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Variable phenotype and severity of sialidosis expressed in two siblings presenting with ataxia and macular cherry-red spots
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Case Reports / Journal of Clinical Neuroscience 20 (2013) 1327–1328
Variable phenotype and severity of sialidosis expressed in two siblings presenting with ataxia and macular cherry-red spots Wladimir Bocca Vieira de Rezende Pinto, Paulo Victor Sgobbi de Souza, José Luiz Pedroso ⇑, Orlando G.P. Barsottini Department of Neurology, Ataxia Unit, Universidade Federal de São Paulo, Rua Botucatu, 740, Vila Clementino, São Paulo 04023-900, Brazil
a r t i c l e
i n f o
Article history: Received 25 September 2012 Accepted 3 December 2012
Keywords: Clinical variability Macular cherry-red spots Neuraminidase deficiency Sialidosis
a b s t r a c t Sialidosis is a rare lysosomal storage disease with a wide clinical spectrum ranging from nearly asymptomatic to severe presentations. We present two Brazilian siblings with sialidosis, the first patient with sialidosis type I, and the second with sialidosis type II. Our report reinforces the relevance of ophthalmologic evaluation in patients with early and late-onset ataxias, if an association with myoclonus or dysmorphic features is present or not. Also, we demonstrate that sialidosis might represent a single genetic entity with variable clinical expression through these two siblings.
1. Introduction Sialidosis is a lysosomal storage disorder of sialic acid-rich glycopeptides and oligosaccharides as a consequence of neuraminidase deficiency. There is a wide clinical spectrum ranging from nearly asymptomatic to severe presentations.1 We describe two Brazilian siblings with sialidosis: the first patient with sialidosis type I, and the second with sialidosis type II. 2. Case report 2.1. Patient 1 A 27-year-old woman, the daughter of non-consanguineous parents, presented to our hospital with a 4 year history of progressive gait ataxia, evolving to slurred speech and dysphagia. Neurological examination showed ataxic gait, dysmetria of the upper limbs, hyperreflexia, horizontal nystagmus and dysarthria. Fundoscopy examination disclosed bilateral macular cherry-red spots (Fig. 1). She had completed high school and her cognition was normal. Brain MRI revealed moderate global cerebral atrophy. Hexosaminidase was normal. Bone marrow biopsy excluded storage diseases. Skin biopsy with cultured fibroblasts demonstrated very low neuraminidase activity levels at 4.1 nmol/h/mg (normal range, 30–38 nmol/h/mg), and normal beta-galactosidase and alpha-iduronidase levels. Sialidosis type I was diagnosed. 2.2. Patient 2 A 30-year-old woman, sister of Patient 1, presented to our hospital with a history of myoclonic seizures since age 17, followed by dysphagia and dysphonia. There was a marked delayed in motor and cognitive functions since childhood. Her cognitive and motor skills had worsened over the last 10 years, and she was currently restricted to bed. She had only achieved an elementary school education. A cognitive assessment was not possible because the patient was bedridden and had an advanced degree of mental deficiency. She had a high forehead and low-set ears, global muscle ⇑ Corresponding author. Tel.: +55 11 5576 4000. E-mail address: [email protected] (J.L. Pedroso).
Ó 2013 Elsevier Ltd. All rights reserved.
atrophy, vertical bilateral ophthalmoparesis, lower limb spasticity, and facial and limb myoclonic jerks. Fundoscopy examination showed bilateral macular cherry-red spots, but no other ocular abnormalities were identified. General blood tests, metabolic evaluation and hexosaminidase were normal. There was no hepatosplenomegaly or splenomegaly. A bone marrow biopsy excluded storage diseases. Brain MRI showed moderate diffuse cerebral atrophy. Other congenital errors of metabolism investigated during her childhood, such as mucopolysaccharidosis, were excluded. Sialidosis type II was suspected.
