Abstract
Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, presents with a wide spectrum of manifestations. Although Gaucher disease has been divided into three clinical types, patients with atypical presentations continue to be recognized. A careful phenotypic and genotypic assessment of patients with unusual symptoms may help define factors that modify phenotype in this disorder. One such example is a rare subgroup of patients with type 3 Gaucher disease who develop progressive myoclonic epilepsy. We evaluated 16 patients with myoclonic epilepsy, nine of whom were diagnosed by age 4 y with severe visceral involvement and myoclonus, and seven with a more chronic course, who were studied between ages 22 and 40. All of the patients had abnormal horizontal saccadic eye movements. Fourteen different genotypes were encountered, yet there were several shared alleles, including V394L (seen on two alleles), G377S (seen on three alleles), and L444P, N188S, and recombinant alleles (each found on four alleles). V394L, G377S, and N188S are mutations that have previously been associated with non-neuronopathic Gaucher disease. The spectrum of genotypes differed significantly from other patients with type 3 Gaucher disease, where genotypes L444P/L444P and R463C/null allele predominated. Northern blot studies revealed a normal glucocerebrosidase transcript, whereas Western studies showed that the patients studied lacked the processed 56 kD isoform of the enzyme, consistent with neuronopathic Gaucher disease. Brain autopsy samples from two patients demonstrated elevated levels of glucosylsphingosine, a toxic glycolipid, which could contribute to the development of myoclonus. Thus, although there were certain shared mutant alleles found in these patients, both the lack of a shared genotype and the variability in clinical presentations suggest that other modifiers must contribute to this rare phenotype.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Alfonso P, Cenarro A, Peréz-Calvo JI, Giralt M, Giraldo P, Pocovà M 2001 Mutation prevalence among 51 unrelated Spanish patients with Gaucher disease: identification of 11 novel mutations. Blood Cells Mol Dis 27: 882–891
Grabowski GA, Horowitz M 1997 Gaucher's disease: molecular, genetic, and enzymological aspects. Baillieres Clin Haematol 10: 635–656
Beutler E, Gelbart T 1998 Hematologically important mutations: Gaucher disease. Blood Cells Mol Dis 24: 2–8
Koprivica V, Stone DL, Park JK, Callahan M, Frisch A, Cohen IJ, Tayebi N, Sidransky E 2000 Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease. Am J Hum Genet 66: 1777–1786
Orvisky E, Park JK, Parker A, Walker JM, Martin BM, Stubblefield BK, Uyama E, Tayebi N, Sidransky E 2002 The identification of eight novel glucocerebrosidase mutations in patients with Gaucher disease. Hum Mutation 19: 458–459
Beutler E, Grabowski 2001 Gaucher disease. In: Scriver CR, Beaudet AL, Valle D, Sly WS (eds) The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York, 3635–3668.
Patterson MC, Horowitz M, Abel RB, Currie JN, Yu K-T, Kaneski C, Higgins JJ, O'Neill RR, Dedio P, Pikus A, Brady RO, Barton NW 1993 Isolated horizontal supranuclear gaze palsy as a marker of severe systemic involvement in Gaucher's disease. Neurology 43: 1993–1997
Sidransky E, Bottler A, Stubblefield B, Ginns EI 1994 DNA mutational analysis of type 1 and type 3 Gaucher patients: how well do mutations predict phenotype?. Hum Mutat 3: 25–28
Grabowski GA 2000 Gaucher disease: considerations in prenatal diagnosis. Prenatal Diag 20: 60–62
Neudorfer O, Giladi N, Elstein D, Abrahamov A, Turezkite T, Aghai E, Reches A, Bembi B, Zimran A 1996 Occurrence of Parkinson's syndrome in type I Gaucher disease. QJM 89: 691–694
Tayebi N, Callahan M, Madike V, Stubblefield BK, Orvisky E, Krasnewich D, Fillano JJ, Sidransky E 2001 Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol Genet Metab 73: 313–321
Elstein D, Klutstein MW, Lahad A, Abrahamov A, Hadas-Halpern I, Zimran A 1998 Echocardiographic assessment of pulmonary hypertension in Gaucher's disease. Lancet 351: 1544–1546
Abrahamov A, Elstein D, Gross-Tsur V, Farber B, Glaser Y, Hadas-Halpern I, Ronen S, Tafakjdi M, Horowitz M, Zimran A 1995 Gaucher's disease variant characterized by progressive calcification of heart valves and unique genotype. Lancet 346: 1000–1003
Uyama E, Takahashi K, Owada M, Okamura R, Naito M, Tsuji S, Kawasaki S, Araki S 1992 Hydrocephalus, corneal opacities, deafness, valvular heart disease, deformed toes and leptomeningeal fibrous thickening in adult siblings: a new syndrome associated with glucocerebrosidase deficiency and a mosaic population of storage cells. Acta Neurol Scand 86: 407–420
Stone DL, Tayebi N, Coble C, Ginns EI, Sidransky E 2000 Cardiovascular fibrosis, hydrocephalus, ophthalmoplegia, and visceral involvement in an American child with Gaucher disease. J Med Genet 37: E40
Sidransky E, Sher DM, Ginns EI 1992 Gaucher disease in the neonate: a distinct Gaucher phenotype is analogous to a mouse model created by targeted disruption of the glucocerebrosidase gene. Pediatr Res 32: 494–498
Stone DL, Tayebi N, Orvisky E, Stubblefield B, Madike V, Sidransky E 2000 Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease. Hum Mutat 15: 181–188
Frederickson DS, Sloan HR 1975 Glucosylceramide lipidoses: Gaucher's disease. In: Stanbury JB, Wyngaarden JB, Frederickson DS (eds) The Metabolic Basis of Inherited Disease. McGraw-Hill, New York, 730–759.
