Acta Pædiatrica ISSN 0803-5253
REGULAR ARTICLE
Epidemiology of lysosomal storage diseases in Sweden Malin Hult1, Niklas Darin2, Ulrika von D€obeln ([email protected])1, Jan-Eric M ansson3 1.Division for Metabolic Diseases, Department of Laboratory Medicine, The Karolinska Institute and Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden 2.Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden 3.Department of Clinical Chemistry, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Keywords Gaucher, Krabbe, Lysosomal storage disease, Mucopolysaccharidosis Correspondence €beln, Centre for Inherited Metabolic Ulrika von Do Diseases, CMMS, L7:05, Karolinska Universitetssjukhuset, SE-17176 Stockholm, Sweden. Tel: +46-8-51771444 | Fax: +46-8-51771474 | Email: [email protected] Received 1 April 2014; revised 21 May 2014; accepted 15 September 2014. DOI:10.1111/apa.12807
ABSTRACT Aim: There are more than 50 inherited lysosomal storage diseases (LSDs), and this study examined the incidence of clinically diagnosed LSDs in Sweden. Methods: The number of patients diagnosed during 1980–2009 was compiled from the registries of the two Swedish diagnostic laboratories that cover the whole country. Results: We identified 433 patients during the 30-year period, with a total incidence of one in every 6100 births and identified fairly constant annual diagnoses during the last 20 years. Krabbe disease was the most common (one in 39 000) followed by Gaucher disease (one in 47 000), metachromatic leukodystrophy and Salla disease. Gaucher disease was more frequent in Sweden than other European countries, due to a founder effect of the mutation (p.L444P) in northern Sweden. Metachromatic leukodystrophy was one of the most common LSDs, in common with other countries. Salla disease, which is very rare elsewhere, was the fourth most common, stemming from a founder mutation in the Salla region of northern Finland brought to Sweden by immigration. Conclusion: The collective incidence of LSDs in Sweden was essentially equal to other European countries, but with a somewhat different disease pattern. Our findings have implications for diagnostic algorithms and treatment strategies.
INTRODUCTION Lysosomal storage diseases (LSDs) are a group of inherited illnesses that lead to a disturbed lysosomal function. They are caused by defective activity of lysosomal enzymes or other lysosome related noncatalytic proteins. More than 50 disorders belong to this subgroup of inborn errors of metabolism and more diseases are likely to be identified in the future, as the number of known lysosomal enzymes and noncatalytic proteins are still increasing. Although each form of LSD is rare, the combined incidence has been estimated to be approximately one in every 5000 live births (1). Recent screening studies on treatable LSDs in newborn infants indicate a higher prevalence than previously reported (2–4). This may be because most of the incidence figures to date have mainly been based on the clinical diagnosis of patients with classical symptoms, while attenuated late-onset forms may have been missed in the adult clinic. This is also supported by recent reports on late-onset forms of Krabbe disease (5,6). The overall live birth prevalence of LSDs in several countries has been reported during the last 15 years (7–12), with figures ranging from 7.6 to 26.9 per 100 000 live births.
Abbreviation LSD, Lysosomal storage disease.
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Knowledge of the incidence of different LSDs in the population is a prerequisite for calculating carrier risks for genetic counselling, developing newborn screening programmes and calculating cost benefits when new and expensive therapies are developed. In this article, we summarise all LSD diagnoses in Sweden between 1980 and 2009 and present the calculated incidence figures of the individual LSDs.
METHODS Data on LSD diagnoses were collected retrospectively from the two units that diagnose LSDs in Sweden: the Depart-
Key notes
The aim of this study was to estimate the incidence of lysosomal storage diseases in Sweden, and it found that Krabbe disease and Gaucher disease were the most common. Our analysis showed that the collective incidence was similar to other European countries, at one in 6100 births, but that the disease pattern was somewhat different from other countries. The results have implications for diagnostic algorithms and treatment strategies.
