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Adult-onset neuronopathic form of Gaucher's disease: a case report
Parkinsonism and Related Disorders 9 (2003) 261–264 www.elsevier.com/locate/parkreldis
Adult-onset neuronopathic form of Gaucher’s disease: a case report J. Guimara˜esa,*, O. Amaralb, M.C. Sa´ Mirandab a University Department of Neurology, Hospital de Egas Moniz, Rua da Junqueira 126, 1349 019 Lisboa, Portugal Instituto de Gene´tica Me´dica Jacinto Magalha˜es, Unidade de Enzimologia, Unidade de Neurobiologia Gene´tica, IBMG, Universidade do Porto, Porto, Portugal
b
Received 5 February 2002; revised 17 July 2002; accepted 17 July 2002
Abstract We report a patient with Gaucher’s disease (GD) developing prominent neurological abnormalities in adult life confirming the existence of an adult neuronopathic form of GD. In this adult-onset form, an akinetic-rigid syndrome poorly responsive to dopatherapy, supranuclear gaze palsy, myoclonic jerks, seizures, cerebellar ataxia, cognitive and psychotic disturbances are frequent manifestations. The widely used clinical classification seems inadequate since it does not consider this rare form of GD. Until further understanding of the pathogenesis of the disease is achieved it is not possible to predict accurately which patients will or will not have late-onset nervous system involvement. q 2003 Elsevier Science Ltd. All rights reserved. Keywords: Gaucher’s disease; Adult; Parkinsonism; Atypical parkinsonism
1. Introduction Gaucher’s disease (GD) is an autosomal recessive lysosomal glycolipid storage disorder characterized by the accumulation of glucosylceramide in phagocytes due to deficient activity of b-glucocerebrosidase (GBA) (E.C. 3.2.1.45). General findings common to all categories of patients are hepatosplenomegaly, hypersplenism, skeletal disease and, less frequently, primary lung involvement, with Gaucher cells in all the organs involved including the bone marrow. Usually, GD is divided into three types according to the absence or presence of neurological manifestations and the rate of their progression [1]. In type I, neurological symptoms and signs are absent. In type II (infantile, acute neuronopathic), the neurological signs usually become evident before six months, the central nervous system involvement is severe and death occurs normally before the age of two years. Brainstem signs (opisthotonus, strabismus, trismus), horizontal supranuclear gaze palsy (HSGP), regression of psychomotor development, seizures, pyramidal signs, rigidity, laryngeal stridor and dysphagia may be * Corresponding author. Tel.: þ 351-3622091; fax: þ 351-3622091. E-mail address: [email protected] (J. Guimara˜es).
found [2,3]. In type III (juvenile, sub-acute neuronopathic), the neurological manifestations occur in the first or second decade. Type III has a more indolent course and death usually supervenes before adult age. All members of this group have one or more neurological signs including HSGP, myoclonus and generalized tonic –clonic epilepsy, dementia, ataxia or spasticity [3]. Communicating hydrocephalus, sensorineural deafness and leptomeningeal fibrosis were also reported [4,5]. However, there is an accumulating evidence that in a few GD patients, prominent neurological abnormalities may become evident during adult life [6 – 18]. Our present case is an example. 1.1. Case report R.F.L.D., is a 53-year-old white man born to consanguineous (first cousins) parents. His 82-year-old father has asymptomatic GD confirmed by enzymatic assays and genotype analysis. The propositus had a brother who at 13 years of age began with frequent seizures, disequilibrium, ‘gait stiffness’ and died in the fourth decade. GD was not investigated. Another brother 50 years of age refused medical examination. He too had a consanguineous marriage and had a son with epilepsy who died at the age of 16, and a daughter of 20 of whom no clinical information is available.