Cogan DG, Chu FC, Reingold D, Barranger J 1981 Ocular motor signs in some metabolic disease. Arch Ophthalmol 99: 1802–1808
Sidransky E, Tsuji S, Stubblefield BK, Currie J, FitzGibbon EJ, Ginns EI 1992 Gaucher patients with oculomotor abnormalities do not have a unique genotype. Clin Genet 41: 1–5
King J 1975 Progressive myoclonic epilepsy due to Gaucher's disease in an adult. J Neuro Neurosurg Psychiatry 38: 849–854
Winkleman MD, Banker BQ, Victor M, Moser HW 1983 Non-infantile neuronopathic Gaucher's disease: a clinicopathologic study. Neurol 33: 994–1008
Neil JF, Glew RH, Peters SP 1979 Familial psychosis and diverse neurologic abnormalities in adult-onset Gaucher's disease. Arch Neurol 36: 95–99
Yoshikawa H, Fueki N, Sasaki M, Sakuragawa N 1991 Uncoupling of blood flow and oxygen metabolism in the cerebellum in type 3 Gaucher disease. Brain Dev 13: 190–192
Seeman PJ, Finckh U, Hoppner J, Lakner V, Liebisch I, Grau G, Rolfs A 1996 Two new missense mutations in a non-Jewish Caucasian family with type 3 Gaucher disease. Neurology 46: 1102–1107
Grover WD, Tucker SH, Wenger DA 1978 Clinical variation in 2 related children with neuronopathic Gaucher disease. Ann Neurol 3: 281–283
Conradi N, Kyllerman M, Mansson JE, Percy AK, Svennorholm L 1991 Late-infantile Gaucher disease in a child with myoclonus and bulbar signs: neuropathological and neurochemical findings. Acta Neuropathol (Berl) 82: 152–157
Dobbelaere D, Sukno S, Defoort-Dhellemmes S, Lamblin MD, Largilliere C 1998 Neurological outcome of a patient with Gaucher disease type III treated by enzymatic replacement therapy. J Inherit Metab Dis 21: 74–76
Verghese J, Goldberg RF, Desnick RJ, Grace ME, Goldman JE, Lee SC, Dickson D, Rapin I 2000 Myoclonus from selective dentate nucleus degeneration in type 3 Gaucher disease. Arch Neurol 57: 389–395
Erickson A 1986 Gaucher disease—Norrbottnian type (III). Neuropaediatric and neurobiological aspects of clinical patterns and treatment. Acta Paediatr Scand Suppl 326: 1–42
Erikson A, Åström M, Månsson JE 1995 Enzyme infusion therapy of the Norrbottnian (type 3) Gaucher disease. Neuropediatrics 26: 205–207
Blom S, Erikson A 1983 Gaucher disease—Norrbottnian type. Neurodevelopmental, neurological, and neurophysiological aspects. Eur J Pediatr 140: 316–322
Stafstrom CE, Tempel BL 2000 Epilepsy genes: the link between molecular dysfunction and pathophysiology. Ment Retard Dev Disabil Res Rev 6: 281–292
Scheffer IE, Berkovic SF 2000 Genetics of the epilepsies. Curr Opin Pediatr 12: 536–542
Delgado-Escueta AV, Ganesh S, Yamakawa K 2001 Advances in the genetics of progressive myoclonus epilepsy. Am J Med Genet 106: 129–138
Wong K, Topalogulu H, Tresser N, Schiffmann R 2000 Dementia with Lewy bodies and Parkinson's disease in a type 1 Gaucher disease patient. J Neuropath Exp Neurol 59: 141
Maniatis T, Fritsch EF, Sambrook J 1989 Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
Tayebi N, Stern H, Dymarskaia I, Herman J, Sidransky E 1996 55-Base pair deletion in certain patients with Gaucher disease complicates screening for common Gaucher alleles. Am J Med Genet 66: 316–319
Tayebi N, Reissner KJ, Lau EK, Stubblefield BK, Klineburgess AC, Martin BM, Sidransky E 1998 Genotypic heterogeneity and phenotypic variation among patients with type 2 Gaucher's disease. Pediatr Res 43: 571–578
Tayebi N, Cushner S, Sidransky E 1996 Differentiation of the glucocerebrosidase gene from pseudogene by long-template PCR: implications for Gaucher disease. Am J Hum Genet 59: 740–741