©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1258–1263
Hult et al.
ment of Clinical Chemistry and Neurochemistry at Sahlgrenska University Hospital in Gothenburg and the Centre for Inherited Metabolic Diseases at Karolinska University Hospital in Stockholm. The study period was defined as diagnoses made between 1980 and 2009. Each entry contained the patient’s birth date, initials, disorder, hometown and year of diagnosis. Data from the two sites were merged, and a comparison was performed to ensure that there were no duplicated entries. Most of the cases were diagnosed at Sahlgrenska University Hospital. Patients affected by neuronal ceroid lipofuscinoses and female carriers of Fabry disease were excluded from the study. Prenatal diagnoses were also excluded, due to the lack of complete data. Ethnical grouping has not been performed. Swedish birth rates were collected from Statistics Sweden (13), the Government agency that produces and coordinates official statistics. Incidences were calculated as the number of diagnoses made during the study period, divided by the number of live births in the corresponding years (7). The following assays were available at the start of the study period: quantitative and qualitative determination of urinary glycosaminoglycans and oligosaccharides; determination of enzyme activities for all sphingolipidoses, except Farber disease, mucopolysaccharidoses types I, VI and VII, Pompe disease, alpha-mannosidosis and sialidosis. During the 1990s, assays were implemented for the remaining mucopolysaccharidoses enzymes and Filipin staining for screening for Niemann–Pick disease type C.
RESULTS A total of 433 patients were diagnosed with 27 different disorders. The average birth rate during the study period was 103 000 per year.
Lysomal storage diseases in Sweden
Figure 1 gives an overview by birth year: number of births, number of patients diagnosed with an LSD and the resulting number per 100 000 births. The collective LSD incidence per 100 000 births was divided into 5-year intervals (Figure 2). Since 1980, the observed incidence has increased from approximately eight to 18 in every 100 000 births, which equates to one in every 12 000–5600 live births. However, it has been fairly constant since 1990, and our further incidence calculations were therefore based on the diagnostic period 1990–2009. During this period, 342 patients were identified, giving a total LSD incidence of 16 per 100 000 births (Table 1).
Figure 2 Total incidence in 5-year diagnosis periods (n = 433). Left panel: incidences per 5-year interval, range 8–18. Right panel: births per year (average), range 94 000–120 000 (average diagnoses per year, range 8–19, not shown).
Figure 1 Patients diagnosed during the 30-year period (n = 433), presented by birth year and compared with birth numbers. Right panel (live births): average birth number per year = 106 000 (range 85 000–135 000). Left panel (cases): prevalence per 100 000 births, range 0–18. Diagnoses per birth year, range 0–22.
©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1258–1263
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Lysomal storage diseases in Sweden
Hult et al.
Table 1 Incidences of individual lysosomal storage diseases (LSDs) diagnosed during the study period 1990–2009 (340 cases identified from 2 080 791 births) Incidences
Lipidoses Fabry Gaucher GM1 gangliosidosis GM2 gangliosidosis (Tay-Sachs + Sandhoff) Tay-Sachs* Sandhoff* Krabbe Metachromatic leukodystrophy Niemann–Pick A, B Niemann–Pick C Wolman/CESD Glycoproteinoses Salla Infantile sialic acid storage disorder Aspartylglucosaminuria Mucolipidosis II a-Fucosidosis a-Mannosidosis† Sialidosis Galactosialidosis Mucopolysaccharidoses MPS I MPS II MPS III (a–d) IIIa‡ IIIb‡ IIIc‡ MPS IVa MPS VI Miscellaneous Pompe Danon Cystinosis Mucolipidosis IV Total
Diagnoses
Diagnoses/ 100 000
201 23 44 7 18 10 8 53 36 6 10 4 59 33 3 13 1 2 2 2 3 56 14 7 21 13 1 7 6 8 26 15 1 8 2 340
9.66 1.11 2.11 0.34 0.87 0.48 0.38 2.55 1.73 0.29 0.48 0.19 2.84 1.59 0.14 0.62 0.05 0.10 0.07 0.10 0.14 2.69 0.67 0.34 1.01 0.62 0.05 0.34 0.29 0.38 1.25 0.72 0.05 0.38 0.10 16.4
% 1/number of births
2 1 1 1
2
2 1
10 000 90 000 47 000 297 000 116 000 208 000 260 000 39 000 58 000 347 000 208 000 520 000 37 000 63 000 694 000 160 000 081 000 040 000 354 000 040 000 694 000 35 000 149 000 297 000 99 000 160 000 081 000 297 000 347 000 260 000 80 000 139 000 081 000 260 000 040 000 6100
Of total 59 7 13 2 5 3 2 15 11 2 3 1 17 9.6 0.9 3.8 0.3 0.6 0.6 0.6 0.9 16 4 2 6 4 0.3 2 2 2 8 4.4 0.3 2.3 0.6 100
Of corresponding subgroup 100 11 22 3 9 5 4 26 18 3 5 2 100 56 5 22 2 3 3 3 5 100 25 13 38 23 2 13 11 14 100 58 4 31 8
CESD = Cholesteryl ester storage disease; MPS = Mucopolysaccharidoses. *The reported number of diagnoses has been included in the total number of GM2 gangliosidosis cases. † The diagnosis period used was 1984–2009, since all cases occurred in 1984 (2 707 893 births). Incidences are expressed as *number of births and have been rounded off to the nearest thousand. ‡ The reported number of diagnoses has been included in the total number of mucopolysaccharidoses (MPS) III cases.
