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Pertti Aula - One of the best experts on this subject based on the ideXlab platform.
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free sialic acid storage Salla Disease in sweden
Acta Paediatrica, 2007Co-Authors: Anders Erikson, Pertti Aula, Nina Aula, Janeric ManssonAbstract:UNLABELLED The first 23 patients diagnosed with Salla Disease in Sweden are presented. A high incidence of the "Finnish" R39C mutation, together with genealogical data, indicates that a large proportion of the mutations are of Finnish origin. All patients had pathologically high levels of free sialic acid in urine and in fibroblasts. The clinical picture confirms what has already been reported from Finland, with early psychomotor retardation, ataxia and speech problems. One-third of the patients had epilepsy. CONCLUSIONS Salla Disease is more common in Sweden than supposed. A large proportion of the mutated alleles seem to be of Finnish origin. The clinical picture is the same as that reported from Finland.
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neurocognitive profiles in Salla Disease
Developmental Medicine & Child Neurology, 2004Co-Authors: Liisa E Alajoki, Pertti Aula, Tarja Varho, Kristiina Posti, Tapio KorhonenAbstract:Salla Disease, a free sialic acid storage disorder, is one of the 36 currently known disorders in Finland that form the Finnish Disease heritage. Salla Disease leads to learning disability* with a wide clinical variation. Two main categories of the Disease have been classified: a conventional subtype and a severe subtype with more severe defects. We present detailed neurocognitive profiles of 41 Finnish patients with Salla Disease (19 females, 22 males; age range 11mo to 63y, median 19y). The neurocognitive development of patients with Salla Disease was assessed by psychological and neuropsychological testing. All patients were also examined by a paediatric neurologist and a speech therapist. The characteristic cognitive profile consisted of a lower non-verbal performance (mean developmental age 13mo) compared with linguistic skills (mean developmental age 17mo). In particular, spatial and visual-constructive impairments were typical of these patients. Tactile and visual discrimination of forms was poor. Tasks demanding hand–eye coordination, maintenance of visual attention, and those requiring short-term visual memory and executive skills were performed better. Receptive language skills were notably better compared with expressive speech. The patients’interactive and non-verbal communication skills were quite strong. Another typical pattern with Salla Disease was severe motor disability. After the second decade of life, the decline in these skills was more pronounced than patients’cognitive deterioration. Our results indicate that even though there is a considerable variation in the clinical findings of patients with Salla Disease, the characteristic neurocognitive profile of the Disease can be outlined.
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phenotypic spectrum of Salla Disease a free sialic acid storage disorder
Pediatric Neurology, 2002Co-Authors: Tarja Varho, Pertti Aula, Martin Renlund, Liisa E Alajoki, Tapio Korhonen, Kristiina M Posti, Samuel Nyman, Matti SillanpaaAbstract:Salla Disease (MIM 269920) represents the mildest phenotype among recessively inherited lysosomal-free sialic acid storage disorders. Although the vast majority of Salla Disease patients in Finland share the same founder mutation, R39C in the SLC17A5 gene, there still is a wide clinical variation among mentally retarded, ataxic patients. We evaluated neurologic and neurocognitive findings of Salla Disease in a cross-sectional study of 41 Finnish patients who were 11 months to 63 years of age (median = 19.5 years). The phenotype of Salla Disease could be classified into two main categories. The majority of patients (90%) had so-called conventional phenotype, including a subgroup of seven patients with relatively mild symptoms. All but two patients with conventional phenotype were homozygous for the Finnish founder mutation. Four severely disabled, profoundly mentally retarded patients, 15-28 years of age, clearly could be clinically delineated as a separate group, likely reflecting the underlying compound heterozygous genotype. A typical developmental pattern could be outlined in the conventional type of the Disease, emphasizing a strong motor handicap in Salla Disease. The cognitive profile consisted of better verbal ability, especially speech comprehension, compared with nonverbal functioning in all patients. Our results indicate a partial genotype-phenotype correlation, although factors other than the molecular background are also involved in the phenotypic manifestation of Salla Disease.
