Alternative titles; symbols
SNOMEDCT: 12246008; ORPHA: 355, 77260; DO: 0110958;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q22 | Gaucher disease, type II | 230900 | Autosomal recessive | 3 | GBA | 606463 |
A number sign (#) is used with this entry because Gaucher disease type II (GD2) is caused by homozygous or compound heterozygous mutation in the gene encoding acid beta-glucosidase (GBA; 606463) on chromosome 1q22.
Mutation in the same gene causes nonneuronopathic Gaucher disease type I (GD1; 230800), subacute neuronopathic type III (GD3; 231000), the rare GD3c subtype (231005), and the perinatal lethal variant (608013), which is often considered to be a severe form of type II.
Type II Gaucher disease (GD2) is an acute neuronopathic form of the disorder with onset in infancy and death often by 2 years of age. Patients are usually normal at birth, but develop hepatosplenomegaly, developmental regression, and growth arrest within a few months of age. Neurologic deterioration proceeds rapidly, with cranial nerve and extrapyramidal tract involvement (Stone et al., 2000).
Owada et al. (1977) reported 3 Japanese patients with neuronopathic Gaucher disease. Glucocerebrosidase activity was almost normal in the liver, but markedly reduced in the spleen and fibroblasts.
Saranjam et al. (2013) reported 2 unrelated infants with severe, lethal type II Gaucher disease. The first was a girl of multiple ethnic descent who presented early in life with respiratory difficulties, poor feeding, failure to thrive, ophthalmoplegia, and developmental delay. Laboratory studies showed anemia and thrombocytopenia, and bone marrow biopsy revealed lipid-laden macrophages characteristic of Gaucher disease. A lysosomal enzyme panel showed severely decreased glucocerebrosidase activity. The patient died at 11 months of age. The second infant was a boy, born to an unrelated Ashkenazi Jewish father and a Sephardic Jewish mother. He was diagnosed at the age of 7 months after a bone marrow aspiration revealed Gaucher cells. The diagnosis was confirmed by deficient glucocerebrosidase activity, and he died at 10 months secondary to respiratory failure.
In a clinical review of Gaucher disease, Daykin et al. (2021) noted that GD2 may present prenatally with hydrops fetalis, in the newborn period, or later in the first year of life. In the newborn period, patients may present with congenital ichthyosis, hepatosplenomegaly, biliary atresia, facial dysmorphology, arthrogryposis, congenital thrombocytopenia, and/or growth abnormalities. The ichthyosis may result from increased glucosylceramide in the stratum corneum, which leads to abnormal histologic appearance of the skin on microscopic examination. Patients presenting later in the infantile period may show failure to thrive, swallowing abnormalities, seizures, developmental delay, and/or abnormal eye movements.
Clinical Variability
Although patients with Gaucher disease type II typically have acute neurologic progression and those with type III have slow progression, Goker-Alpan et al. (2003) described 9 children with an intermediate phenotype of delayed age of onset, rapid progression of neurologic disease with refractory seizures, and oculomotor abnormalities. Based on the clinical presentation along with the detected genotypic heterogeneity found by identification of all 18 alleles, Goker-Alpan et al. (2003) concluded that neuronopathic Gaucher disease is more likely to be a continuum of phenotypes from the severe perinatal cases to mild involvement with oculomotor problems.
Filocamo et al. (2005) reported a 25-month-old girl with an atypical form of neuronopathic Gaucher disease between types II and III caused by a homozygous double mutation in the GBA gene (606463.0047). Onset of symptoms occurred at age 5 months with hepatosplenomegaly. A few months later, she developed neurologic features, including spasticity with persistent retroflexion of the neck, convergent strabismus, oculomotor apraxia, and abnormal MRI changes. At age 25 months, she showed slow symptom progression and was able to sit alone, walk with support, and pronounce some words.
Svennerholm et al. (1986) found an average residual activity of beta-glucosidase in forebrain tissue from 3 patients with the infantile type of Gaucher disease to be 5%, compared to 12% in 6 patients with Gaucher disease type III.
Beutler and Kuhl (1986) studied processing of glucocerebrosidase in the 3 types of Gaucher disease. Normal cells initially formed a 60-kD polypeptide antigen that was gradually replaced by a broad band of antigen averaging 63 kD, which they thought represented the mature enzyme. While processing in 6 unrelated patients with Gaucher disease type I and in 1 patient with type III was similar to normal, 3 patients with the severe infantile form (type II) showed an unstable enzyme. The 60-kD band appeared only transiently and the mature 63-kD band was never seen. The authors concluded that an unstable precursor characterizes type II Gaucher disease.
