone therapy

Restoration of the mutant enzyme activity by small molecule compounds (chaperones) capable of crossing the blood-brain barrier is a new approach to treat LSDs [60], [[61]. Currently, there is an effort to identify candidate molecules [62,63]. However, this treatment will be helpful only for mutations in GBA1 that result in an unstable mutant protein and may not be appropriate for patients with null alleles. Induced pluripotent stem cells (iPSCs) generated from fibroblasts of patients with Type 2 GD may facilitate studies of candidate molecules. Gaucher iPSC lines show deficient GCase and were differentiated into macrophages that exhibit substrate accumulation [64]. This GD phenotype in macrophages was successfully reversed with a new molecular chaperone [65].

9.3. Gene therapy

Gene therapy is a potentially promising future therapeutic strategy for genetic diseases with enzymatic deficiencies like GD [66], although the effectiveness of gene therapy in CNS disease is not clear. Intracerebral injection of the vector carrying the wild-type gene may be a possible strategy [66].

9.4. Additional treatment targets

As we advance our understanding of the mechanisms involved in neurodegeneration, other potential targets will likely be identified. Insights from basic science research like the potential role RIPK3 [22] may provide new leads for future drug development.