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central and peripheral nervous system dysfunction in the clinical variation of Salla Disease
Neurology, 2000Co-Authors: Tarja Varho, Pertti Aula, Pirkko Sonninen, Satu K Jaaskelainen, U Tolonen, L Vainionpaa, Matti SillanpaaAbstract:Objective: To evaluate the degree of possible peripheral nervous system (PNS) involvement in addition to CNS manifestations in Salla Disease, a free sialic acid storage disorder leading to severe mental retardation with a wide clinical variation. Background: Salla Disease is a lysosomal storage disorder that affects the white matter of the CNS. MRI findings and recent 1 H MRS study results provide evidence for delayed central myelination, but there is no previous evidence for PNS involvement in this Disease. The gene coding for a presumptive sialic acid transport protein has recently been identified, and the first Disease-causing mutations have been characterized. Methods: Nerve conduction studies; evoked potentials to visual (VEP), brainstem auditory (BAEP), and somatosensory stimuli (SEP); and EEG were carried out on 22 patients (age range 2 months to 57 years) with biochemically and genetically confirmed Salla Disease. Brain MRI were available on 14 patients. Results: Nerve conduction studies revealed abnormalities in nearly half of the patients (10/21). The four severely disabled patients and the oldest patient had greatly reduced nerve conduction velocities and prolonged distal latencies compatible with demyelinating polyneuropathy. In addition, SEP was abnormal in the majority of the patients, but VEP and BAEP in only a few cases. PNS involvement was clearly associated with both the phenotypic severity and MRI findings. Conclusions: The results indicate that dysmyelination in Salla Disease occurs not only in the CNS but also in the peripheral nervous system, contributing to the phenotypic variation, which can now be correlated with the molecular basis of the Disease.
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a new gene encoding an anion transporter is mutated in sialic acid storage Diseases
Nature Genetics, 1999Co-Authors: Frans W Verheijen, Pertti Aula, Elly Verbeek, Nina Aula, Cecile E M T Beerens, Adrie C Havelaar, Marijke Joosse, Leena Peltonen, H Galjaard, Peter J Van Der SpekAbstract:Sialic acid storage Diseases (SASD, MIM 269920) are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland1,2 (Salla Disease). The main symptoms are hypotonia, cerebellar ataxia and mental retardation; visceromegaly and coarse features are also present in infantile cases3. Progressive cerebellar atrophy and dysmyelination have been documented by magnetic resonance imaging (ref. 4). Enlarged lysosomes are seen on electron microscopic studies and patients excrete large amounts of free sialic acid in urine. A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid5 is impaired in lysosomal membranes from Salla and ISSD patients6. The locus for Salla Disease was assigned to a region of approximately 200 kb on chromosome 6q14–q15 in a linkage study using Finnish families7,8. Salla Disease and ISSD were further shown to be allelic disorders9. A physical map with P1 and PAC clones was constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622, providing the basis for precise physical positioning of the gene10. Here we describe a new gene, SLC17A5 (also known as AST), encoding a protein (sialin) with a predicted transport function that belongs to a family of anion/cation symporters (ACS). We found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla Disease and six different SLC17A5 mutations in six ISSD patients of different ethnic origins. Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage Diseases.
Tarja Varho - One of the best experts on this subject based on the ideXlab platform.
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a 13 year follow up of finnish patients with Salla Disease
Journal of Neurodevelopmental Disorders, 2015Co-Authors: Tarja Varho, Tapio Korhonen, Liisa Paavola, Anne M Remes, Marika J Harila, Kari MajamaaAbstract:Background Salla Disease (SD) is a rare lysosomal storage disorder leading to severe intellectual disability. SD belongs to the Finnish Disease heritage, and it is caused by mutations in the SLC17A5 gene. The aim of the study was to investigate the course of neurocognitive features of SD patients in a long-term follow-up.