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J. Guimara˜es et al. / Parkinsonism and Related Disorders 9 (2003) 261–264
R.F.L.D. in his twenties had several episodes of paludism and viral hepatitis during his military life in Africa. Otherwise, he had been a healthy school teacher. At the age of 46, in a routine blood test analysis, thrombocytopenia was found, and at that time he had his first episode of persistent epistaxis. Episodic and moderate osseous pains felt previously for several years as well as protruding abdomen were then interpreted as probable GD manifestations. Subsequent physical examination disclosed splenomegaly and laboratory investigation showed a deficit of GBA in leukocytes and cultural fibroblasts. Genotype analysis revealed homozygozity for G377S confirming the diagnosis of GD. Further analysis by Southern blotting of Ssp I digested genomic DNA indicated the presence of an additional band inherited from the mother. Although the precise origin of such band is unknown, it is likely to result from a recombination event. At the age of 49, a flexed posture, bradykinesia and a small stepped gait was noticed and a diagnosis of Parkinson’s disease was made despite the poor response to conventional anti-parkinsonian therapy. Enzyme replacement therapy (ERT) was then started with Imiglucerase at 60 IU/kg every other week with good systemic response. However, his neurological condition progressively worsened even with high doses of levodopa. Action myoclonous appeared at the age of 50 years. We saw him for the first time last February (after 45th month of ERT) and his medication at that moment was Levodopa plus I.D.C. 1250 mg/day, Clonazepan 1.5 mg/day and Gabapentin 800 mg/day. He was severely akinetic, with tendency to trunk deviation to the right in the sitting position, unable to get up from a chair without help. He walked with a flexed posture, with small and irregular steps, start and turn hesitation and reduction of arms swing. Speech freezing, hypophonia, micrographia, slight resting tremor at the hands and generalized rigidity were also observed, as well as eyelid opening freezing or apraxia, and marked supranuclear ophthalmoparesis in the horizontal and vertical gaze, the down gaze being less affected. Action myoclonus was frequent and severe, particularly during the execution of skilful manual gestures. Memory and visuospatial constructive abilities were impaired without other obvious cognitive dysfunctions. There was no Romberg’s sign and muscle strength, stretch and cutaneous plantar reflexes, co-ordination, sensory functions, fundi and other cranial nerves were normal. The EEG showed some sharp waves or spike and wave complexes over both parietal – occipital regions and abundant generalized discharges of spikes, polyspikes and slow wave complexes. This generalized paroxysmal activity increased in amount with photic stimulation during which eyelid and left upper limb myoclonic jerks were observed. Cranial C.T. scan and MRI were normal. Slit-lamp examination and laboratory studies including thyroid function tests, serum copper and ceruloplasmin were normal.
2. Discussion In this patient the diagnosis of GD is firmly established by a deficiency of b-GBA activity and by DNA analysis. The first clinical manifestations, thrombocytopenia and splenomegaly preceded by osseous pains, appearing in adult age, are suggestive of this being a case of type I GD. This non-neuronopathic form is the most common: more than 99% of the cases are type I, being particularly prevalent among the Ashkenazi Jews [19]. Presentation in type I GD is variable, ranging from onset of symptoms in infancy to asymptomatic disease in octogenarians [20]. The course of the disease is also variable with sudden acceleration at all ages. Even among family members with the same genotype, the severity of the disease may differ [14,21]. Only patients belonging to this category are believed to live beyond the third decade of life [2]. In type I, the nervous system may be secondarily involved as a consequence of systemic disease: conus medullaris syndrome from spontaneous hematomyelia and lumbosacral plexopathies because of coagulopathy; myelopathy, cauda equina syndrome and radiculophaties due to osseous involvement and secondary pathologic fractures [22]. Our patient at first sight does not appear to fit the diagnosis of type I GD, developing signs of central nervous system involvement at the age of 49, unless we speculate the possibility of his suffering from two separate disease entities. The patient’s age of disease onset obviously excludes it from being a type II GD, and despite sharing several neurological signs frequently found in type III (supranuclear gaze palsy, action myoclonous, cognitive impairment) once more the patient’s age of onset rules out such a phenotype. Nevertheless our patient is not unique and sporadic cases of GD have been reported very similar to our case (Table 1). Van Bogaert and Froelich [6] in 1939, drew attention to the possibility of neurological manifestations in GD patients during adulthood. Despite this, only in 1973 was a second report published by Miller et al. [7], describing two GD patients whose neurological symptoms began, respectively, at 29 years of age, with convulsions, cognitive impairment, oculomotor disturbances and cerebellar ataxia; and at 36 years with seizures, cognitive decline, oculomotor abnormalities and cerebellar ataxia. Neurological problems have been reported to manifest from 17 to 55 years of age and frequently include an akinetic-rigid syndrome and just as often co-existing with other neurological manifestations such as supranuclear gaze palsy, myoclonic jerks, convulsions, cerebellar ataxia, and psychotic manifestations [6 –18]. The conclusion is that these patients have a neuronopathic form of GD beginning in adult age, and that the phenotype of this sub-type includes much more than parkinsonian symptomatology and basal ganglia dysfunction.
