Prevalence of Lysosomal Storage Disorders

ORIGINAL CONTRIBUTION

Peter J. Meikle, PhD Context Lysosomal storage disorders represent a group of at least 41 genetically dis- John J. Hopwood, PhD tinct, biochemically related, inherited diseases. Individually, these disorders are con- Alan E. Clague, FRCPN sidered rare, although high prevalence values have been reported in some populations. These disorders are devastating for individuals and their families and result in William F. Carey, PhD considerable use of resources from health care systems; however, the magnitude of the problem is not well defined. To date, no comprehensive study has been performed on the prevalence of these disorders as a group. YSOSOMAL STORAGE DISORDERS (LSDs) represent a group of at Objective To determine the prevalence of lysosomal storage disorders individually least 41 distinct genetic dis- and as a group in the Australian population. eases, each one resulting from a Design Retrospective case studies. Ldeficiency of a particular lysosomal pro- Setting Australia, from January 1, 1980, through December 31, 1996. tein or, in a few cases, from nonlyso- Main Outcome Measure Enzymatic diagnosis of a lysosomal storage disorder. somal proteins, that are involved in lysosomal biogenesis. Most LSDs are Results Twenty-seven different lysosomal storage disorders were diagnosed in 545 individuals. The prevalence ranged from 1 per 57 000 live births for Gaucher disease inherited in an autosomal recessive man- to 1 per 4.2 million live births for sialidosis. Eighteen of 27 disorders had more than 10 ner, with the exception of Fabry disease diagnosed cases. As a group of disorders, the combined prevalence was 1 per 7700 and mucopolysaccharidosis (MPS) type live births. There was no significant increase in the rate of either clinical diagnoses or II, which show X-linked recessive inher- prenatal diagnoses of lysosomal storage disorders during the study period. itance. Conclusions Individually, lysosomal storage disorders are rare genetic diseases. How- The number of LSDs is steadily in- ever, as a group, they are relatively common and represent an important health prob- creasing as new disorders are character- lem in Australia. ized biochemically and genetically. A de- JAMA. 1999;281:249-254 www.jama.com ficiency of cathepsin K has recently been described that results in an LSD called the same gene. However, genotype- the substrate type is used to group LSDs pyknodysostosis.1 In the last 2 years, in- phenotype correlations do not always into broad categories, including MPSs, fantile neuronal ceroid lipofuscinosis hold. In Gaucher disease, for example, lipidoses, glycogenoses, and oligosac- (NCL), also known as Batten disease, has there are sometimes substantial differ- charidoses.6 These categories show many been shown to result from a deficiency ences in the clinical manifestation of the clinical similarities within groups as well of palmityl protein thioesterase,2,3 and disease between siblings and, in some in- as significant similarities between groups. classic late-infantile NCL has been shown stances, one sibling is severely affected Common features of many LSDs in- to result from a deficiency of a carboxy- while another is virtually free of dis- clude bone abnormalities, organo- peptidase.4 Many LSDs have been clas- ease.5 Other factors, including genetic megaly, central nervous system dysfunc- sified into clinical subtypes (such as the background and environmental fac- tion, and coarse hair and facies. Hurler-Scheie definition of MPS type I tors, presumably play a role in disease or the infantile-, juvenile-, and adult- progression. Author Affiliations: Lysosomal Diseases Research Unit onset forms of Pompe disease), but it is Although each LSD results from mu- and National Referral Laboratory, Department of clear that most LSDs have a broad con- tations in a different gene and conse- Chemical Pathology, Women’s and Children’s Hos- tinuum of clinical severity and age of pre- quent deficiency of enzyme activity or pital, Adelaide, Australia (Drs Meikle, Hopwood, and Carey); and the Division of Chemical Pathology, Royal sentation. protein function, all LSDs share a com- Brisbane Hospitals Campus, Queensland Health Pa- With the advent of molecular biol- mon biochemical characteristic in that the thology Service, Brisbane, Australia (Dr Clague). Corresponding Author and Reprints: Peter J. Meikle, ogy and the characterization of many disorder results in an accumulation of PhD, Lysosomal Diseases Research Unit, Depart- of the LSD genes, it is now recognized normally degraded substrates within ly- ment of Chemical Pathology, Women’s and Chil- dren’s Hospital, 72 King William Rd, North Adelaide, that the range of severity may in part sosomes. The particular substrates stored 5006, South Australia (e-mail: pmeikle@medicine be ascribed to different mutations within and the site(s) of storage vary, although .adelaide.edu.au).

