Myoclonic Epilepsy in Gaucher Disease: Genotype-Phenotype Insights from a Rare Patient Subgroup

Park, Joseph K.; Orvisky, Eduard; Tayebi, Nahid; Kaneski, Christine R.; LaMarca, Mary E.; Stubblefield, Barbara; Martin, Brian M.; Schiffmann, Raphael; Sidransky, Ellen

doi:10.1203/01.pdr.0000049515.79882.94

Cited by 98 publications

(75 citation statements)

References 67 publications

(63 reference statements)

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“…Among patients with type 2 GD, recombinant and rare alleles are especially prevalent [Stone et al, 2000b]. In patients with type 3 GD, those primarily manifesting with visceral manifestations often carry c.1448T4C (L444P) and/or c.1504C4T (R463C), while c.680A4G (N188S), c.1246G4A (G377S) and c.1297G4T (V394L) are more commonly seen in patients with myoclonic epilepsy, often together with a null or recombinant allele [Koprivica et al, 2000;Kowarz et al, 2005;Park et al, 2003]. One atypical phenotype, which includes calcification or fibrosis of the cardiac valves, corneal opacities, hydrocephalus, and dysmorphic features, is specifically associated with mutation c.1342G4C (D409 H) [Abrahamov et al, 1995;Chabas et al, 1995;Uyama et al, 1992].…”

Section: Clinical Significancementioning

confidence: 99%

“…Approximately 30 different homozygous genotypes have been reported in the literature (Table 2). There is clearly a dosage effect with some alleles, such as c.354G4C (K79N), c.680A4G (N188S) or c.1246G4A (G377S), where homozygosity for the mutation results in type 1 disease, while compound heterozygosity with a null allele leads to a type 3 phenotype [Germain et al, 1998;Kim et al, 1996;Park et al, 2003;Zhao et al, 2003a]. Likewise, individuals homozygous for c.754T4A (F213I) or c.1448T4C (L444P) usually develop chronic neuronopathic GD [Ida et al, 1996;Koprivica et al, 2000], but either mutation together with a null allele is more likely to have a type 2 phenotype [Stone et al, 2000b].…”

Section: Clinical Significancementioning

confidence: 99%

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Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

et al. 2008

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Communicated by William S. SlyGaucher disease (GD) is an autosomal recessive disorder caused by the deficiency of glucocerebrosidase, a lysosomal enzyme that catalyses the hydrolysis of the glycolipid glucocerebroside to ceramide and glucose. Lysosomal storage of the substrate in cells of the reticuloendothelial system leads to multisystemic manifestations, including involvement of the liver, spleen, bone marrow, lungs, and nervous system. Patients with GD have highly variable presentations and symptoms that, in many cases, do not correlate well with specific genotypes. Almost 300 unique mutations have been reported in the glucocerebrosidase gene (GBA), with a distribution that spans the gene. These include 203 missense mutations, 18 nonsense mutations, 36 small insertions or deletions that lead to either frameshifts or in-frame alterations, 14 splice junction mutations, and 13 complex alleles carrying two or more mutations in cis. Recombination events with a highly homologous pseudogene downstream of the GBA locus also have been identified, resulting from gene conversion, fusion, or duplication. In this review we discuss the spectrum of GBA mutations and their distribution in the patient population, evolutionary conservation, clinical presentations, and how they may affect the structure and function of glucocerebrosidase.

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Section: Clinical Significancementioning

confidence: 99%

Section: Clinical Significancementioning

confidence: 99%

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

et al. 2008

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“…Brazilians with SCD have a higher prevalence of the CAR haplotype compared with African Americans. This haplotype is associated with lower levels of HbF than other haplotypes [4,5]. Patients with sickle cell anemia were heterozygous or homozygous for the CAR haplotype chromosome or lacked a CAR haplotype chromosome; HbSC disease patients had or did not have a CAR haplotype chromosome.…”

Section: Genetic Modulation Of Hbf In Brazilians With Hbsc Disease Anmentioning

confidence: 99%

“…Unlike N370S, the G377S mutation is rare and usually seen in patients of Portuguese and Spanish descent [1] and is also seen in type 3 GD (neuropathic GD) [5]. The N370S (c.1226A>G) and G377S (c.1246G>A) mutations are known mutations [3], but to our knowledge, G377S (c.1246G>T) has not been previously described.…”