We calculated the incidence of the individual LSDs diagnosed during the period 1990–2009 (Table 1), with the exception of a-mannosidosis, which was calculated from the period 1984–2009 because the only two identified cases occurred in 1984. The incidence of the individual disorders ranged from 2.55 per 100 000 for Krabbe disease, which was the most common, to 0.05 per 100 000 for mucolipidosis II and Danon disease, which were the least common. The disorders were divided into four groups: lipidoses, mucopolysaccharidoses, glycoproteinoses and miscella-
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neous, with the last category containing Pompe disease, Danon disease, cystinosis and mucolipidosis IV. The lipidosis group dominated, representing 59% of all LSD cases (Figure 3), and the four most common disorders – Krabbe disease, Gaucher disease, metachromatic leukodystrophy and Salla disease – accounted for almost 50% of all the LSD cases. The median age at diagnosis was calculated for each disorder for the whole 30-year study period from 1980 to 2009 (Table 2), and this showed that the median was 2 years and the range was 0–67 years. The average age at
©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1258–1263
Hult et al.
Lysomal storage diseases in Sweden
LSD subgroup frequencies 26 8%
diagnosis was 11 years. Lipidoses showed the greatest diversity of age at diagnosis. Patients with Gaucher disease, GM1 gangliosidosis, GM2 gangliosidosis, Krabbe disease and Wolman disease had a median age of 1 year at diagnosis, whereas Fabry disease was detected at a median age of 31 years, with a range of 6–59 years illustrating the diverse clinical courses within this group.
Lipidoses
56 16%
Glycoproteinoses Mucopolysaccharidoses
59 17%
201 59%
Other
Figure 3 The relative frequency of lysosomal storage diseases (LSD) subgroups in the percentage (%) of all cases (n = 342), including two alphaMannosidosis cases. The most common subgroup was sphingolipidoses, which accounted for 59% of all cases.
Table 2 Age at diagnosis expressed in whole years (n = 433). Diagnosis interval: 1980–2009. An age of zero indicates A (IVS4 + 919G>A). Hum Mutat 2009; 10: 1397–405. 16. Krabbe K. A new familial infantile form of diffuse brain-sclerosis. Brain 1916; 39: 74–114. € m M, Erikson A, Pettersson U. Gaucher 17. Dahl N, Lagerstro disease type III (Norrbottnian type) is caused by a single mutation in exon 10 of the glucocerebrosidase gene. Am J Hum Genet 1990; 47: 275–8. 18. Hruska KS, LaMarca ME, Scott CR, Sidranski E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat 2008; 29: 567–83. 19. Erikson A, Aula N, Aula P, M ansson J-E. Free sialic acid storage disease in Sweden. Acta Paediatr 2002; 91: 1324–7.
©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1258–1263
Hult et al.
20. Kallinen j, Heinonen S, Palotie A, Mannermaa A, Ryvanen M. Antenatal gene tests in low –risk pregnancies: molecular screening for aspartylglucosaminuria (AGU) and infantile neuronal ceroid lipofuscinosis (INCL) in Finland. Prenat Diagn 2001; 5: 409–12.
Lysomal storage diseases in Sweden
€ki P, Timonen R, Verheijen F, Mancini G, 21. Aula N, Saloma M ansson JE, et al. The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation. Am J Hum Genet 2000; 67: 832–40.