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Increased Brain Glucose Utilization in Salla Disease (Free Sialic Acid Storage Disorder)
2015Co-Authors: Hanna Suhonen-polvi, Martin Renlund, Tarja Varho, Leena Haataja, Ulla Ruotsalainen, Merja Haaparanta, Olof Solin, Irma Holopainen, Tuula Manner, Periti AulaAbstract:Salla Disease is an autosomal recessive lysosomal free sialic acid storage disorder characterized by psychomotor retardation and ataxia. MRI studies have revealed evidence of dysmyelin-ation, but the biological mechanism of the brain dysfunction is unknown. Methods: Nine patients with Salla Disease (age 2.5 mo-42 y) presenting the Disease in varying degrees of severity were studied by PET using 2-fluoro-2-deoxy-o-glucose (FDG) as a tracer. Local cerebral metabolic rates for glucose (LCMRGIc) in individual brain regions were compared with controls. Results: The FDG PET results showed significantly increased LCMRGIc values in the frontal and sensorimotor cortex and especially in the basal ganglia of the patients. Cerebellar hypometabolism was present in all seven patients with marked ataxia, whereas the less severely affected patients without obvious ataxia had normal or even high glucose uptake in the cerebellum. Conclusion: The increased cerebral glucose utilization is a constant finding in Salla Disease and may reflect the basic defect of the sialic acid metabolism in this disorder. The FDG PET findings in the cerebellum suggest a correlation between glucose uptake and the severity of the clinical symptoms. Key Words: Salla Disease; PET; fluorodeoxyglucose;cerebral metabolis
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Brain Involvement in Salla Disease
2014Co-Authors: Pirkko Sonninen, Tarja Varho, Taina Autti, Raili RaininkoAbstract:BACKGROUND AND PURPOSE: Our purpose was to document the nature and progression of brain abnormalities in Salla Disease, a lysosomal storage disorder, with MR imaging. METHODS: Fifteen patients aged 1 month to 43 years underwent 26 brain MR examinations. In 10 examinations, signal intensity was measured and compared with that of healthy volun-teers of comparable ages. RESULTS: MR images of a 1-month-old asymptomatic child showed no pathology. In all other patients, abnormal signal intensity was found: on T2-weighted images, the cerebral white matter had a higher signal intensity than the gray matter, except in the internal capsules. In six patients, the white matter was homogeneous on all images. In four patients, the periven-tricular white matter showed a somewhat lower signal intensity; in five patients, a higher signal intensity. In the peripheral cerebral white matter, the measured signal intensity remained at a high level throughout life. No abnormalities were seen in the cerebellar white matter. Atrophic changes, if present, were relatively mild but were found even in the cerebellum and brain stem. The corpus callosum was always thin. CONCLUSION: In Salla Disease, the cerebral myelination process is defective. In some pa-tients, a centrifugally progressive destructive process is also seen in the cerebral white matter. Better myelination in seen in patients with milder clinical symptoms. Salla Disease, first diagnosed in 1979 (1), is a re-cessively inherited lysosomal storage Disease caused by an error in sialic acid metabolism. Free sialic acid accumulates in the lysosomes of various tissues because of a defect in the mechanism of transport across the lysosomal membrane (2, 3). Recently, the gene locus has been found in the long arm of chromosome 6 (4). In patients with Salla Disease, intrauterine growth is normal. The first signs of neurologic ab-normality, usually visible at 3 to 6 months of age, are hypotonia, ataxia, often nystagmus, and always retarded motor development. The main feature is severe psychomotor retardation, but there is wide phenotypic variation. Developmental delay pro-gresses slowly, and deterioration becomes more pronounced during the second or third decade. Lif