Downloaded From: https://jamanetwork.com/ on 09/30/2021 PREVALENCE OF LYSOSOMAL STORAGE DISORDERS

There have been a number of reports limited studies on the prevalence of some care systems and will be a key factor in on the prevalence of particular disor- LSDs in different countries.10-15 How- the adoption of screening and treat- ders in select populations. Of note is the ever, in general, these studies have not ment programs for LSDs. level of Gaucher disease and Tay-Sachs been comprehensive and have not cov- In this article, we present a summary disease in the Ashkenazi Jewish popu- ered all LSDs. As the development of of all LSD diagnoses in Australia for the lation, reported to be 1 per 855 and 1 therapies for this group of disorders pro- period 1980 through 1996. per 3900, respectively.5,7 Prevalences as ceeds and the possibilities for neonatal high as 1 per 18 500 for aspartylgly- screening are explored, it becomes im- METHODS cosaminuria in the Finnish population8 portant to obtain accurate values for In this study, patients diagnosed as hav- and 1 per 24 000 for MPS type III in the prevalence of the disorders. These data ing an LSD have a reduced level of 1 or Netherlands9 have also been reported. In will be required to accurately assess the more lysosomal proteins, which leads to addition, there have been a number of cost of these disorders to public health the storage of substrate within their ly-

Table 1. Diagnosis of Lysosomal Storage Disorders in Australia* No. of Diagnoses† Incidence Prevalence Carrier Disorder Protein Deficiency Postnatal Prenatal Total in Thousands‡ in Thousands§ Frequency࿣ Aspartylglucosaminuria Aspartylglucosaminidase 2 0 2 2111 2111 726 Cystinosis Cystine transporter 15 7 22 281 192 219 Fabry disease ␣-Galactosidase 36 0 36 117 117 117 000¶ Gaucher disease ␤-Glucoceramidase 71 3 74 59 57 119