3. Discussion Sialidosis or mucolipidosis type I (MIM 256550) represents a rare autosomal recessive disorder, resulting from alpha-N-acetylneuraminidase deficiency caused by a mutation in the neuraminidase gene (NEU), located on 6p21.33, giving rise to abnormal intracellular accumulation of sialyloligosaccharides. A definitive diagnosis is reached when a mutation in the NEU gene is identified, or when a deficiency of neuraminidase activity in leukocytes and cultured fibroblasts is identified through skin biopsy.1,2 Neuraminidase deficiency may present as at least five different diseases entities: (1) primary neuraminidase deficiency without dysmorphism (sialidosis type I); (2) primary neuraminidase deficiency with dysmorphism – congenital form; (3) primary neuraminidase deficiency with dysmorphism – childhood onset (sialidosis type II); (4) combined neuraminidase and galactosidase deficiency – infantile onset (infantile galactosialidosis); or (5) combined neuraminidase and galactosidase deficiency – juvenile or adult onset (juvenile and adult galactosialidosis).1 There is a wide range of clinical manifestations expressed by sialidosis type I and type II, as demonstrated in our patients. Sialidosis type I is a later-onset and less severe disease, with patients frequently developing cerebellar ataxia, myoclonic epilepsy, myoclonus, and macular cherry-red spots. Varying degrees of hypotonia, hyperreflexia, nystagmus, slurred speech and visual disturbances may occur. Sialidosis type II has an earlier onset and is more severe. Somatic and dysmorphic features are prominent, including hepatosplenomegaly, dysostosis multiplex, periosteal cloaking, coarse facies, macroglossia, high forehead, anteverted nares, cataracts, mental retardation, myoclonus, seizures, ataxia, hypotonia and car-
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Case Reports / Journal of Clinical Neuroscience 20 (2013) 1327–1328
Fig. 1. Fundoscopy examination showing bilateral macular cherry-red spots in Patient 1. (This figure is available in colour at www.sciencedirect.com)
diomyopathy. Neuroimaging shows varying degrees of brain and cerebellar atrophy. Treatment remains limited to palliative care.3,4 In general, there is a close correlation between the residual activity of the mutant enzymes and the clinical severity of the disease. Bonten et al. described 11 patients with sialidosis in 2000, and found that patients with the severe infantile type II disease had catalytic inactive neuraminidase, while patients with the mild type I disease had catalytic active neuraminidase.5 In this study, the patients with a higher residual neuraminidase activity had milder symptoms and a longer lifespan.5 Although residual neuraminidase may influence the clinical phenotype and disease severity, our report does not support this hypothesis, as our patient with type I disease and mild symptoms had very low neuraminidase activity levels. Special attention should be given to ophthalmologic evaluation in patients with early-onset ataxia. Fundoscopy may show the classical macular cherry-red spot (or ‘‘perifoveal white patch’’), resulting from the storage and depositing of sphingolipids and oligosaccharides in the retinal ganglionic cells of the macula. This phenomenon is a classical marker for sialidosis but also may be seen in other neurological diseases, such as GM1 gangliosidosis, hexosaminidase deficiency, Niemann-Pick disease and Gaucher disease.6 doi:http://dx.doi.org/10.1016/j.jocn.2012.12.014
Overall, our report reinforces the relevance of ophthalmologic evaluation in patients with early and late-onset ataxias, with, and even without, associated myoclonus or dysmorphic features. Also, we demonstrate with the presentation of two siblings that sialidosis might represent a single genetic entity with variable clinical expression.
References 1. Young ID, Young EP, Mossman J, et al. Neuraminidase deficiency: case report and review of the phenotype. J Med Genet 1987;24:283–90. 2. Seyrantepe V, Poupetova H, Froissart R, et al. Molecular pathology of NEU1 gene in sialidosis. Hum Mutat 2003;22:343–52. 3. Palmeri S, Villanova M, Malandrini A, et al. Type I sialidosis: a clinical, biochemical and neuroradiological study. Eur Neurol 2000;43:88–94. 4. Rodríguez Criado G, Pshezhetsky AV, Rodriguez Becarra A, et al. Clinical variability of type II sialidosis by C808T mutation. Am J Med Genet A 2003;116A:368–71. 5. Bonten EJ, Arts WF, Beck M, et al. Novel mutations in lysosomal neuraminidase identify functional domains and determine clinical severity in sialidosis. Hum Mol Genet 2000;9:2715–25. 6. Leavitt JA, Kotagal S. The ‘‘cherry red’’ spot. Pediatr Neurol 2007;37:74–5.