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neurocognitive profiles in Salla Disease
Developmental Medicine & Child Neurology, 2004Co-Authors: Liisa E Alajoki, Pertti Aula, Tarja Varho, Kristiina Posti, Tapio KorhonenAbstract:Salla Disease, a free sialic acid storage disorder, is one of the 36 currently known disorders in Finland that form the Finnish Disease heritage. Salla Disease leads to learning disability* with a wide clinical variation. Two main categories of the Disease have been classified: a conventional subtype and a severe subtype with more severe defects. We present detailed neurocognitive profiles of 41 Finnish patients with Salla Disease (19 females, 22 males; age range 11mo to 63y, median 19y). The neurocognitive development of patients with Salla Disease was assessed by psychological and neuropsychological testing. All patients were also examined by a paediatric neurologist and a speech therapist. The characteristic cognitive profile consisted of a lower non-verbal performance (mean developmental age 13mo) compared with linguistic skills (mean developmental age 17mo). In particular, spatial and visual-constructive impairments were typical of these patients. Tactile and visual discrimination of forms was poor. Tasks demanding hand–eye coordination, maintenance of visual attention, and those requiring short-term visual memory and executive skills were performed better. Receptive language skills were notably better compared with expressive speech. The patients’interactive and non-verbal communication skills were quite strong. Another typical pattern with Salla Disease was severe motor disability. After the second decade of life, the decline in these skills was more pronounced than patients’cognitive deterioration. Our results indicate that even though there is a considerable variation in the clinical findings of patients with Salla Disease, the characteristic neurocognitive profile of the Disease can be outlined.
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phenotypic spectrum of Salla Disease a free sialic acid storage disorder
Pediatric Neurology, 2002Co-Authors: Tarja Varho, Pertti Aula, Martin Renlund, Liisa E Alajoki, Tapio Korhonen, Kristiina M Posti, Samuel Nyman, Matti SillanpaaAbstract:Salla Disease (MIM 269920) represents the mildest phenotype among recessively inherited lysosomal-free sialic acid storage disorders. Although the vast majority of Salla Disease patients in Finland share the same founder mutation, R39C in the SLC17A5 gene, there still is a wide clinical variation among mentally retarded, ataxic patients. We evaluated neurologic and neurocognitive findings of Salla Disease in a cross-sectional study of 41 Finnish patients who were 11 months to 63 years of age (median = 19.5 years). The phenotype of Salla Disease could be classified into two main categories. The majority of patients (90%) had so-called conventional phenotype, including a subgroup of seven patients with relatively mild symptoms. All but two patients with conventional phenotype were homozygous for the Finnish founder mutation. Four severely disabled, profoundly mentally retarded patients, 15-28 years of age, clearly could be clinically delineated as a separate group, likely reflecting the underlying compound heterozygous genotype. A typical developmental pattern could be outlined in the conventional type of the Disease, emphasizing a strong motor handicap in Salla Disease. The cognitive profile consisted of better verbal ability, especially speech comprehension, compared with nonverbal functioning in all patients. Our results indicate a partial genotype-phenotype correlation, although factors other than the molecular background are also involved in the phenotypic manifestation of Salla Disease.
Frans W Verheijen - One of the best experts on this subject based on the ideXlab platform.