J. Guimara˜es et al. / Parkinsonism and Related Disorders 9 (2003) 261–264
263
Table 1 Neurologic manifestations in adult patients with Gaucher’s disease Author
Agea
Neurologic manifestations
Van Bogaert and Froehlich [6] Miller et al. [7]
42 29
Rigidity in lower limbs Convulsions, mental deterioration, supranuclear gaze palsy, cerebellar ataxia Convulsions, cognitive decline, supranuclear gaze palsy, cerebellar ataxia Epilepsy, myoclonic jerks, oculomotor abnormalities and mild intellectual impairment (?) Bradimimia, rest tremor, myoclonic jerking, cognitive impairment, acute psychotic episodes Several acute psychotic episodes, convulsions Psychiatric symptoms, bradykinesia, shuffling gait, rigidity, mask-like facies, tremor, dystonia, intellectual deterioration ‘Atypical parkinson syndrome’: unilateral bradykinesia and hemiparesis Seizures, myoclonus, cerebellar ataxia supranuclear gaze palsy Seizures, myoclonus, cerebellar syndrome, supranuclear gaze palsy Bradykinesia, rigidity, tapeto-retinal degeneration Distal tremor, rigidity, akinesia, refractory to levodopa six patients: extrapyramidal signs: tremors, rigidity, bradykinesia, expressionless facies, slurred and monotonous speech, myoclonic jerks (one patient), psychiatric symptoms (two patients) Parkinsonian symptoms Atypical parkinsonian syndrome: hypokinesia, rigidity, tremor, poor response to conventional anti-parkinsonian therapy Parkinsonism: bilateral akinetic-rigid symptoms, poor response to conventional anti-parkinsonian therapy Resting and intention tremor, akinesia, rigidity, gait and postural disturbances, poor response to levodopa; supra nuclear gaze palsy, cognitive decline, myoclonic jerks, pyramidal signs Akinetic-rigid syndrome poorly reactive to levodopa, supranuclear ophtalmoparesis, action myoclonus, mild cognitive impairment
36 King [8]
17
Neil et al. [9]
41 28 55
Sack [10]
46
Winkelman et al. [11] Mckeran et al. [12] Turpin et al. [13]
29 38 37 38
Neudorfer et al. [14]
41–55
Tylki-Szymanska et al. [15] Cormmand et al. [16]
47 40
Machaczka et al. [17]
39
Tayebi et al. [18]
42
Present case
49
a
At onset of neurologic manifestation.
It is not possible at the present time to predict accurately which patients will have late-onset nervous system involvement. Until further understanding of the pathogenesis of the disease is achieved we prefer a clinical classification in which the main division is between nonneuronopathic and neuronopathic [11], but the latter is further sub-divided into infantile, juvenile, and an adult form. Furthermore, our present case is the second GD patient with neurological manifestations to be described as being responsive to ERT at the systemic level but simultaneously demonstrating progressive neurologic deterioration [18]. The good systemic response is probably due to the decrease in the number of activated macrophages, as documented by the reduction chitotriosidase activity (a Gaucher cell marker) from 50-fold to 2-fold the normal value. A preliminary investigation of the possible association of atypical parkinsonian symptoms with GBA genotypes has shown that patients had no genotypes in common [23].