GM1 gangliosidosis ␤-Galactosidase 10 1 11 422 384 310 Krabbe disease Galactoceramidase 21 9 30 201 141 188 ␣-Mannosidosis ␣-Mannosidase 4 0 4 1056 1056 514 Metachromatic leukodystrophy Galactose-3-sulfatase 35 11 46 121 92 152 MPS type I (Hurley-Scheie) ␣-Iduronidase 38 10 48 111 88 148 MPS type II (Hunter) Iduronate-2-sulfatase 26 5 31 162 136 136 000¶ MPS type III-A (Sanfilippo A) Glucosamine-N-sulfatase 33 4 37 128 114 169 MPS type III-B (Sanfilippo B) ␣-N-Acetylglucosaminidase 18 2 20 235 211 230 MPS type III-C (Sanfilippo C) Acetylcoenzyme A:␣- 3031407 1407 593 glucosaminide-N- acetyltransferase MPS type III-D (Sanfilippo D) N-Acetylglucosamine- 4041056 1056 514 6-sulfatase MPS type IV-A (Morquip A) N-Acetylgalactosamine- 21 4 25 201 169 206 6-sulfatase MPS type VI (Maroteaux-Lamy) N-Acetylgalactosamine- 17 1 18 248 235 242 4-sulfatase MPS type VII (Sly) ␤-Glucuronidase 2 0 2 2111 2111 726 Mucolipidosis type II/III Phosphotransferase 10 3 13 422 325 285 Multiple sulfatase Multiple sulfatase factor, 3031407 1407 593 deficiency all sulfatases Niemann-Pick disease Shingomyelinase 16 1 17 264 248 249 type A/B Niemann-Pick disease NPC1 20 0 20 211 211 230 type C Pompe disease ␣-Glucosidase 21 8 29 201 146 191 Sandhoff disease ␤-Hexosaminidase, ␤ subunit 10 1 11 422 384 310 Sialic acid storage disease Sialic acid transporter 7 1 8 603 528 363 Sialidosis Neuraminidase 1 0 1 4222 4222 1027 Tay-Sachs disease ␤-Hexosaminidase, ␣ subunit 19 2 21 222 201 224 Wolman disease Acid lipase 6 2 8 704 528 363 Total/Combined 470 75 545 9.0 7.7 47 *MPS indicates mucopolysaccharidosis. †Data are number of diagnoses made in Australia during 1980-1996. ‡Incidence was calculated by dividing the number of postnatal diagnoses by the number of births during the study period. §Prevalence was calculated by dividing the number of postnatal plus prenatal diagnoses by the number of births during the study period. ࿣Carrier frequency was calculated by dividing the prevalence value by 4 and finding the square root. ¶Carrier frequency for X-linked disorders was assumed to be equal to the prevalence values because the incidence of carrier births should equal the prevalence of affected births for these disorders.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 PREVALENCE OF LYSOSOMAL STORAGE DISORDERS

sosomes and results in the develop- affected individuals diagnosed in the Aus- would have had some patients recorded ment of clinical problems and a subse- tralian population. In addition, there were in those states. quent reduction in their quality of life. 75 positive LSD prenatal diagnoses for af- We determined the median age of the Retrospective data on the enzymatic fected fetuses, yielding a total of 545 di- patients at diagnosis for each LSD and diagnosis of LSDs, both from patient re- agnoses (TABLE 1). There was no signifi- report these together with the low and ferrals and prenatal diagnoses for the cant increase in the rate of either clinical high values for each disorder (TABLE 4). period January 1, 1980, through Decem- diagnoses or prenatal diagnoses during the Although for some disorders, the number 31, 1996, were collected from the study period (FIGURE). These diagnoses ber of diagnoses was not high enough to National Referral Laboratory, Depart- represent 27 different LSDs, whereas there make these data statistically significant, ment of Chemical Pathology, Women’s were 10 LSDs for which there were no di- it still gives an indication of the range of and Children’s Hospital, Adelaide, Aus- agnoses in Australia during this period ages at which these disorders can pre- tralia, and from the Division of Chemi- (TABLE 2). The prevalence of these dis- sent. Most disorders (18/27) had more cal Pathology, Royal Brisbane Hospitals, orders ranged from 1 per 57 000 for Gau- than 10 diagnoses in this period. These Brisbane, Australia. All diagnoses were cher disease to 1 per 4.2 million for sia- data demonstrate that certain disor- performed at these 2 centers and this rep- lidosis. The prevalence of LSDs as a group ders, in particular Fabry disease, can pre- resents all enzymatic analyses per- was calculated to be 1 per 7700 live births. formed in Australia during this period. No When prenatal diagnoses were not con- Figure. Postnatal and Prenatal Lysosomal data were collected on the diagnosis of sidered, the incidence for LSDs was 1 per Storage Disorder Diagnoses Made in pyknodysostosis, glycogen-storage dis- 9000 live births. Mucopolysaccharido- Australia From 1980 Through 1996 ease type II-B, or the various forms of sis, a particularly well-defined subgroup Postnatal Prenatal Australian Batten disease, which are currently not of LSDs, had a combined prevalence of 1 Diagnoses Diagnoses Birth Rate diagnosed enzymatically in Australia. per 22 500 and represented 35% of all Data on the number of births in Aus- LSDs. Carrier frequencies were calcu- 50 300