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Infantile Sialic Acid Storage Disease: Serial Ultrasound and Magnetic Resonance Imaging Features
2015Co-Authors: Cecilia Parazzini, Frans W Verheijen, Grazia M S Mancini, Saverio Arena, Lucrezia Marchetti, Francesca Menni, Mirella Filocamo, Fabio Triulzi, Rossella PariniAbstract:Lysosomal free sialic acid storage Diseases are rare inborn errors of metabolism with autosomal recessive inheritance that are caused by a defect in the lysoso-mal membrane-specific carrier for sialic acid and uronic acids (1). The gene, SLC17A5 (MIM 604322), localized on chromosome 6q14-q15 (2), has recently been identified and sequenced (3). The defective egress of free sialic acid from the lysosome leads to both an excessive store of sialic acid in many tissues and considerable excretion in the urine (4). Cases are classified into two different phenotypes that share the same biochemical abnormality, the most severe being the infantile sialic acid storage Disease (MIM 269920) and the mild one being Salla Disease (MIM 604322). We herein report a case of infantile sialic acid storag
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elevated csf n acetylaspartylglutamate in patients with free sialic acid storage Diseases
Neurology, 2010Co-Authors: Fanny Mochel, Udo F H Engelke, Julie Barritault, B Yang, Nathan Mcneill, Jerry N Thompson, Adeline Vanderver, Nicole I Wolf, Michel A A P Willemsen, Frans W VerheijenAbstract:Mutations in the SLC17A5 gene encoding the lysosomal transporter sialin are associated with the free sialic acid storage Diseases (SASD): Salla Disease (or the Finnish type of sialuria), the more severe infantile free sialic acid storage Disease (ISSD), and intermediate phenotypes with clinical findings of both Salla Disease and ISSD.1 SASD are characterized by the abnormal retention of free sialic acid in the lysosome (Online Mendelian Inheritance in Man 604369 and 269920). Patients with SASD usually present with nystagmus, progressive cerebellar ataxia, spasticity, and severe psychomotor delay. These symptoms are associated with diffuse supratentorial hypomyelination, thin corpus callosum, and cortical and cerebellar atrophy. The increase of free sialic acid in urine has been considered the biochemical hallmark of the Disease.1 However, we have recently reported that patients with SASD can present without sialuria.2 The mechanisms leading to hypomyelination in SASD remain largely unknown. Here, we report the increase of N- acetylaspartylglutamate (NAAG) in the CSF of patients with SASD, which may provide new insight into the pathophysiology of the Disease.
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an italian severe Salla Disease variant associated with a slc17a5 mutation earlier described in infantile sialic acid storage Disease
Clinical Genetics, 2002Co-Authors: Roberta Biancheri, Frans W Verheijen, Elly Verbeek, Andrea Rossi, Roberto Gaggero, L Roccatagliata, R Gatti, Op Van Diggelen, G M S ManciniAbstract:The present study reports two Italian brothers affected by severe Salla Disease (sialic acid storage Disease), a slowly progressive autosomal recessive neurodegenerative disorder prevalent in the Finnish population. Mutations of the SLC17A5 gene, which encodes a protein called sialin, are the primary cause of both Salla Disease and infantile sialic acid storage Disease (ISSD), a clinically distinct severe disorder. All Finnish patients with Salla Disease show a R39C mutation. Both patients showed moderate intellectual disability, spastic ataxic syndrome, hypomyelination and cerebellar atrophy on magnetic resonance imaging (MRI), and lysosomal storage, all typical of Salla Disease. Mutation analysis of the SLC17A5 gene in the younger brother revealed no R39C mutation, but a 15-bp deletion in exon 6 on one of the alleles. This mutation is the same described in French-Canadian patients with ISSD. Salla Disease must be suspected in patients with unexplained psychomotor retardation associated with ataxia and/or pyramidal symptoms, and MRI findings consistent with cerebral hypomyelination, irrespective of the patient's ethnic origin. A mutation screening based on R39C change does not exclude Salla Disease outside Finland. Conversely, mutations found in ISSD can be expected, even in patients showing the Salla phenotype (e.g. symptoms at the milder end of the spectrum).