Case Reports / Journal of Clinical Neuroscience 20 (2013) 1327–1328
Variable phenotype and severity of sialidosis expressed in two siblings presenting with ataxia and macular cherry-red spots Wladimir Bocca Vieira de Rezende Pinto, Paulo Victor Sgobbi de Souza, José Luiz Pedroso ⇑, Orlando G.P. Barsottini Department of Neurology, Ataxia Unit, Universidade Federal de São Paulo, Rua Botucatu, 740, Vila Clementino, São Paulo 04023-900, Brazil
a r t i c l e
i n f o
Article history: Received 25 September 2012 Accepted 3 December 2012
Keywords: Clinical variability Macular cherry-red spots Neuraminidase deficiency Sialidosis
a b s t r a c t Sialidosis is a rare lysosomal storage disease with a wide clinical spectrum ranging from nearly asymptomatic to severe presentations. We present two Brazilian siblings with sialidosis, the first patient with sialidosis type I, and the second with sialidosis type II. Our report reinforces the relevance of ophthalmologic evaluation in patients with early and late-onset ataxias, if an association with myoclonus or dysmorphic features is present or not. Also, we demonstrate that sialidosis might represent a single genetic entity with variable clinical expression through these two siblings.
1. Introduction Sialidosis is a lysosomal storage disorder of sialic acid-rich glycopeptides and oligosaccharides as a consequence of neuraminidase deficiency. There is a wide clinical spectrum ranging from nearly asymptomatic to severe presentations.1 We describe two Brazilian siblings with sialidosis: the first patient with sialidosis type I, and the second with sialidosis type II. 2. Case report 2.1. Patient 1 A 27-year-old woman, the daughter of non-consanguineous parents, presented to our hospital with a 4 year history of progressive gait ataxia, evolving to slurred speech and dysphagia. Neurological examination showed ataxic gait, dysmetria of the upper limbs, hyperreflexia, horizontal nystagmus and dysarthria. Fundoscopy examination disclosed bilateral macular cherry-red spots (Fig. 1). She had completed high school and her cognition was normal. Brain MRI revealed moderate global cerebral atrophy. Hexosaminidase was normal. Bone marrow biopsy excluded storage diseases. Skin biopsy with cultured fibroblasts demonstrated very low neuraminidase activity levels at 4.1 nmol/h/mg (normal range, 30–38 nmol/h/mg), and normal beta-galactosidase and alpha-iduronidase levels. Sialidosis type I was diagnosed. 2.2. Patient 2 A 30-year-old woman, sister of Patient 1, presented to our hospital with a history of myoclonic seizures since age 17, followed by dysphagia and dysphonia. There was a marked delayed in motor and cognitive functions since childhood. Her cognitive and motor skills had worsened over the last 10 years, and she was currently restricted to bed. She had only achieved an elementary school education. A cognitive assessment was not possible because the patient was bedridden and had an advanced degree of mental deficiency. She had a high forehead and low-set ears, global muscle ⇑ Corresponding author. Tel.: +55 11 5576 4000. E-mail address: [email protected] (J.L. Pedroso).
Ó 2013 Elsevier Ltd. All rights reserved.
atrophy, vertical bilateral ophthalmoparesis, lower limb spasticity, and facial and limb myoclonic jerks. Fundoscopy examination showed bilateral macular cherry-red spots, but no other ocular abnormalities were identified. General blood tests, metabolic evaluation and hexosaminidase were normal. There was no hepatosplenomegaly or splenomegaly. A bone marrow biopsy excluded storage diseases. Brain MRI showed moderate diffuse cerebral atrophy. Other congenital errors of metabolism investigated during her childhood, such as mucopolysaccharidosis, were excluded. Sialidosis type II was suspected.