tralia were collected from the Austra- lated from the prevalence values and No. of Births in Thousands 40 lian Bureau of Statistics (Canberra). Data ranged from 1 per 119 for Gaucher dis- were compiled according to disorder, ease to 1 per 1027 for sialidosis (Table 1). 200 30 year of diagnosis, and age of patient (in- Comparison of the number of LSD diag-

cluding prenatal diagnoses), and corre- noses in the different states of Australia 20 lated with Australian birth rates for each (TABLE 3) indicates similar prevalence val- 100 No. of Diagnoses

year. Instances in which there were 2 or ues in all major population centers. The 10 more affected siblings were identified. exceptions, Australian Capital Territory,

Incidence rates were calculated by di- Northern Territory, and Tasmania, are all 0 0 viding the number of postnatal diag- low-population areas that use genetic ser- 1980 19821984 19861988 19901992 1994 1996 Year noses by the number of births during the vices in neighboring states and, as such, study period. Prevalence rates were calculated by dividing the number of postnatal plus prenatal diagnoses by the num- Table 2. Disorders Not Detected Enzymatically in the Australian Population ber of births during the study period. The Disorder Protein Deficiency total number with prenatal diagnoses Cobalamin deficiency type F Cobalamin transporter who were not live-born were not in- Farber disease Acid cermidase cluded in the denominator because this Fucosidosis ␣-Fucosidase figure was not accurately known and Galactosialidosis Neuraminidase, ␤-galactosidase, protective protein would not have made a significant dif- Gaucher disease (variant) Saposin C ference to the prevalence figures. Car- Glycogen storage disease II-B*† Unknown rier frequency was calculated by divid- ␤-Mannosidosis ␤-Mannosidase ing the prevalence value by 4 and finding Metachromatic leukodystrophy (variant) Saposin B the square root. Carrier frequency for X- Mucopolysaccharidosis type IV-B (Morquio B) ␤-Galactosidase linked disorders was equal to the preva- Neuronal ceroid lipofuscinosis (infantile)* Palmitoyl protein thioesterase lence values because the incidence of car- Neuronal ceroid lipofuscinosis (late infantile)* Carboxypeptidase rier births should equal the prevalence Pycnodysostosis*† Cathepsin K of affected births for these disorders. Schindler disease‡ ␣-N-Acetylgalactosaminidase Tay-Sachs disease type AB ␤-Hexosaminidase activator protein RESULTS *Currently not screened for enzymatically in Australia. †Prevalence levels are extremely low. For the period January 1980 through De- ‡Screening in Australia commenced in 1995 (prevalence Ͻ1 per 500 000). cember 1996, there were 470 LSD-

Downloaded From: https://jamanetwork.com/ on 09/30/2021 PREVALENCE OF LYSOSOMAL STORAGE DISORDERS