The finding of one case with a complex allele resulting from the fusion between GBA and metaxin suggested the involvement of genes contiguous to GBA [23]. Metaxin is a gene located adjacently to GBA that encodes a protein which is part of an import complex in the outer membrane of the mammalian mitochondrion [24]. More recently, the same group reported that the common N370S mutation, which has always been considered to be neuroprotective, was present in seven of nine patients studied [25]. Mutation G377S, present in homozygosity in the patient here reported, has also previously shown to be potentially neuroprotective [26] therefore suggesting that, as in other cases of GD associated with parkinsonian symptoms, the molecular defect involved has to go beyond the GBA genotype. Further investigation of the possible association of parkinsonian symptoms and alterations in genes contiguous to GBA also needs to be carried out. Recently, the extensive molecular investigation of GBA, metaxin, a-synuclein and parkin genes in a patient with GD and
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parkinsonian symptoms revealed the existence of a rearrangement affecting the metaxin gene locus, thus suggesting the possible involvement of this contiguous gene locus in the appearance of atypical parkinsonian features [18]. It is, however, unclear how this rearrangement contributes to the atypical GD phenotype described. The increasing evidence that GD may occur in adulthood with central nervous system dysfunction suggests a need to reexamine certain gaps in our understanding of the pathogenesis of the disease and in the classification of this group of disorders.
Acknowledgements The authors thank Dr M. Honavar for her valuable comments and help to write the text in English.
References [1] Knudson AG, Kaplan WD. Genetics of the sphingolipidoses. In: Aronson SM, Volk BW, editors. Cerebral sphingolipidoses: a symposium on Tay-Sachs disease and allied disorders. New York: Academic Press; 1962. p. 395–411. [2] Brady RO. Glucosyl ceramide lipidosis. Gaucher’s disease. In: Stanbury JB, Wyngaarden JB, Frederickson DS, editors. The metabolic basis of inherited disease. New York: McGraw-Hill; 1978. p. 731 –46. [3] Patterson MC, Horowitz M, Abel RB, Currie JN, Yu K-T, Kaneski C, Higgins JJ, O’Neill RR, Fedio P, Pikus A, Brady RD, Barton NW. Isolated horizontal supranuclear gaze palsy as a marker of severe systemic involvement in Gaucher’s disease. Neurology 1993;43: 1993–7. [4] Uyama E, Takahashi K, Owada M, Okamura R, Naito M, Tsuji S, Kawasaki S, Araki S. Hydrocephalus, corneal opacities, deafness, valvular heart disease, deformed toes and leptomeningeal fibrous thikening in adult siblings: a new syndrome associated with glucocerebrosidase deficiency and a mosaic population of storage cells. Acta Neurol Scand 1992;86:407 –20. [5] Stone DL, Tayebi N, Coble C, Ginns EI, Sidransky E. Cardiovascular fibrosis, hydrocephalus, ophthalmoplegia, and visceral involvement in an American child with Gaucher’s disease. J Med Genet 2000;37– 40. [6] Van Bogaert L, Froehlich A. Un cas de maladie de Gaucher de l’adulte avec syndrome de Raynaud, pigmentation et rigidite´ du type extrapyramidal aux membres infe´rieurs. Ann Med (Paris) 1939;45: 57–70. [7] Miller JD, McLuer R, Kaufer JN. Gaucher’s disease: neurologic disorder in adult siblings. Ann Int Med 1973;78:883–7. [8] King JO. Progressive myoclonic epilepsy due to Gaucher’s disease in an adult. JNNP 1975;38:849–54. [9] Neil JF, Glew RH, Peters SP. Familial psychosis and diverse neurologic abnormalities in adult-onset Gaucher’s disease. Arch Neurol 1979;36:95–9.