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confidence: 99%

Novel G377S (c.1246G>T) mutation associated with Gaucher disease type 1

et al. 2013

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To the editor: My father, Kenneth M. Moser, MD, was a pioneer in pulmonary medicine. His passion and best known work was in pulmonary vascular diseases, but he also underlined the importance of invasive diagnostics in approaching acute diffuse pulmonary infiltrates [1]. After spending decades hearing about his efforts to save the lives of those suffering from pulmonary diseases, it never occurred to me that I would almost die from a serious respiratory illness.Diagnosed with myelofibrosis in 2009, my body has been afflicted by all the attendant symptoms including anemia, thrombocytopenia, splenomegaly, hepatomegaly, rashes, night sweats, bone pain, and extramedullary hematopoiesis (EMH) [2]. In the attentive care of my doctor and his team at the Mayo Clinic, my course of treatment had been fairly straightforward. As my disease became more aggressive, routine surveillance was supplanted by the use of experimental drugs. It was not until I developed acute respiratory distress syndrome (ARDS) in January 2013 that the direction my treatment should take became unclear.I was already in the hospital regaining strength from a challenging series of surgeries to evacuate a spontaneous retroperitoneal hematoma when my oxygen saturation level began to plummet. Despite never needing oxygen before, within a matter of days, I needed 4 L of oxygen to maintain saturation in the mid-90s. I was moved to the intensive care unit and given nebulizer treatments with little effect. The regular nasal cannula was soon replaced by a humidified high pressure nasal cannula which quickly gave way to a continuous positive airway pressure. On chest films, pleural effusion, atelectasis, and infiltrates consistent with pneumonia were detected. I received high doses of antibiotics and prednisone, however, my condition continued to deteriorate. A subsequent bronchoscopy revealed diffuse alveolar hemorrhage. I was put on a ventilator. As Friday evening set in, an array of determined Mayo Clinic doctors from multiple disciplines convened to solve the riddle of the source of my ARDS and develop a treatment strategy.My hematologist hypothesized that pulmonary EMH was responsible for my acute deterioration, a rare and infrequently reported complication of advanced myelofibrosis, however, to him the most parsimonious explanation for the ARDS [3]. He advocated for a bone marrow scan that confirmed the suspected diagnosis and 2 hours after the bone marrow scan, I received a 100-cGy dose of radiation to my lungs [4]. On Tuesday morning, four days after the radiation, my lungs had cleared enough to take me off the ventilator. Later that afternoon, I was sitting in a chair, relishing several cups of sherbet. The next day, I took a walker assisted stroll around the unit. Two days after being extubated, I was moved from to a general floor where my recovery progressed at a steady pace. It has been three months since that single dose of radiation to my lungs saved my life. I am home now, I have a good quality of life and with my doctor's help, I will do my best t...

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“…Studies of genotype/phenotype correlation in this disorder increasingly implicate the contribution of genetic modifiers (Dipple and McCabe2000;Koprivica et al 2000;Park et al 2003). The region of chromosome 1q21 encompassing the human glucocerebrosidase gene (GBA) is particularly gene rich, with seven genes and two pseudogenes located within 85 kb of sequence (Long et al 1996;Winfield et al 1997).…”

Section: Introductionmentioning

confidence: 99%

A novel alteration in metaxin 1, F202L, is associated with N370S in Gaucher disease

et al. 2004

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The gene for glucocerebrosidase (GBA), the enzyme deficient in Gaucher disease, is located in a generich region on 1q21. Metaxin 1(MTX1) is a convergently transcribed gene contiguous to the 3¢ end of the GBA pseudogene. A single nucleotide alteration in MTX1, 628T fi C, resulting in the amino acid change F202L, was identified in patients with Gaucher disease in association with the common N370S mutation inGBA. The polymorphism was also present on 4.6% of 152 control alleles, but could have functional consequences that have a modifying role in Gaucher disease.

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Myoclonic Epilepsy in Gaucher Disease: Genotype-Phenotype Insights from a Rare Patient Subgroup

Cited by 98 publications

References 67 publications

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

Novel G377S (c.1246G>T) mutation associated with Gaucher disease type 1

A novel alteration in metaxin 1, F202L, is associated with N370S in Gaucher disease

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