3. Discussion Sialidosis or mucolipidosis type I (MIM 256550) represents a rare autosomal recessive disorder, resulting from alpha-N-acetylneuraminidase deficiency caused by a mutation in the neuraminidase gene (NEU), located on 6p21.33, giving rise to abnormal intracellular accumulation of sialyloligosaccharides. A definitive diagnosis is reached when a mutation in the NEU gene is identified, or when a deficiency of neuraminidase activity in leukocytes and cultured fibroblasts is identified through skin biopsy.1,2 Neuraminidase deficiency may present as at least five different diseases entities: (1) primary neuraminidase deficiency without dysmorphism (sialidosis type I); (2) primary neuraminidase deficiency with dysmorphism – congenital form; (3) primary neuraminidase deficiency with dysmorphism – childhood onset (sialidosis type II); (4) combined neuraminidase and galactosidase deficiency – infantile onset (infantile galactosialidosis); or (5) combined neuraminidase and galactosidase deficiency – juvenile or adult onset (juvenile and adult galactosialidosis).1 There is a wide range of clinical manifestations expressed by sialidosis type I and type II, as demonstrated in our patients. Sialidosis type I is a later-onset and less severe disease, with patients frequently developing cerebellar ataxia, myoclonic epilepsy, myoclonus, and macular cherry-red spots. Varying degrees of hypotonia, hyperreflexia, nystagmus, slurred speech and visual disturbances may occur. Sialidosis type II has an earlier onset and is more severe. Somatic and dysmorphic features are prominent, including hepatosplenomegaly, dysostosis multiplex, periosteal cloaking, coarse facies, macroglossia, high forehead, anteverted nares, cataracts, mental retardation, myoclonus, seizures, ataxia, hypotonia and car-
1328
Case Reports / Journal of Clinical Neuroscience 20 (2013) 1327–1328
Fig. 1. Fundoscopy examination showing bilateral macular cherry-red spots in Patient 1. (This figure is available in colour at www.sciencedirect.com)
diomyopathy. Neuroimaging shows varying degrees of brain and cerebellar atrophy. Treatment remains limited to palliative care.3,4 In general, there is a close correlation between the residual activity of the mutant enzymes and the clinical severity of the disease. Bonten et al. described 11 patients with sialidosis in 2000, and found that patients with the severe infantile type II disease had catalytic inactive neuraminidase, while patients with the mild type I disease had catalytic active neuraminidase.5 In this study, the patients with a higher residual neuraminidase activity had milder symptoms and a longer lifespan.5 Although residual neuraminidase may influence the clinical phenotype and disease severity, our report does not support this hypothesis, as our patient with type I disease and mild symptoms had very low neuraminidase activity levels. Special attention should be given to ophthalmologic evaluation in patients with early-onset ataxia. Fundoscopy may show the classical macular cherry-red spot (or ‘‘perifoveal white patch’’), resulting from the storage and depositing of sphingolipids and oligosaccharides in the retinal ganglionic cells of the macula. This phenomenon is a classical marker for sialidosis but also may be seen in other neurological diseases, such as GM1 gangliosidosis, hexosaminidase deficiency, Niemann-Pick disease and Gaucher disease.6 doi:http://dx.doi.org/10.1016/j.jocn.2012.12.014
Overall, our report reinforces the relevance of ophthalmologic evaluation in patients with early and late-onset ataxias, with, and even without, associated myoclonus or dysmorphic features. Also, we demonstrate with the presentation of two siblings that sialidosis might represent a single genetic entity with variable clinical expression.
References 1. Young ID, Young EP, Mossman J, et al. Neuraminidase deficiency: case report and review of the phenotype. J Med Genet 1987;24:283–90. 2. Seyrantepe V, Poupetova H, Froissart R, et al. Molecular pathology of NEU1 gene in sialidosis. Hum Mutat 2003;22:343–52. 3. Palmeri S, Villanova M, Malandrini A, et al. Type I sialidosis: a clinical, biochemical and neuroradiological study. Eur Neurol 2000;43:88–94. 4. Rodríguez Criado G, Pshezhetsky AV, Rodriguez Becarra A, et al. Clinical variability of type II sialidosis by C808T mutation. Am J Med Genet A 2003;116A:368–71. 5. Bonten EJ, Arts WF, Beck M, et al. Novel mutations in lysosomal neuraminidase identify functional domains and determine clinical severity in sialidosis. Hum Mol Genet 2000;9:2715–25. 6. Leavitt JA, Kotagal S. The ‘‘cherry red’’ spot. Pediatr Neurol 2007;37:74–5.