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a new gene encoding an anion transporter is mutated in sialic acid storage Diseases
Nature Genetics, 1999Co-Authors: Frans W Verheijen, Pertti Aula, Elly Verbeek, Nina Aula, Cecile E M T Beerens, Adrie C Havelaar, Marijke Joosse, Leena Peltonen, H Galjaard, Peter J Van Der SpekAbstract:Sialic acid storage Diseases (SASD, MIM 269920) are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland1,2 (Salla Disease). The main symptoms are hypotonia, cerebellar ataxia and mental retardation; visceromegaly and coarse features are also present in infantile cases3. Progressive cerebellar atrophy and dysmyelination have been documented by magnetic resonance imaging (ref. 4). Enlarged lysosomes are seen on electron microscopic studies and patients excrete large amounts of free sialic acid in urine. A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid5 is impaired in lysosomal membranes from Salla and ISSD patients6. The locus for Salla Disease was assigned to a region of approximately 200 kb on chromosome 6q14–q15 in a linkage study using Finnish families7,8. Salla Disease and ISSD were further shown to be allelic disorders9. A physical map with P1 and PAC clones was constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622, providing the basis for precise physical positioning of the gene10. Here we describe a new gene, SLC17A5 (also known as AST), encoding a protein (sialin) with a predicted transport function that belongs to a family of anion/cation symporters (ACS). We found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla Disease and six different SLC17A5 mutations in six ISSD patients of different ethnic origins. Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage Diseases.
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Salla Disease variant in a dutch patient potential value of polymorphonuclear leucocytes for heterozygote detection
European Journal of Pediatrics, 1992Co-Authors: Grazia M S Mancini, Frans W Verheijen, Op Van Diggelen, H C Janse, W J Kleijer, F A Beemer, F G I JennekensAbstract:A Dutch child with psychomotor retardation, impaired speech, ataxia, sialic acid storage and vacuolized skin fibroblasts and lymphocytes was diagnosed as having free sialic acid storage Disease. Slight corneal opacities, pale optic disks at the fundus oculi and vertebral abnormalities, not earlier reported in Salla Disease, were peculiar to this case. Free sialic acid was about tenfold increased in urine and cultured fibroblasts, without changes in the glycoconjugate-bound sialic acid pool. A subsequent pregnancy of the patient's mother was monitored by assay of sialic acid in chorionic villi and amniotic fluid. An unaffected foetus was predicted. Sialic acid was also assayed in peripheral blood total leucoyctes, and in mononuclear and polymorphonuclear (PMN) leucocyte subpopulations. Each of these leucocyte fractions from the patient showed 10- to 30-fold increase in sialic acid content. The PMN subpopulation provided the most restricted range of control values and showed slightly increased values for the patient's parents. These results suggest that the assay of sialic acid in PMN might be useful for the identification of heterozygotes in sialic acid storage Disease. Studies on a larger number of obligate heterozygotes are needed to confirm this observation.
Roberta Biancheri - One of the best experts on this subject based on the ideXlab platform.
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Homozygosity for the p.K136E mutation in the SLC17A5 gene as cause of an Italian severe Salla Disease
Neurogenetics, 2005Co-Authors: Roberta Biancheri, Andrea Rossi, G M S Mancini, H. A. Verbeek, R. Schot, F. Corsolini, S. Assereto, F. W. Verheijen, C. Minetti, M. FilocamoAbstract:Lysosomal free sialic acid storage Diseases are recessively inherited allelic neurodegenerative disorders that include Salla Disease (SD) and infantile sialic acid storage Disease (ISSD) caused by mutations in the SLC17A5 gene encoding for a lysosomal membrane protein, sialin, transporting sialic acid from lysosomes. The classical form of SD, enriched in the Finnish population, is related to the p.R39C designed Salla_FIN founder mutation. A more severe phenotype is due both to compound heterozygosity for the p.R39C mutation and to different mutations. The p.R39C has not been reported in ISSD. We identified the first case of SD caused by the homozygosity for p.K136E (c.406A>G) mutation, showing a severe clinical picture, as demonstrated by the early age at onset, the degree of motor retardation, the occurrence of peripheral nerve involvement, as well as cerebral hypomyelination. Recently, in vitro functional studies have shown that the p.K136E mutant produces a mislocalization and a reduced activity of the intracellular sialin. We discuss the in vivo phenotypic consequence of the p.K136E in relation to the results obtained by the in vitro functional characterization of the p.K136E mutant. The severity of the clinical picture, in comparison with the classical SD, may be explained by the fact that the p.K136E mutation mislocalizes the protein to a greater degree than p.R39C. On the other hand, the presence of a residual transport activity may account for the absence of hepatosplenomegaly, dysostosis multiplex, and early lethality typical of ISSD and related to the abolished transport activity found in this latter form.
