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Other entities represented in this entry:
SNOMEDCT: 5963005; ORPHA: 355, 77261; DO: 0110959;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q22 | Gaucher disease, type III | 231000 | Autosomal recessive | 3 | GBA | 606463 |
A number sign (#) is used with this entry because Gaucher disease type III (GD3) is caused by homozygous or compound heterozygous mutation in the gene encoding acid beta-glucosidase (GBA; 606463) on chromosome 1q22.
Mutations in the same gene cause Gaucher disease type 1 (230800), type 2 (230900), and subtype IIIC (231005).
Gaucher disease type III (GD3) is the subacute form of neuronopathic Gaucher disease. It has later onset and slower progression compared to the acute form of neuronopathic Gaucher disease, type II.
Patterson et al. (1993) suggested that there are 2 phenotypic subgroups of Gaucher disease type III: type IIIA, which is characterized by myoclonus and dementia, and type IIIB, characterized by early onset of isolated horizontal supranuclear gaze palsy and aggressive systemic disease. See also Gaucher disease type IIIC (231005), which is associated with cardiovascular calcifications.
Herrlin and Hillborg (1962) reported a pedigree with juvenile Gaucher disease and neurologic signs.
Miller et al. (1973) described Gaucher disease with neurologic manifestations in 3 adult sibs. Features included seizures and decreased beta-glucocerebrosidase activity.
Dreborg et al. (1980) reported clinical studies of a large number of patients with a distinctive type of Gaucher disease that they termed the 'Norrbottnian type' because of its origin from the province of Norrbotten, the northern-most county in Sweden. Median age at onset was 2.5 years (range 8 months to 14.5 years). Initially, affected patients had normal intelligence and short stature with splenomegaly. Patients later developed abnormal eye movements and some developed seizures. The severity of the clinical symptoms and signs and course of the disease differed markedly not only between families but also between sibs. Splenectomy accelerated deterioration, especially with regard to skeletal and central nervous system manifestations. Biochemical studies were performed by Hakansson (1979).
Tibblin et al. (1982) reported anemia, leukopenia, and thrombocytopenia in patients with the Norrbottnian type of Gaucher disease. Splenectomy resulted in improvement of these hematologic parameters.
Erikson and Wahlberg (1985) found that patients with the Norrbottnian type of Gaucher disease showed horizontal gaze abnormalities during the first 10 years of life, similar to congenital oculomotor apraxia. Other ocular features included squint, white retinal infiltrations, and myopia.
Gross-Tsur et al. (1989) reported 2 sisters, aged 6.5 and 5.5 years, respectively, in whom the presenting sign of Gaucher disease was oculomotor apraxia. The authors noted that the oculomotor deficit in Gaucher disease is usually characterized by failure of volitional horizontal gaze with preservation of vertical ocular movements.
Raja et al. (2007) reported 2 brothers with Gaucher disease diagnosed as adults who both developed severe parkinsonism, cognitive impairment, and mood disorders. They were of southern Italian descent, and consanguinity was suspected. One brother presented with symptoms of bipolar disorder at age 49 and developed parkinsonism a few months later. Further studies showed brain hyperintensities on MRI and EEG abnormalities. The second brother presented with depressive symptoms at age 49 that worsened over the following years. He then developed parkinsonism with dystonic features. Both patients also had biliary lithiasis. The first brother had a history of meningitis, and at least 2 presumably unaffected family members had depression. Genetic analysis identified a homozygous mutation (606463.0001) in the GBA gene in both brothers. Raja et al. (2007) suggested that some Gaucher patients may develop motor or cognitive neurologic symptoms later in life.
Benko et al. (2008) reported an unusual case in which a 3-year-old boy had both Gaucher disease type III, resulting from a homozygous mutation in the GBA gene (L444P; 606463.0001) on chromosome 1q22, and Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), resulting from a homozygous mutation in the MPZ gene (159440) on chromosome 1q23.3. Further analysis showed that the father also carried the MPZ mutation and had CMT1B, and that the boy had complete paternal isodisomy of chromosome 1 with no evidence of the maternal chromosome 1. Benko et al. (2008) noted the atypical form of inheritance as well as the unique molecular mechanism of 2 concurrent mendelian disorders in this patient.
In a clinical review of Gaucher disease type III, Daykin et al. (2021) noted that it is a clinically heterogeneous disorder that is typically diagnosed based on neurologic manifestations. Most patients are diagnosed in childhood, but adult presentations have been observed. Three GD3 subtypes include GD3A, characterized by the development of myoclonic epilepsy; GD3B, characterized by abnormal saccades and significant visceral involvement; and GD3C (231005), characterized by corneal opacities, aortic calcification, and/or hydrocephalus. Ophthalmologic findings in GD3 include slowing of horizontal saccades and sometimes also vertical saccades. White vitreous opacities, consisting of Gaucher cells, can be seen and correlate with more severe disease. EEG abnormalities, including background slowing, are seen in most patients. A wide range of cognitive outcomes have been reported, ranging from severely compromised to above average. GD3A typically manifests with severe neurologic manifestations including progressive myoclonic epilepsy. Pulmonary disease includes interstitial lung disease caused by infiltration of Gaucher cells in the lungs. Skeletal involvement, which is particularly common in GD3B and the Norrbottnian subtype, includes bone pain, bone crises, and osteopenia among other findings.