[10] Sack GH. Clinical diversity in Gaucher’s disease. J Hopk Med J 1980; 146:166–70. [11] Winkelman MD, Bauker BQ, Victor M, Moser HW. Non-infantile neuronopathic Gaucher’s disease: a clinico-pathologic study. Neurology 1983;33:994– 1008. [12] Mckeran RD, Bradbury P, Taylor D, Stern G. Neurological involvement in type I (adult) Gaucher’s disease. J Neurol Neurosurg Psychiatry 1985;48:172– 5. [13] Turpin JC, Dubois G, Brice A, Masson M, Nadaud MC, Boutry JM, Schram AW, Tager JM, Baumann N. Parkinsonian symptomatology in a patient with type I (adult) Gaucher’s disease. In: Salvayre R, Douste-Blazyl L, Gatt S, editors. Lipid storage disorders, biological and medical aspects. New York: Plenum Press; 1987. p. 103 –4. [14] Neudorfer O, Giladi N, Elstein D, Abrahamov A, Turezkite T, Aghai E, Reches A, Bembi B, Zimran A. Ocurrence of Parkinson’s syndrome in type I Gaucher disease. Q J Med 1996;89:691–4. [15] Tylki-Szymanska A, Millat G, Maire I, Czartoryska B. Type I and III Gaucher’s disease in Poland: incidence of the most common mutations and phenotypic manifestations. Eur J Hum Genet 1996;4: 334 –7. [16] Cormand B, Grinberg D, Gort L, Chaba´s A, Vilageliu L. Molecular analysis and clinical findings in the spanish Gaucher disease population: putative haplotype of the N370S ancestral chromosome. Hum Mutat 1998;11:295– 305. [17] Machaczka M, Rucinska M, Skotnicki A, Jurczak W. Parkinson’s syndrome preceding clinical manifestation of Gaucher’s disease. Am J Hematol 1999;61:216–9. [18] Tayebi N, Callahan M, Madike V, Stubblefield BK, Orvisky E, Krasnewich D, Fillano JJ, Sidransky E. Gaucher disease and Parkinsonism: a phenotypic and genotypic characterization. Mol Gen Metabol 2001;73:313 –21. [19] Beutler E. Gaucher’s disease. NEJM 1991;325(19):1354–60. [20] Charrow J, Esplin JA, Gribble J, Kaplan P, Kolodny E, Pastores GM, Scott CR, Wappner RS, Weinreb NJ, Wisch JS. Gaucher disease. Recommendations on diagnosis, evaluation and monitoring. Arch Intern Med 1998;158:1754–60. [21] Amaral O, Fortuna AM, Lacerda L, Pinto R, Sa´ Miranda MC. Molecular characterisation of type 1 Gaucher disease families and patients: intrafamilial heterogeneity at the clinical level. J Med Genet 1994;31(5):401– 4. [22] Grewal RP, Doppelt SH, Thompson MA, Katz D, Brady RO, Barton NW. Neurologic complications of nonneuronopathic Gaucher’s disease. Arch Neurol 1991;48:1271 –2. [23] Sidransky E, Tayebi N, Callahan M, Stone D, Madike V, Filiano J, Bembi B, Tylki-Szymanska A, Ginns E. Are genes contiguous to glucocerebrosidase involved in patients with Gaucher disease who have Parkinsonian symptoms? Am J Hum Genet 1999;65(A112):594. [24] Winfield S, Tayebi N, Martin B, Ginns E, Sidransky E. Identification of three additional genes contiguous to the glucocerebrosidase locus on chromossome 1q21: implications for Gaucher disease. Gen Res 1997;7:1020–6. [25] Sidransky E, Tayebi N, Callahan M, Park J, Stubblefield BK. Patients with Gaucher disease and Parkinsonian symptoms do not share a common genotype. Eur J Hum Genet 2001;9(331):P1180. [26] Amaral O, Marca˜o A, Sa´ Miranda MC, Desnick RJ, Grace ME. Gaucher disease: expression and characterization of mild and severe acid beta-glucosidase mutations in Portuguese type 1 patients. Eur J Hum Genet 2000;8(2):95 –102.