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cerebellar white matter involvement in Salla Disease
Neuroradiology, 2004Co-Authors: Roberta Biancheri, Mg Mancini, Antonio Rossi, Carlo MinettiAbstract:Sir, We read with interest the article by Linnankivi et al. [1], in which they report the first Finnish case of Salla Disease (SD) with involvement of the cerebellar white matter. In that paper, they stated that the typical MRI findings of SD are (1) abnormally high T2-signal intensity of cerebral white matter, due to hypomyelination, and (2) hypoplasia of the corpus callosum. Mild cerebral, cerebellar and brainstem atrophy may occur in some severe cases, they said. They go on to remark that, although cerebellar white matter abnormalities had not been reported in previous MRI studies of Finnish cases, they were aware of two British cases with cerebellar white matter involvement, described in the literature [2]. On the basis of these reports, they stated that cerebellar white matter involvement does not exclude the diagnosis of SD. To reinforce the above statement, we would like to point out that we have observed and published a fourth case of SD showing cerebellar white matter involvement [3]. The patient is an Italian boy with a 15 base-pair deletion (802–816) in the exon 6 in one allele of the gene SLC17A5. Interestingly, the typical mutation found in Finnish SD cases (a missense R39C mutation) was not found in our patient, whereas the identified mutation was the same as earlier described in infantile sialicacid-storage Disease. The second mutation has been suggested to lie in a non-coding area of the gene and/or the promotor area. MRI, performed at age 10 years, showed global supratentorial white matter involvement, extreme thinning of the corpus callosum, and hypomyelination of cerebellar folia (Fig. 1). SD is a recessively inherited, lysosomal storage disorder that is relatively common in Finland, with sporadic cases in other countries [4]. The clinical picture is characterized by hypotonia, nystagmus, psychomotor developmental delay, ataxia followed by spasticity, and mental retardation. The accumulation of
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an italian severe Salla Disease variant associated with a slc17a5 mutation earlier described in infantile sialic acid storage Disease
Clinical Genetics, 2002Co-Authors: Roberta Biancheri, Frans W Verheijen, Elly Verbeek, Andrea Rossi, Roberto Gaggero, L Roccatagliata, R Gatti, Op Van Diggelen, G M S ManciniAbstract:The present study reports two Italian brothers affected by severe Salla Disease (sialic acid storage Disease), a slowly progressive autosomal recessive neurodegenerative disorder prevalent in the Finnish population. Mutations of the SLC17A5 gene, which encodes a protein called sialin, are the primary cause of both Salla Disease and infantile sialic acid storage Disease (ISSD), a clinically distinct severe disorder. All Finnish patients with Salla Disease show a R39C mutation. Both patients showed moderate intellectual disability, spastic ataxic syndrome, hypomyelination and cerebellar atrophy on magnetic resonance imaging (MRI), and lysosomal storage, all typical of Salla Disease. Mutation analysis of the SLC17A5 gene in the younger brother revealed no R39C mutation, but a 15-bp deletion in exon 6 on one of the alleles. This mutation is the same described in French-Canadian patients with ISSD. Salla Disease must be suspected in patients with unexplained psychomotor retardation associated with ataxia and/or pyramidal symptoms, and MRI findings consistent with cerebral hypomyelination, irrespective of the patient's ethnic origin. A mutation screening based on R39C change does not exclude Salla Disease outside Finland. Conversely, mutations found in ISSD can be expected, even in patients showing the Salla phenotype (e.g. symptoms at the milder end of the spectrum).
Marjo S Van Der Knaap - One of the best experts on this subject based on the ideXlab platform.