sent relatively late in life, with a mean Table 3. Prevalence of Lysosomal Storage Disorders by State age at diagnosis of 28.6 years, although 95% for some individuals diagnosis was made No. of No. of Confidence in the first year of life. Clinicians should State Births* Diagnoses† Prevalence‡ Limits note the wide range of the clinical spec- Australian Capital Territory 80 211 2 40 106 ND§ trum presenting in these disorders. In New South Wales 1 450 878 207 7009 6554, 7533 some LSDs, including Krabbe disease, Northern Territory 57 221 3 19 074 ND§ MPS type I, Pompe disease, and Sand- Queensland 719 534 78 9225 8287, 10 403 hoff disease, the median age at diagno- South Australia 332 210 44 7550 6561, 8890 sis was younger than 1 year, although the Tasmania 116 842 9 12 982 9737, 19 472 range of ages in each disorder still re- Victoria 1 059 294 145 7305 6745, 7967 flected a considerable variation in the Western Australia 403 840 57 7085 6256, 8167 clinical spectrum. Total Australia 4 222 323 545 7747 7429-8094 *Data are number of births recorded in each state during the period 1980-1996. Of the 470 clinical diagnoses, there †Data are number of diagnoses (postnatal and prenatal) of all lysosomal storage disorders from each state during 1980- were 79 individuals who had 1 or more 1996. ‡Prevalence was calculated by dividing the number of postnatal plus prenatal diagnoses by the number of births affected siblings. There were 4 families during the study period. §ND indicates 95% confidence limits were not determined (number of diagnoses was insufficient to calculate mean- with twins, 9 families with an index case ingful confidence limit). who in full knowledge had 1 or more additional affected children, and 26 families who had had 2 affected children before the first had an LSD diagnosed. In 9 of these 26 families, the affected indi- Table 4. Age at Diagnosis of Patients With Lysosomal Storage Disorders* viduals were adults (older than 18 years) No. of Median Age when the disease was diagnosed. Diagnosis Diagnoses† (Range), y‡ Aspartylglucosaminuria 2 8.0 (7.0-9.0) COMMENT Cystinosis 14 1.0 (0.1-14.2) The prevalence values for individual LSDs Fabry disease 32 28.6 (0.0-55.7) clearly define these as rare genetic dis- Gaucher disease 66 9.5 (0.0-73.2) G gangliosidosis 9 1.2 (0.4-15.2) orders. Gaucher disease was the most M1 Krabbe disease 20 0.5 (0.0-5.5) common, with a prevalence of 1 per ␣-Mannosidosis 2 10.5 (3.9-17.1) 57 000 births. However, when taken as Metachromatic leukodystrophy 31 2.3 (0.0-30.0) a group, LSDs are far more common, MPS type I (Hurler-Scheie) 35 1.0 (0.3-29.1) with a prevalence of 1 per 7700 births. MPS type II (Hunter) 23 2.8 (0.0-22.0) Each year in Australia there are, on av- MPS type III-A (Sanfilippo A) 31 3.5 (0.2-17.1) erage, 28 LSD diagnoses made, with an MPS type III-B (Sanfilippo B) 17 3.5 (0.0-21.4) additional 4 to 5 prenatal diagnoses. Al- MPS type III-C (Sanfilippo C) 3 10.7 (5.7-12.0) though exact national figures for the MPS type III-D (Sanfilippo D) 4 3.1 (0.4-7.4) number of MPS referrals are unavail- MPS type IV-A (Morquio A) 20 3.4 (0.0-19.0) able, in South Australia, 150 to 250 urine MPS type VI (Maroteaux-Lamy) 16 1.4 (0.0-43.4) screening tests for MPS are performed MPS type VII (Sly) 1 0.0 each year to diagnose MPS, on average, Mucolipidosis type II/III 10 0.8 (0.0-24.8) in 1 patient. White-cell enzymology, Multiple sulfatase deficiency 2 8.1 (7.3-8.8) which is performed for most other LSDs, Niemann-Pick disease type A/B 14 22.8 (0.7-44.1) is performed on 400 to 450 patients per Niemann-Pick disease type C 19 9.3 (0.1-37.7) year nationally, resulting in an average Pompe disease 20 0.5 (0.1-55.0) of 18 diagnoses. These estimates sug- Sandhoff disease 9 1.0 (0.8-1.9) gest considerable overlap between clini- Sialic acid storage disease 7 0.4 (0.0-36.1) cal features of LSDs and other condi- Sialidosis 1 0.3 tions, but may also indicate the presence Tay-Sachs disease§ 18 1.1 (0.8-50.5) of additional as yet undefined LSDs. Al- Wolman disease 6 0.6 (0.1-5.5) though prenatal diagnosis is possible for Total Lysosomal Storage Disorders 432 2.7 (0-73.2) most LSDs, no practical prenatal screen- *MPS indicates mucopolysaccharidosis. †Data are number of postnatal diagnoses made in each group for which age data were available. ing tests are available for any LSD. ‡In some instances, early diagnosis was facilitated by an older affected sibling as an index case. Age at diagnosis of The life expectancy of a patient with 0.0 refers to individuals diagnosed in the first 2 weeks after birth. §Includes variants of hexosaminidase A deficiency. an LSD depends on the particular dis-