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 and 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. Neurologic features included spasticity with persistent retroflexion of the neck, convergent strabismus, oculomotor apraxia, and abnormal MRI changes. Genetic analysis identified homozygosity for a complex allele containing 2 GBA mutations in cis (H255Q and D409H; see 606463.0047).
In 10 Swedish families with the Norrbottnian form of Gaucher disease, Dahl et al. (1988) found linkage to an MspI polymorphism in the GBA gene. The results suggested that the mutation occurred only once in the Swedish population.
Svennerholm et al. (1991) described the beneficial effects of bone marrow transplantation in Gaucher disease type III.
Erikson et al. (1995) reported that infusion therapy with a macrophage-targeted glucosylceramidase decreased hepatosplenomegaly, normalized hematologic parameters, and prevented progression of neurologic deterioration in all 8 of their patients treated from 13 to 29 months.
Rice et al. (1996) reported a 5-year-old patient with type III Gaucher disease who was treated with enzyme replacement therapy (ERT) at a dose of 60 U/kg every 2 weeks since age 2.5 years and showed no progression of neurologic involvement. Two other type III patients who were treated at the same dose beginning at ages 14 years and 41 years, respectively, showed no measurable neurologic change.
Vellodi et al. (2001) reported a European consensus on the management of neuronopathic Gaucher disease. They recommended 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 ERT reversed, stabilized, or slowed the progression of neurologic involvement in some patients. In patients with established acute neuronopathic disease, ERT had little effect on the progressively downhill course.
Schiffmann et al. (2008) reported the results of a randomized control study of miglustat, a substrate reduction therapy that inhibits glucosylceramide synthase (UGCG; 602874), in 30 adult patients with Gaucher disease type III. Twenty-nine patients received enzyme replacement therapy during the 24-month study period. There were no significant differences in vertical saccadic eye movement velocity or in other neurologic or neuropsychologic evaluations between the patients who received miglustat and those who did not. Organ volumes and hematologic parameters remained stable in both treatment groups. However, patients receiving miglustat showed some improvement in pulmonary function and decrease of chitotriosidase (600031) levels compared to patients receiving enzyme replacement therapy alone. Schiffmann et al. (2008) concluded that this therapy did not appear to have significant benefits on the neurologic manifestations of GD type III, but may have positive effects on systemic disease.
In a clinical review, Daykin et al. (2021) noted that because ERT does not cross the blood brain barriers, it is effective treatment for many visceral symptoms of GD3, but it does not address neuropathic manifestations. They further noted that improvements in visceral and hematologic manifestations improved quality of life and longevity.
Dahl et al. (1990) showed that the Norrbottnian form of Gaucher disease is caused by homozygosity for the leu444-to-pro (L444P; 606463.0001) mutation in the GBA gene.
Koprivica et al. (2000) found that homozygosity for L444P was associated with type III Gaucher disease.
Park et al. (2003) studied 16 patients with Gaucher disease type III who were part of a rare patient subgroup manifesting progressive myoclonic epilepsy (IIIA). Fourteen different genotypes were found, yet there were several shared alleles, including V394L (606463.0005), G377S (606463.0040), and N188S (606463.0026). The genotypes differed from those found in most patients with type III, and some of the shared alleles in these patients had previously been associated with nonneuronopathic Gaucher disease. Western studies showed that the patients lacked the processed 56-kD enzyme isoform usually indicative of neuronopathic disease. Although the genotype spectrum was distinct from the rest of Gaucher type III disease, Park et al. (2003) concluded that lack of a specific shared genotype and the variability of clinical presentations indicated a contribution by other genetic and environmental modifiers.
The Swedish families with the Norrbottnian type of Gaucher disease are found in 2 geographically distinct clusters. Dahl et al. (1990, 1993) demonstrated that both clusters are caused by the same GBA mutation (L444P). Mutation analysis was combined with a genealogic reconstruction of 19 contemporary index families. Each cluster was traced back to a single ancestral couple who were not known to be related to each other; however, the molecular studies were considered compatible with a single founder who arrived in northern Sweden in or before the 16th century. There was a single connection between the 2 pedigrees as published: the mother of an affected individual in one cluster came from the other isolate.
Sun et al. (2010) backcrossed saposin C (PSAP; 176801)-deficient mice (C -/-) to point-mutated GCase (V394L/V394L) (606463.0005) mice. The resultant mice (4L;C*) began to exhibit CNS abnormalities at 30 days, and death occurred at 48 days due to neurological deficits. Axonal degeneration was evident in brainstem, spinal cord, and white matter of cerebellum accompanied by increasing infiltration of the brainstem, cortex, and thalamus by microglial cells and activation of astrocytes. Electron microscopy showed inclusion bodies in neuronal processes and degenerating cells. Accumulation of p62 (SQSTM1; 601530) and Lamp2 (309060) were prominent in the brain, suggesting the impairment of autophagosome/lysosome function. This phenotype was different from either V394L/V394L or C -/- alone. Relative to V394L/V394L mice, 4L;C* mice had diminished GCase protein and activity. Marked increases of glucosylsphingosine (GS) and moderate elevation of glucosylceramide (GC) were found in 4L;C* brains. Visceral tissues had increases of GS and GC, but no storage cells were found. Neuronal cells in thick hippocampal slices from 4L;C* mice had significantly attenuated long-term potentiation, presumably resulting from substrate accumulation. The 4L;C* mouse mimicked the CNS phenotype and biochemistry of some type 3 (subacute neuronopathic) variants of Gaucher disease.
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