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magnetic resonance imaging pattern recognition in hypomyelinating disorders
Brain, 2010Co-Authors: Marjan E Steenweg, Susan Blaser, Adeline Vanderver, Nicole I Wolf, Grazia M S Mancini, Alberto Bizzi, Tom J De Koning, Wessel N Van Wieringen, Frederik Barkhof, Marjo S Van Der KnaapAbstract:Hypomyelination is observed in the context of a growing number of genetic disorders that share clinical characteristics. The aim of this study was to determine the possible role of magnetic resonance imaging pattern recognition in distinguishing different hypomyelinating disorders, which would facilitate the diagnostic process. Only patients with hypomyelination of known cause were included in this retrospective study. A total of 112 patients with Pelizaeus–Merzbacher Disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, Pelizaeus–Merzbacher-like Disease, infantile GM1 and GM2 gangliosidosis, Salla Disease and fucosidosis were included. The brain scans were rated using a standard scoring list; the raters were blinded to the diagnoses. Grouping of the patients was based on cluster analysis. Ten clusters of patients with similar magnetic resonance imaging abnormalities were identified. The most important discriminating items were early cerebellar atrophy, homogeneity of the white matter signal on T2-weighted images, abnormal signal intensity of the basal ganglia, signal abnormalities in the pons and additional T2 lesions in the deep white matter. Eight clusters each represented mainly a single disorder (i.e. Pelizaeus–Merzbacher Disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, infantile GM1 and GM2 gangliosidosis, Pelizaeus–Merzbacher-like Disease and fucosidosis); only two clusters contained multiple Diseases. Pelizaeus–Merzbacher-like Disease was divided between two clusters and Salla Disease did not cluster at all. This study shows that it is possible to separate patients with hypomyelination disorders of known cause in clusters based on magnetic resonance imaging abnormalities alone. In most cases of Pelizaeus–Merzbacher Disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, Pelizaeus–Merzbacher-like Disease, infantile GM1 and GM2 gangliosidosis and fucosidosis, the imaging pattern gives clues for the diagnosis.
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magnetic resonance imaging pattern recognition in hypomyelinating disorders
Brain, 2010Co-Authors: Marjan E Steenweg, Nicole I Wolf, Grazia M S Mancini, Tom J De Koning, Adeline Vanderve, Susa Lase, Alberto Izzi, Wessel N Van Wieringe, Frederik Arkhof, Marjo S Van Der KnaapAbstract:Hypomyelination is observed in the context of a growing number of genetic disorders that share clinical characteristics. The aim of this study was to determine the possible role of magnetic resonance imaging pattern recognition in distinguishing different hypomyelinating disorders, which would facilitate the diagnostic process. Only patients with hypomyelination of known cause were included in this retrospective study. A total of 112 patients with Pelizaeus-Merzbacher Disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, Pelizaeus-Merzbacher-like Disease, infantile GM1 and GM2 gangliosidosis, Salla Disease and fucosidosis were included. The brain scans were rated using a standard scoring list; the raters were blinded to the diagnoses. Grouping of the patients was based on cluster analysis. Ten clusters of patients with similar magnetic resonance imaging abnormalities were identified. The most important discriminating items were early cerebellar atrophy, homogeneity of the white matter signal on T2-weighted images, abnormal signal intensity of the basal ganglia, signal abnormalities in the pons and additional T2 lesions in the deep white matter. Eight clusters each represented mainly a single disorder (i.e. Pelizaeus-Merzbacher Disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, infantile GM1 and GM2 gangliosidosis, Pelizaeus-Merzbacher-like Disease and fucosidosis); only two clusters contained multiple Diseases. Pelizaeus-Merzbacher-like Disease was divided between two clusters and Salla Disease did not cluster at all. This study shows that it is possible to separate patients with hypomyelination disorders of known cause in clusters based on magnetic resonance imaging abnormalities alone. In most cases of Pelizaeus-Merzbacher Disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, Pelizaeus-Merzbacher-like Disease, infantile GM1 and GM2 gangliosidosis and fucosidosis, the imaging pattern gives clues for the diagnosis.