Adult-onset neuronopathic form of Gaucher’s disease: a case report J. Guimara˜esa,*, O. Amaralb, M.C. Sa´ Mirandab a University Department of Neurology, Hospital de Egas Moniz, Rua da Junqueira 126, 1349 019 Lisboa, Portugal Instituto de Gene´tica Me´dica Jacinto Magalha˜es, Unidade de Enzimologia, Unidade de Neurobiologia Gene´tica, IBMG, Universidade do Porto, Porto, Portugal
b
Received 5 February 2002; revised 17 July 2002; accepted 17 July 2002
Abstract We report a patient with Gaucher’s disease (GD) developing prominent neurological abnormalities in adult life confirming the existence of an adult neuronopathic form of GD. In this adult-onset form, an akinetic-rigid syndrome poorly responsive to dopatherapy, supranuclear gaze palsy, myoclonic jerks, seizures, cerebellar ataxia, cognitive and psychotic disturbances are frequent manifestations. The widely used clinical classification seems inadequate since it does not consider this rare form of GD. Until further understanding of the pathogenesis of the disease is achieved it is not possible to predict accurately which patients will or will not have late-onset nervous system involvement. q 2003 Elsevier Science Ltd. All rights reserved. Keywords: Gaucher’s disease; Adult; Parkinsonism; Atypical parkinsonism
1. Introduction Gaucher’s disease (GD) is an autosomal recessive lysosomal glycolipid storage disorder characterized by the accumulation of glucosylceramide in phagocytes due to deficient activity of b-glucocerebrosidase (GBA) (E.C. 3.2.1.45). General findings common to all categories of patients are hepatosplenomegaly, hypersplenism, skeletal disease and, less frequently, primary lung involvement, with Gaucher cells in all the organs involved including the bone marrow. Usually, GD is divided into three types according to the absence or presence of neurological manifestations and the rate of their progression [1]. In type I, neurological symptoms and signs are absent. In type II (infantile, acute neuronopathic), the neurological signs usually become evident before six months, the central nervous system involvement is severe and death occurs normally before the age of two years. Brainstem signs (opisthotonus, strabismus, trismus), horizontal supranuclear gaze palsy (HSGP), regression of psychomotor development, seizures, pyramidal signs, rigidity, laryngeal stridor and dysphagia may be * Corresponding author. Tel.: þ 351-3622091; fax: þ 351-3622091. E-mail address: [email protected] (J. Guimara˜es).
found [2,3]. In type III (juvenile, sub-acute neuronopathic), the neurological manifestations occur in the first or second decade. Type III has a more indolent course and death usually supervenes before adult age. All members of this group have one or more neurological signs including HSGP, myoclonus and generalized tonic –clonic epilepsy, dementia, ataxia or spasticity [3]. Communicating hydrocephalus, sensorineural deafness and leptomeningeal fibrosis were also reported [4,5]. However, there is an accumulating evidence that in a few GD patients, prominent neurological abnormalities may become evident during adult life [6 – 18]. Our present case is an example. 1.1. Case report R.F.L.D., is a 53-year-old white man born to consanguineous (first cousins) parents. His 82-year-old father has asymptomatic GD confirmed by enzymatic assays and genotype analysis. The propositus had a brother who at 13 years of age began with frequent seizures, disequilibrium, ‘gait stiffness’ and died in the fourth decade. GD was not investigated. Another brother 50 years of age refused medical examination. He too had a consanguineous marriage and had a son with epilepsy who died at the age of 16, and a daughter of 20 of whom no clinical information is available.
1353-8020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. PII: S 1 3 5 3 - 8 0 2 0 ( 0 2 ) 0 0 0 9 6 - 2
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J. Guimara˜es et al. / Parkinsonism and Related Disorders 9 (2003) 261–264
R.F.L.D. in his twenties had several episodes of paludism and viral hepatitis during his military life in Africa. Otherwise, he had been a healthy school teacher. At the age of 46, in a routine blood test analysis, thrombocytopenia was found, and at that time he had his first episode of persistent epistaxis. Episodic and moderate osseous pains felt previously for several years as well as protruding abdomen were then interpreted as probable GD manifestations. Subsequent physical examination disclosed splenomegaly and laboratory investigation showed a deficit of GBA in leukocytes and cultural fibroblasts. Genotype analysis revealed homozygozity for G377S confirming the diagnosis of GD. Further analysis by Southern blotting of Ssp I digested genomic DNA indicated the presence of an additional band inherited from the mother. Although the precise origin of such band is unknown, it is likely to result from a recombination event. At