©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1258–1263
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REGULAR ARTICLE
Epidemiology of lysosomal storage diseases in Sweden Malin Hult1, Niklas Darin2, Ulrika von D€obeln ([email protected])1, Jan-Eric M ansson3 1.Division for Metabolic Diseases, Department of Laboratory Medicine, The Karolinska Institute and Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden 2.Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden 3.Department of Clinical Chemistry, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Keywords Gaucher, Krabbe, Lysosomal storage disease, Mucopolysaccharidosis Correspondence €beln, Centre for Inherited Metabolic Ulrika von Do Diseases, CMMS, L7:05, Karolinska Universitetssjukhuset, SE-17176 Stockholm, Sweden. Tel: +46-8-51771444 | Fax: +46-8-51771474 | Email: [email protected] Received 1 April 2014; revised 21 May 2014; accepted 15 September 2014. DOI:10.1111/apa.12807
ABSTRACT Aim: There are more than 50 inherited lysosomal storage diseases (LSDs), and this study examined the incidence of clinically diagnosed LSDs in Sweden. Methods: The number of patients diagnosed during 1980–2009 was compiled from the registries of the two Swedish diagnostic laboratories that cover the whole country. Results: We identified 433 patients during the 30-year period, with a total incidence of one in every 6100 births and identified fairly constant annual diagnoses during the last 20 years. Krabbe disease was the most common (one in 39 000) followed by Gaucher disease (one in 47 000), metachromatic leukodystrophy and Salla disease. Gaucher disease was more frequent in Sweden than other European countries, due to a founder effect of the mutation (p.L444P) in northern Sweden. Metachromatic leukodystrophy was one of the most common LSDs, in common with other countries. Salla disease, which is very rare elsewhere, was the fourth most common, stemming from a founder mutation in the Salla region of northern Finland brought to Sweden by immigration. Conclusion: The collective incidence of LSDs in Sweden was essentially equal to other European countries, but with a somewhat different disease pattern. Our findings have implications for diagnostic algorithms and treatment strategies.
INTRODUCTION Lysosomal storage diseases (LSDs) are a group of inherited illnesses that lead to a disturbed lysosomal function. They are caused by defective activity of lysosomal enzymes or other lysosome related noncatalytic proteins. More than 50 disorders belong to this subgroup of inborn errors of metabolism and more diseases are likely to be identified in the future, as the number of known lysosomal enzymes and noncatalytic proteins are still increasing. Although each form of LSD is rare, the combined incidence has been estimated to be approximately one in every 5000 live births (1). Recent screening studies on treatable LSDs in newborn infants indicate a higher prevalence than previously reported (2–4). This may be because most of the incidence figures to date have mainly been based on the clinical diagnosis of patients with classical symptoms, while attenuated late-onset forms may have been missed in the adult clinic. This is also supported by recent reports on late-onset forms of Krabbe disease (5,6). The overall live birth prevalence of LSDs in several countries has been reported during the last 15 years (7–12), with figures ranging from 7.6 to 26.9 per 100 000 live births.
Abbreviation LSD, Lysosomal storage disease.
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Knowledge of the incidence of different LSDs in the population is a prerequisite for calculating carrier risks for genetic counselling, developing newborn screening programmes and calculating cost benefits when new and expensive therapies are developed. In this article, we summarise all LSD diagnoses in Sweden between 1980 and 2009 and present the calculated incidence figures of the individual LSDs.
METHODS Data on LSD diagnoses were collected retrospectively from the two units that diagnose LSDs in Sweden: the Depart-
Key notes
The aim of this study was to estimate the incidence of lysosomal storage diseases in Sweden, and it found that Krabbe disease and Gaucher disease were the most common. Our analysis showed that the collective incidence was similar to other European countries, at one in 6100 births, but that the disease pattern was somewhat different from other countries. The results have implications for diagnostic algorithms and treatment strategies.