Tayebi N, Cushner S, Kleijer W, Lau E, Damschroder-Williams PJ, Stubblefield BK, Den Hollander JD, Sidransky E 1997 Prenatal lethality of a homozygous null mutation in the human glucocerebrosidase gene. Am J Med Genet 73: 41–47
Peters SP, Coyle P, Glew RH 1976 Differentiation of beta-glucosidase in human tissues using sodium taurocholate. Arch Biochem Biophys 175: 569–582
Orvisky E, Sidransky E, McKinney CE, LaMarca ME, Samimi R, Krasnewich D, Martin BM, Ginns EI 2000 Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation. Pediatr Res 48: 233–237
Eyal N, Firon N, Wilder S, Kolodny EH, Horowitz M 1991 Three unique base pair changes in a family with Gaucher disease. Hum Genet 87: 328–332
Park JK, Tayebi N, Stubblefield BK, LaMarca ME, MacKenzie JJ, Stone DL, Sidransky E 2002 The E326K mutation and Gaucher disease: mutation or polymorphism?. Clin Genet 61: 32–34
Tayebi N, Park J, Madike V, Sidransky E 2000 Gene rearrangement on 1q21 introducing a duplication of the glucocerebrosidase pseudogene and a metaxin fusion gene. Hum Genet 107: 400–403
Ginns EI, Brady RO, Pirrucello S, Moore C, Sorrell S, Furbish FS, Murray GJ, Tager J, Barranger JA 1982 Mutations of glucocerebrosidase: discrimination of neurologic and non-neurologic phenotypes of Gaucher's disease. Proc Natl Acad Sci U S A 79: 5607–5610
Erickson AH, Ginns EI, Barranger JA 1985 Biosynthesis of the lysosomal enzyme glucocerebrosidase. J Biol Chem 26: 4319–4324
Theophilus BD, Latham T, Grabowski GA, Smith FI 1989 Comparison of RNase A, a chemical cleavage and GC-clamped denaturing gradient gel electrophoresis for the defection of mutations in exon 9 of the human acid beta-glucosidase gene. Nucleic Acids Res 17: 7707–7722
Grace ME, Newman KM, Scheinker V, Berg-Fussman A, Grabowski GA 1994 Analysis of human acid β-glucosidase by site-directed mutagenesis and heterologous expression. J Biol Chem 269: 2283–2291
Beutler E, Gelbart T, Kuhl W, Zimran A, West C 1992 Mutations in Jewish patients with Gaucher disease. Blood 79: 1662–1666
Kim JW, Liou BB, Lai MY, Ponce E, Grabowski GA 1996 Gaucher disease: identification of three new mutations in the Korean and Chinese (Taiwanese) populations. Hum Mutat 7: 214–218
Choy FY, Wong K, Shi HP 1999 Glucocerebrosidase mutations among Chinese neuronopathic and non-neuronopathic Gaucher disease patients. Am J Med Genet 84: 484–486
Laubscher KH, Glew RH, Lee RE, Okinaka RT 1994 Use of denaturing gradient gel electrophoresis to identify mutant sequences in the beta-glucocerebrosidase gene. Hum Mutat 3: 411–415
Amaral O, Larcerda L, Marcao A, Pinto E, Tamagnini G, Sa Miranda MC 1999 Homozygosity for two mild glucocerebrosidase mutations of probable Iberian origin. Clin Genet 56: 100–102
Rothwell JC, Obeso JA, Marsden CD 1984 On the significance of giant somatosensory evoked potentials in cortical myoclonus. J Neurol Neurosurg Psychiatry 47: 33–42
Manganotti P, Tamburin S, Zanette G, Fiaschi A 2001 Hyperexcitable cortical responses in progressive myoclonic epilepsy: a TMS study. Neurology 57: 1793–1799
Garvey MA, Toro C, Goldstein S, Alarescu G, Wiggs EA, Hallet M, Schiffmann R 2001 Somatosensory evoked potentials as a marker of disease burden in type 3 Gaucher disease. Neurology 56: 391–394
Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC 1990 Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 61: 931–937
Pennacchio LA, Lehesjoki AE, Stone NE, Willour VL, Virtaneva K, Miao J, D'Amato E, Ramirez L, Faham M, Koskiniemi M, Warrington JA, Norio R, de la Chapelle A, Cox DR, Myers RM 1996 Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science 271: 1731–1734