Gornati et al. (2002) examined the lipid composition of the liver, spleen, brain, cerebellum, and cerebrospinal fluid of a type II Gaucher patient who died at age 5 months. The glycolipid analysis demonstrated a marked increase of total amounts not only in the peripheral tissues but also in the cerebellum and cerebrospinal fluid, with a prevalence of glucosylceramide. A relative reduction in gangliosides was observed in all analyzed tissue, with a relative increase in ganglioside GD3 in the nervous tissue. The fatty acid composition of glucosylceramide showed a prevalence of stearic acid in the central nervous system, while in the peripheral tissues palmitic acid was prevalent. Gornati et al. (2002) suggested that their results indicated a different origin of the glucosylceramide stored in different tissues.
Holleran et al. (2006) reported an infant with type II Gaucher disease in whom ultrastructural abnormalities in the skin were identified prior to development of the more typical neurologic manifestations of the disease. At 5 weeks of age, his neurologic examination and skin appearance were described as normal. A skin biopsy performed at age 9 weeks showed disorganized lamellar membranes within the stratum corneum interspersed with amorphous nonlamellar microclefts presumably resulting from pockets of accumulated hydrophilic glucosylceramide, consistent with an epidermal lipid processing defect. The infant developed more severe neurologic complications by age 6 months. Holleran et al. (2006) noted that these skin abnormalities have been described only in patients with type II Gaucher disease and thus can be used for early discrimination among the several forms of the disorder.
Type II Gaucher disease shows autosomal recessive inheritance. Saranjam et al. (2013) reported 2 unrelated infants with severe, lethal type II Gaucher disease who were compound heterozygous for 2 mutations in the GBA gene, one of which was L444P (606463.0001). While the other mutation was identified in the paternal line of each patient (see, e.g., T323I, 606463.0017), the L444P allele was not detected in DNA samples from either patient's mother, suggesting that it occurred either as a result of germline mosaicism or as a de novo mutation in 1 ovum that took place during cell division. The findings had implications for genetic counseling, in that even if only 1 parent is found to be a carrier for a recessive disorder, the chance of having an affected child may not be zero. Saranjam et al. (2013) noted that the L444P change occurs at a known mutational hotspot.
Vellodi et al. (2001) reported a European consensus on the management of Gaucher disease. They recommended enzyme replacement therapy (ERT) with macrophage-targeted recombinant human glucocerebrosidase and found that it ameliorates systemic involvement in nonneuronopathic as well as neuronopathic Gaucher disease, enhancing the quality of life. There was also evidence that enzyme replacement therapy reversed, stabilized, or slowed the progression of neurologic involvement in some patients. In patients with established acute neuronopathic disease, enzyme replacement therapy had little effect on the progressively downhill course.
Tsuji et al. (1987) identified a homozygous mutation in the GBA gene (L444P; 606463.0001) in patients with Gaucher disease type II.
Wigderson et al. (1989) reported a patient with type II disease who was compound heterozygous for 2 mutations in the GBA gene: L444P and P415R (606463.0002).
Grace et al. (1990) used site-directed mutagenesis and characterization of the expressed mutant beta-glucosidase to understand the molecular basis of the phenotypic variation between type II and type III Gaucher disease. The results suggested that the presence of at least 1 nonfunctional GBA allele in type II patients may provide a molecular basis for the distinct phenotypes between types II and III.
Stone et al. (2000) identified mutations in the GBA gene in 17 unrelated patients with type II Gaucher disease with onset ranging from 3 to 12 months of age.
Koto et al. (2021) surveyed hospitals in Japan about patients with lysosomal storage diseases (LSDs) treated between 2013-2016 and 2018-2019. Sixty-nine individuals with Gaucher disease were identified, of whom 37.7% had GD type I, 23.2% had GD type II, 30.4% had GD type III, and 8.7% had an unknown type. Koto et al. (2021) noted that the high prevalence of GD type II was a feature that was characteristic of Japan. Koto et al. (2021) calculated a birth prevalence of Gaucher disease in Japan of 0.19 per 100,000.
Wei et al. (2008) proposed that activation of the unfolded protein response (UPR) may be a common mediator of apoptosis in neuronopathic lysosomal storage diseases (LSDs), such as Gaucher disease type II. Farfel-Becker et al. (2009) examined whether the UPR is activated in neuronal forms of GD using a selection of neuronal disease models and a combination of Western blotting and semiquantitative and quantitative real-time PCR analysis. There were no changes in either protein or mRNA levels of a number of typical UPR markers including BiP (HSPA5; 138120), CHOP (DDIT3; 126337), XBP1 (194355), HERP (HERPUD1; 608070), and GRP58 (PDIA3; 602046), in either cultured Gaucher neurons or astrocytes, or in brain regions from mouse models, even at late symptomatic stages. Farfel-Becker et al. (2009) concluded that the unfolded protein response is not necessarily a common mediator for apoptosis in all neurodegenerative lysosomal storage diseases.