©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1258–1263
Hult et al.
ment of Clinical Chemistry and Neurochemistry at Sahlgrenska University Hospital in Gothenburg and the Centre for Inherited Metabolic Diseases at Karolinska University Hospital in Stockholm. The study period was defined as diagnoses made between 1980 and 2009. Each entry contained the patient’s birth date, initials, disorder, hometown and year of diagnosis. Data from the two sites were merged, and a comparison was performed to ensure that there were no duplicated entries. Most of the cases were diagnosed at Sahlgrenska University Hospital. Patients affected by neuronal ceroid lipofuscinoses and female carriers of Fabry disease were excluded from the study. Prenatal diagnoses were also excluded, due to the lack of complete data. Ethnical grouping has not been performed. Swedish birth rates were collected from Statistics Sweden (13), the Government agency that produces and coordinates official statistics. Incidences were calculated as the number of diagnoses made during the study period, divided by the number of live births in the corresponding years (7). The following assays were available at the start of the study period: quantitative and qualitative determination of urinary glycosaminoglycans and oligosaccharides; determination of enzyme activities for all sphingolipidoses, except Farber disease, mucopolysaccharidoses types I, VI and VII, Pompe disease, alpha-mannosidosis and sialidosis. During the 1990s, assays were implemented for the remaining mucopolysaccharidoses enzymes and Filipin staining for screening for Niemann–Pick disease type C.
RESULTS A total of 433 patients were diagnosed with 27 different disorders. The average birth rate during the study period was 103 000 per year.
Lysomal storage diseases in Sweden
Figure 1 gives an overview by birth year: number of births, number of patients diagnosed with an LSD and the resulting number per 100 000 births. The collective LSD incidence per 100 000 births was divided into 5-year intervals (Figure 2). Since 1980, the observed incidence has increased from approximately eight to 18 in every 100 000 births, which equates to one in every 12 000–5600 live births. However, it has been fairly constant since 1990, and our further incidence calculations were therefore based on the diagnostic period 1990–2009. During this period, 342 patients were identified, giving a total LSD incidence of 16 per 100 000 births (Table 1).
Figure 2 Total incidence in 5-year diagnosis periods (n = 433). Left panel: incidences per 5-year interval, range 8–18. Right panel: births per year (average), range 94 000–120 000 (average diagnoses per year, range 8–19, not shown).
Figure 1 Patients diagnosed during the 30-year period (n = 433), presented by birth year and compared with birth numbers. Right panel (live births): average birth number per year = 106 000 (range 85 000–135 000). Left panel (cases): prevalence per 100 000 births, range 0–18. Diagnoses per birth year, range 0–22.
©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1258–1263
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Lysomal storage diseases in Sweden
Hult et al.
Table 1 Incidences of individual lysosomal storage diseases (LSDs) diagnosed during the study period 1990–2009 (340 cases identified from 2 080 791 births) Incidences
Lipidoses Fabry Gaucher GM1 gangliosidosis GM2 gangliosidosis (Tay-Sachs + Sandhoff) Tay-Sachs* Sandhoff* Krabbe Metachromatic leukodystrophy Niemann–Pick A, B Niemann–Pick C Wolman/CESD Glycoproteinoses Salla Infantile sialic acid storage disorder Aspartylglucosaminuria Mucolipidosis II a-Fucosidosis a-Mannosidosis† Sialidosis Galactosialidosis Mucopolysaccharidoses MPS I MPS II MPS III (a–d) IIIa‡ IIIb‡ IIIc‡ MPS IVa MPS VI Miscellaneous Pompe Danon Cystinosis Mucolipidosis IV Total
Diagnoses
Diagnoses/ 100 000
201 23 44 7 18 10 8 53 36 6 10 4 59 33 3 13 1 2 2 2 3 56 14 7 21 13 1 7 6 8 26 15 1 8 2 340
9.66 1.11 2.11 0.34 0.87 0.48 0.38 2.55 1.73 0.29 0.48 0.19 2.84 1.59 0.14 0.62 0.05 0.10 0.07 0.10 0.14 2.69 0.67 0.34 1.01 0.62 0.05 0.34 0.29 0.38 1.25 0.72 0.05 0.38 0.10 16.4
% 1/number of births
2 1 1 1
2
2 1
10 000 90 000 47 000 297 000 116 000 208 000 260 000 39 000 58 000 347 000 208 000 520 000 37 000 63 000 694 000 160 000 081 000 040 000 354 000 040 000 694 000 35 000 149 000 297 000 99 000 160 000 081 000 297 000 347 000 260 000 80 000 139 000 081 000 260 000 040 000 6100
Of total 59 7 13 2 5 3 2 15 11 2 3 1 17 9.6 0.9 3.8 0.3 0.6 0.6 0.6 0.9 16 4 2 6 4 0.3 2 2 2 8 4.4 0.3 2.3 0.6 100
Of corresponding subgroup 100 11 22 3 9 5 4 26 18 3 5 2 100 56 5 22 2 3 3 3 5 100 25 13 38 23 2 13 11 14 100 58 4 31 8
CESD = Cholesteryl ester storage disease; MPS = Mucopolysaccharidoses. *The reported number of diagnoses has been included in the total number of GM2 gangliosidosis cases. † The diagnosis period used was 1984–2009, since all cases occurred in 1984 (2 707 893 births). Incidences are expressed as *number of births and have been rounded off to the nearest thousand. ‡ The reported number of diagnoses has been included in the total number of mucopolysaccharidoses (MPS) III cases.