International Batten Disease Consortium 1995 Isolation of a novel gene underlying Batten disease, CLN3. Cell 82: 949–957
Minassian BA, Lee JR, Herbrick JA, Huizenga J, Soder S, Mungall AJ, Dunham I, Gardner R, Fong CY, Carpenter S, Jardim L, Satishchandra P, Andermann E, Snead OC, Lopes-Cendes I, Tsui LC, Delgado-Escueta AV, Rouleau GA, Scherer SW 1998 Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet 20: 171–174
Noebels J 2001 The inherited epilepsies. In: Scriver CR, Beaudet AL, Valle D, Sly WS (eds) The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York, 5807–5832.
Tinuper P, Plazzi G, Monari L, Sangiorgi S, Pellissier JF, Cerullo A, Provini F, Capellari S, Baruzzi A, Lugaresi E, Montagna P 1994 Arylsulfatase A pseudodeficiency and Lafora bodies in a patient with progressive myoclonic epilepsy. Epilepsia 35: 332–335
Tsuji S, Choudary PV, Martin BM, Stubblefield BK, Mayor JA, Barranger JA, Ginns EI 1987 A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease. N Engl J Med 316: 570–575
Kawame H, Hasegawa Y, Eto Y, Maekawa K 1992 Rapid identification of mutations in the glucocerebrosidase gene of Gaucher disease patients by analysis of single-strand conformation polymorphisms. Hum Genet 90: 294–296
Sinclair G, Choy FY, Humphries L 1998 A novel complex allele and two new point mutations in type 2 (acute neuronopathic) Gaucher disease. Blood Cells Mol Dis 24: 420–427
He GS, Grace ME, Grabowski GA 1992 Gaucher disease: four rare alleles encoding F213I, F289Y, T323I and P289L in type I variants. Hum Mutat 1: 423–427
Eyal N, Wilder S, Horowitz M 1990 Prevalent and rare mutations among Gaucher patients. Gene 96: 277–283
Beutler E, Gelbart T 1990 Gaucher disease associated with a unique Kpn I restriction site: identification of the amino acid substitution. Ann Hum Genet 54: 149–153
Germain DP, Kaneski CR, Brady RO 2001 Mutation analysis of the acid beta-glucosidase gene in a patient with type 3 Gaucher disease and neutralizing antibody to alglucerase. Mutat Res 483: 89–94
Acknowledgements
The authors thank Dr. Sihoun Hahn, Dr. Jennifer MacKenzie, Dr. Gregory Pastores, and Dr. Erdem Tuzun for their generous contributions of clinical information and samples. We also thank Marie Hall for secretarial assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Park, J., Orvisky, E., Tayebi, N. et al. Myoclonic Epilepsy in Gaucher Disease: Genotype-Phenotype Insights from a Rare Patient Subgroup. Pediatr Res 53, 387–395 (2003). https://doi.org/10.1203/01.PDR.0000049515.79882.94
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.PDR.0000049515.79882.94
This article is cited by
-
A review of type 3 Gaucher disease: unique neurological manifestations and advances in treatment
Acta Neurologica Belgica (2024)
-
The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects
Orphanet Journal of Rare Diseases (2020)
-
A comprehensive monocentric ophthalmic study with Gaucher disease type 3 patients: vitreoretinal lesions, retinal atrophy and characterization of abnormal saccades
Orphanet Journal of Rare Diseases (2019)
-
Progressive myoclonus epilepsy in Gaucher Disease due to a new Gly–Gly mutation causing loss of an Exonic Splicing Enhancer
Journal of Neurology (2019)
-
Biochemical and molecular characterization of adult patients with type I Gaucher disease and carrier frequency analysis of Leu444Pro - a common Gaucher disease mutation in India
BMC Medical Genetics (2018)