the age of 49, a flexed posture, bradykinesia and a small stepped gait was noticed and a diagnosis of Parkinson’s disease was made despite the poor response to conventional anti-parkinsonian therapy. Enzyme replacement therapy (ERT) was then started with Imiglucerase at 60 IU/kg every other week with good systemic response. However, his neurological condition progressively worsened even with high doses of levodopa. Action myoclonous appeared at the age of 50 years. We saw him for the first time last February (after 45th month of ERT) and his medication at that moment was Levodopa plus I.D.C. 1250 mg/day, Clonazepan 1.5 mg/day and Gabapentin 800 mg/day. He was severely akinetic, with tendency to trunk deviation to the right in the sitting position, unable to get up from a chair without help. He walked with a flexed posture, with small and irregular steps, start and turn hesitation and reduction of arms swing. Speech freezing, hypophonia, micrographia, slight resting tremor at the hands and generalized rigidity were also observed, as well as eyelid opening freezing or apraxia, and marked supranuclear ophthalmoparesis in the horizontal and vertical gaze, the down gaze being less affected. Action myoclonus was frequent and severe, particularly during the execution of skilful manual gestures. Memory and visuospatial constructive abilities were impaired without other obvious cognitive dysfunctions. There was no Romberg’s sign and muscle strength, stretch and cutaneous plantar reflexes, co-ordination, sensory functions, fundi and other cranial nerves were normal. The EEG showed some sharp waves or spike and wave complexes over both parietal – occipital regions and abundant generalized discharges of spikes, polyspikes and slow wave complexes. This generalized paroxysmal activity increased in amount with photic stimulation during which eyelid and left upper limb myoclonic jerks were observed. Cranial C.T. scan and MRI were normal. Slit-lamp examination and laboratory studies including thyroid function tests, serum copper and ceruloplasmin were normal.
2. Discussion In this patient the diagnosis of GD is firmly established by a deficiency of b-GBA activity and by DNA analysis. The first clinical manifestations, thrombocytopenia and splenomegaly preceded by osseous pains, appearing in adult age, are suggestive of this being a case of type I GD. This non-neuronopathic form is the most common: more than 99% of the cases are type I, being particularly prevalent among the Ashkenazi Jews [19]. Presentation in type I GD is variable, ranging from onset of symptoms in infancy to asymptomatic disease in octogenarians [20]. The course of the disease is also variable with sudden acceleration at all ages. Even among family members with the same genotype, the severity of the disease may differ [14,21]. Only patients belonging to this category are believed to live beyond the third decade of life [2]. In type I, the nervous system may be secondarily involved as a consequence of systemic disease: conus medullaris syndrome from spontaneous hematomyelia and lumbosacral plexopathies because of coagulopathy; myelopathy, cauda equina syndrome and radiculophaties due to osseous involvement and secondary pathologic fractures [22]. Our patient at first sight does not appear to fit the diagnosis of type I GD, developing signs of central nervous system involvement at the age of 49, unless we speculate the possibility of his suffering from two separate disease entities. The patient’s age of disease onset obviously excludes it from being a type II GD, and despite sharing several neurological signs frequently found in type III (supranuclear gaze palsy, action myoclonous, cognitive impairment) once more the patient’s age of onset rules out such a phenotype. Nevertheless our patient is not unique and sporadic cases of GD have been reported very similar to our case (Table 1). Van Bogaert and Froelich [6] in 1939, drew attention to the possibility of neurological manifestations in GD patients during adulthood. Despite this, only in 1973 was a second report published by Miller et al. [7], describing two GD patients whose neurological symptoms began, respectively, at 29 years of age, with convulsions, cognitive impairment, oculomotor disturbances and cerebellar ataxia; and at 36 years with seizures, cognitive decline, oculomotor abnormalities and cerebellar ataxia. Neurological problems have been reported to manifest from 17 to 55 years of age and frequently include an akinetic-rigid syndrome and just as often co-existing with other neurological manifestations such as supranuclear gaze palsy, myoclonic jerks, convulsions, cerebellar ataxia, and psychotic manifestations [6 –18]. The conclusion is that these patients have a neuronopathic form of GD beginning in adult age, and that the phenotype of this sub-type includes much more than parkinsonian symptomatology and basal ganglia dysfunction.
