Advances in Gaucher Disease 9 Table 1. Up-regulated proteins in the CSF of type 3 GD patients Gene symbol Protein Fold change and P value CHIT 1 Chitotriosidase-1 57.7 (<0.01) GPNMB Transmembrane glycoprotein NMB 42.3 (<0.01) SCTSS Isoform 2 of Cathepsin 6.7 (<0.05) IGKC Ig kappa chain V-III region GOL 6.6 (<0.01) LYZ Lysozyme C 6.3 (<0.01) CFD Complement factor D 3.1 (<0.01) PLD3 Phospholipase D3 2.4 (<0.01) CSF from type 3 GD patients and age matched controls (n=4) was digested with trypsin and subjected to label-free quantitative global proteomic analysis using liquid chromatography and tandem mass spectrometry (LC-MS/MS). pearance of neurological involvement in a patient with biochemically proven GD, for which there is no explanation other than GD.3 Gaucher Disease Type 2 (acute neuronopathic, GD2) GD2 is rare and is characterized by a rapid neurodegenerative course often with extensive visceral involvement and death within the first 2 years of life. Patients with this type may present at birth or during infancy with increased tone, seizures, strabismus, and organomegaly. Disruption of the epidermal layers of the skin, observed on skin biopsy findings, may manifest before the onset of neurological symptoms, but this may not always be clinically apparent.3 Failure to thrive, hepatosple-nomegaly, swallowing abnormalities, supranuclear gaze paresis that often progresses to nuclear paralysis, and stridor due to laryngospasm are typical in infants with GD2. Progressive myoclonic encephalopathy develops after age 1 year. The progressive neurodegeneration that includes the brain stem combined with severe myoclonic epilepsy leads to death, usually caused by aspiration and respiratory compromise. A severe neonatal form can present in utero or perinatally with hydrops fetalis, congenital ichthyosis, or both. Gaucher Disease Type 3 (chronic neuronopathic, GD3): Clinical Syndromes This broad category of Gaucher disease includes several different phenotypes and can present in infancy, childhood and even in adulthood. In addition to organomegaly and bone involvement, by definition, individuals with GD3 have neurologic involvement. Visceral and neurological involvement varies widely from one patient to another creating a large spectrum of clinical disease. Supranuclear gaze palsy consisting of slow saccades typically affecting horizontal more than vertical eye movements is virtually always present to some degree and may be the sole neurologic abnormality. On the other hand, some patients develop myoclonic encephalopathy that quite rapidly progresses and causes dementia and early death. For an unknown reason, systemic disease is often mild in this form of GD3.3 One rare subgroup of patients with GD3 present with oculomotor findings, calcifications of the mitral and aortic valves, and corneal opacities. This phenotype is associated with homozygosity for the D409H mutant allele. The most common form of GD3 is typically associated with homozygosity for the L444P mutation and was initially exemplified by the genetic isolate from the Norrbottnian region of Sweden. These individuals present in early childhood with visceral (including interstitial pulmonary disease) and skeletal involvement and oculomotor abnormalities and may later develop seizures. There is a wide range of cognitive abilities ranging from severe autism spectrum disorder to above average intelligence. Dysphagia, dysarthria and stridor may occur in the most severely affected patients. Dementia does not typical occur in this form of GD3. Epidemiology: Mode of Inheritance and Prevalence Although GD1 is particularly prevalent among Jews of Ashkenazi origin, the neuronopathic forms of GD are panethnic. The estimated worldwide incidence of GD type 3 is about 1:100,000. In Western countries, patients with GD3 constitute about 5% of the population of patients with GD.4 As noted earlier, Sweden is a striking exception where Gaucher type 3 is be found in relatively high prevalence. The contemporary Swedish index families are found in two geographically distinct clusters with the highest worldwide prevalence of Gaucher type 3 disease.4 In contrast to Western countries, a majority of GD patients in populous non-European countries such as Japan, China, Taiwan, Korea, India and Egypt have GD34. As there is yet no satisfactory treatment for the neurological manifestations of GD3, the substantial numbers of GD3 patients worldwide constitute a significant medically underserved population. Pathophysiology and Diagnostic Testing Clinical findings are central to making the diagnosis of neuronopathic Gaucher disease; confirmation depends on finding neurological abnormalities that are not explained by another etiology.3 The diagnosis of GD is established by finding low glucocerebrosidase activity in peripheral blood cells or other patient cells or tissues. Although complete sequencing of the GBA1 gene is highly recommended in all patients suspected doi:10.1371/journal.pone.0120194.t001
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