Enquist et al. (2007) generated transgenic mice with targeted disruption of the Gba gene, but low expression of the gene in skin to prevent early lethality. The mice showed a phenotype similar to the severe neuronopathic form of GD, including rapid motor dysfunction, seizures, and hyperextension of the neck associated with severe neurodegeneration and apoptotic neuronal cell death. Some neurons had large vacuoles indicating neuronal lipid accumulation. A second mouse model with Gba deficiency restricted to neural and glial cell progenitors demonstrated a similar neuropathology as the first mouse model, but with a delayed onset and slower disease progression. These findings indicated that Gba deficiency within microglial cells of hematopoietic origin is not the primary determinant of the CNS pathology, but may influence disease progression. The findings also showed that normal hematopoietic-derived microglial cells could not rescue the neurodegenerative phenotype.
In a mouse model of neuronopathic GD in which glucocerebrosidase deficiency is limited to neural and glial progenitor cells (Enquist et al., 2007), Vitner et al. (2010) showed significant changes in the levels and distribution of cathepsins in brain. Cathepsin mRNA expression, activity, and protein levels were significantly elevated, with the time course of the increase correlating with the progression of disease severity. Significant changes in cathepsin D (CTSD; 116840) distribution in the brain were detected, with cathepsin D elevated in areas where neuronal loss, astrogliosis, and microgliosis were observed. Cathepsin D elevation was greatest in microglia and astrocytes, and also in neurons in a manner consistent with its release from the lysosome to the cytosol. Ibubrofen treatment significantly reduced cathepsin D mRNA levels in the cortex of these mice, and cathepsin levels were also altered in mouse models of other sphingolipidoses. Vitner et al. (2010) suggested the involvement of cathepsins in the neuropathology of neuronal forms of GD and of other lysosomal storage diseases, and hypothesized a crucial role for reactive microglia in neuronal degeneration in these diseases.
Beutler, E., Kuhl, W. Glucocerebrosidase processing in normal fibroblasts and in fibroblasts from patients with type I, type II, and type III Gaucher disease. Proc. Nat. Acad. Sci. 83: 7472-7474, 1986. [PubMed: 3463977] [Full Text: https://doi.org/10.1073/pnas.83.19.7472]
Daykin, E. C., Ryan, E., Sidransky, E. Diagnosing neuronopathic Gaucher disease: new considerations and challenges in assigning Gaucher phenotypes. Molec. Genet. Metab. 132: 49-58, 2021. [PubMed: 33483255] [Full Text: https://doi.org/10.1016/j.ymgme.2021.01.002]
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Farfel-Becker, T., Vitner, E., Dekel, H., Leshem, N., Enquist, I. B., Karlsson, S., Futerman, A. H. No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease. Hum. Molec. Genet. 18: 1482-1488, 2009. [PubMed: 19193629] [Full Text: https://doi.org/10.1093/hmg/ddp061]
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Koto, Y., Sakai, N., Lee, Y., Kakee, N., Matsuda, J., Tsuboi, K., Shimozawa, N., Okuyama, T., Nakamura, K., Narita, A., kobayashi, H., Uehara, R., Nakamura, Y., Kato, K., Eto, Y. Prevalence of patients with lysosomal storage disorders and peroxisomal disorders: a nationwide survey in Japan. Molec. Genet. Metab. 133: 277-288, 2021. [PubMed: 34090759] [Full Text: https://doi.org/10.1016/j.ymgme.2021.05.004]
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Vitner, E. B., Dekel, H., Zigdon, H., Shachar, T., Farfel-Becker, T., Eilam, R., Karlsson, S., Futerman, A. H. Altered expression and distribution of cathepsins in neuronopathic forms of Gaucher disease and in other sphingolipidoses. Hum. Molec. Genet. 19: 3583-3590, 2010. [PubMed: 20616152] [Full Text: https://doi.org/10.1093/hmg/ddq273]
Wei, H., Kim, S. J., Zhang, Z., Tsai, P. C., Wisniewski, K. E., Mukherjee, A. B. ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones. Hum. Molec. Genet. 17: 469-477, 2008. [PubMed: 17989065] [Full Text: https://doi.org/10.1093/hmg/ddm324]
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