J. Guimara˜es et al. / Parkinsonism and Related Disorders 9 (2003) 261–264
263
Table 1 Neurologic manifestations in adult patients with Gaucher’s disease Author
Agea
Neurologic manifestations
Van Bogaert and Froehlich [6] Miller et al. [7]
42 29
Rigidity in lower limbs Convulsions, mental deterioration, supranuclear gaze palsy, cerebellar ataxia Convulsions, cognitive decline, supranuclear gaze palsy, cerebellar ataxia Epilepsy, myoclonic jerks, oculomotor abnormalities and mild intellectual impairment (?) Bradimimia, rest tremor, myoclonic jerking, cognitive impairment, acute psychotic episodes Several acute psychotic episodes, convulsions Psychiatric symptoms, bradykinesia, shuffling gait, rigidity, mask-like facies, tremor, dystonia, intellectual deterioration ‘Atypical parkinson syndrome’: unilateral bradykinesia and hemiparesis Seizures, myoclonus, cerebellar ataxia supranuclear gaze palsy Seizures, myoclonus, cerebellar syndrome, supranuclear gaze palsy Bradykinesia, rigidity, tapeto-retinal degeneration Distal tremor, rigidity, akinesia, refractory to levodopa six patients: extrapyramidal signs: tremors, rigidity, bradykinesia, expressionless facies, slurred and monotonous speech, myoclonic jerks (one patient), psychiatric symptoms (two patients) Parkinsonian symptoms Atypical parkinsonian syndrome: hypokinesia, rigidity, tremor, poor response to conventional anti-parkinsonian therapy Parkinsonism: bilateral akinetic-rigid symptoms, poor response to conventional anti-parkinsonian therapy Resting and intention tremor, akinesia, rigidity, gait and postural disturbances, poor response to levodopa; supra nuclear gaze palsy, cognitive decline, myoclonic jerks, pyramidal signs Akinetic-rigid syndrome poorly reactive to levodopa, supranuclear ophtalmoparesis, action myoclonus, mild cognitive impairment
36 King [8]
17
Neil et al. [9]
41 28 55
Sack [10]
46
Winkelman et al. [11] Mckeran et al. [12] Turpin et al. [13]
29 38 37 38
Neudorfer et al. [14]
41–55
Tylki-Szymanska et al. [15] Cormmand et al. [16]
47 40
Machaczka et al. [17]
39
Tayebi et al. [18]
42
Present case
49
a
At onset of neurologic manifestation.
It is not possible at the present time to predict accurately which patients will have late-onset nervous system involvement. Until further understanding of the pathogenesis of the disease is achieved we prefer a clinical classification in which the main division is between nonneuronopathic and neuronopathic [11], but the latter is further sub-divided into infantile, juvenile, and an adult form. Furthermore, our present case is the second GD patient with neurological manifestations to be described as being responsive to ERT at the systemic level but simultaneously demonstrating progressive neurologic deterioration [18]. The good systemic response is probably due to the decrease in the number of activated macrophages, as documented by the reduction chitotriosidase activity (a Gaucher cell marker) from 50-fold to 2-fold the normal value. A preliminary investigation of the possible association of atypical parkinsonian symptoms with GBA genotypes has shown that patients had no genotypes in common [23].
The finding of one case with a complex allele resulting from the fusion between GBA and metaxin suggested the involvement of genes contiguous to GBA [23]. Metaxin is a gene located adjacently to GBA that encodes a protein which is part of an import complex in the outer membrane of the mammalian mitochondrion [24]. More recently, the same group reported that the common N370S mutation, which has always been considered to be neuroprotective, was present in seven of nine patients studied [25]. Mutation G377S, present in homozygosity in the patient here reported, has also previously shown to be potentially neuroprotective [26] therefore suggesting that, as in other cases of GD associated with parkinsonian symptoms, the molecular defect involved has to go beyond the GBA genotype. Further investigation of the possible association of parkinsonian symptoms and alterations in genes contiguous to GBA also needs to be carried out. Recently, the extensive molecular investigation of GBA, metaxin, a-synuclein and parkin genes in a patient with GD and
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parkinsonian symptoms revealed the existence of a rearrangement affecting the metaxin gene locus, thus suggesting the possible involvement of this contiguous gene locus in the appearance of atypical parkinsonian features [18]. It is, however, unclear how this rearrangement contributes to the atypical GD phenotype described. The increasing evidence that GD may occur in adulthood with central nervous system dysfunction suggests a need to reexamine certain gaps in our understanding of the pathogenesis of the disease and in the classification of this group of disorders.
Acknowledgements The authors thank Dr M. Honavar for her valuable comments and help to write the text in English.
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