We calculated the incidence of the individual LSDs diagnosed during the period 1990–2009 (Table 1), with the exception of a-mannosidosis, which was calculated from the period 1984–2009 because the only two identified cases occurred in 1984. The incidence of the individual disorders ranged from 2.55 per 100 000 for Krabbe disease, which was the most common, to 0.05 per 100 000 for mucolipidosis II and Danon disease, which were the least common. The disorders were divided into four groups: lipidoses, mucopolysaccharidoses, glycoproteinoses and miscella-
1260
neous, with the last category containing Pompe disease, Danon disease, cystinosis and mucolipidosis IV. The lipidosis group dominated, representing 59% of all LSD cases (Figure 3), and the four most common disorders – Krabbe disease, Gaucher disease, metachromatic leukodystrophy and Salla disease – accounted for almost 50% of all the LSD cases. The median age at diagnosis was calculated for each disorder for the whole 30-year study period from 1980 to 2009 (Table 2), and this showed that the median was 2 years and the range was 0–67 years. The average age at
©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1258–1263
Hult et al.
Lysomal storage diseases in Sweden
LSD subgroup frequencies 26 8%
diagnosis was 11 years. Lipidoses showed the greatest diversity of age at diagnosis. Patients with Gaucher disease, GM1 gangliosidosis, GM2 gangliosidosis, Krabbe disease and Wolman disease had a median age of 1 year at diagnosis, whereas Fabry disease was detected at a median age of 31 years, with a range of 6–59 years illustrating the diverse clinical courses within this group.
Lipidoses
56 16%
Glycoproteinoses Mucopolysaccharidoses
59 17%
201 59%
Other
Figure 3 The relative frequency of lysosomal storage diseases (LSD) subgroups in the percentage (%) of all cases (n = 342), including two alphaMannosidosis cases. The most common subgroup was sphingolipidoses, which accounted for 59% of all cases.
Table 2 Age at diagnosis expressed in whole years (n = 433). Diagnosis interval: 1980–2009. An age of zero indicates A (IVS4 + 919G>A). Hum Mutat 2009; 10: 1397–405. 16. Krabbe K. A new familial infantile form of diffuse brain-sclerosis. Brain 1916; 39: 74–114. € m M, Erikson A, Pettersson U. Gaucher 17. Dahl N, Lagerstro disease type III (Norrbottnian type) is caused by a single mutation in exon 10 of the glucocerebrosidase gene. Am J Hum Genet 1990; 47: 275–8. 18. Hruska KS, LaMarca ME, Scott CR, Sidranski E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat 2008; 29: 567–83. 19. Erikson A, Aula N, Aula P, M ansson J-E. Free sialic acid storage disease in Sweden. Acta Paediatr 2002; 91: 1324–7.
©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1258–1263
Hult et al.
20. Kallinen j, Heinonen S, Palotie A, Mannermaa A, Ryvanen M. Antenatal gene tests in low –risk pregnancies: molecular screening for aspartylglucosaminuria (AGU) and infantile neuronal ceroid lipofuscinosis (INCL) in Finland. Prenat Diagn 2001; 5: 409–12.
Lysomal storage diseases in Sweden
€ki P, Timonen R, Verheijen F, Mancini G, 21. Aula N, Saloma M ansson JE, et al. The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation. Am J Hum Genet 2000; 67: 832–40.
©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1258–1263
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