Downloaded From: https://jamanetwork.com/ on 09/30/2021 PREVALENCE OF LYSOSOMAL STORAGE DISORDERS

order, the severity, and the treatment timates of incidence values would be low. severe MPS I who has not had a bone mar- available. In MPS, this can range from le- This is unlikely because all unexpected row transplant to be approximately Aust thal fetal hydrops to an almost-normal child deaths in Australia result in post- $80 000 (US $56 000) per year, based on life expectancy.16 In most, if not all, dis- mortem examinations, including histo- hospital admissions, hospital proce- orders, there is a strong correlation pathology studies. We also assumed that dures, and outpatient visits during a 2.5- among age at diagnosis, severity, and life the parents of affected individuals were year period. In addition, such a patient expectancy. The difference between the heterozygous for the disorders (with the would require full-time nursing home care median age (2.7 years) and average age exception of X-linked disorders). If this while attending a special school, further (9.7 years) at diagnosis of an LSD in Aus- were not the case, then our estimates of increasing the cost to the community. Bone tralia reflects the relatively few adult pa- carrier frequency would be low; how- marrow transplantation costs, on aver- tients who have an almost-normal life ex- ever, homozygous parents, in what are age, Aust $41 000 (US $29 000). Enzyme pectancy. Based on the average age at predominantly childhood disorders, are replacement therapy for Gaucher disease diagnosis of 9.7 years and an average of not common and, as such, would have currently costs between Aust $140 000 and 28 affected individuals born each year, little effect on our carrier frequency es- $250 000 (US $98 000-$175 000) per we estimate that there are currently about timates. year, although the cost for enzyme replace- 270 individuals with an undiagnosed The Australian population is predomi- ment therapy should decrease as more effi- LSD and possibly up to twice that num- nantly of British extraction, with a sig- cient enzyme production systems are ber of patients with a diagnosed LSD in nificant contribution from other Euro- developed. Given that some of the affected Australia. pean countries and, to a lesser extent, individuals are at the less-severe end of the That there were only 2 centers in- Asian countries. As such, this popula- clinical spectrum, the total cost to the com- volved in the enzymatic diagnosis of LSDs tion would be comparable with that of munity for individuals with an LSD in Aus- greatly facilitated the collection of data for most Anglo-Celtic countries. There- tralia is thought to be in the tens of mil- this study; as a consequence, we have a fore, these results could be extrapo- lions of dollars per year. Although it is high level of confidence that few diag- lated to the white non-Hispanic popu- useful to determine the cost of these dis- noses were missed. Our confidence is sup- lations in the United States, Canada, and orders to the community, in particular to ported by the state-by-state breakdown the United Kingdom. However, a higher the health care system, this represents only of the prevalence values for the LSDs, with proportion of Ashkenazi Jews in a com- a fraction of the real cost, in human terms, the 5 major population centers showing munity may increase the prevalence of of these disorders. similar prevalence data. Had 1 or more Gaucher disease and Tay-Sachs disease. There were 39 families with more than states missed a significant number of cases, Although no data are available on the 1 affected child; this highlights the need this would present as uneven prevalence ethnic background of those diagnosed as for early diagnosis of these disorders be- values among states. In addition, there was having an LSD, we see no evidence that cause in most cases, there were 2 affected no significant variation in the number of the Ashkenazi Jewish population con- children born before the first was diag- diagnoses made per year during the study tributed significantly to the figures for ei- nosed as having an LSD. Early detection period; this would suggest that the pa- ther Gaucher disease or Tay-Sachs dis- of LSDs, such as that possible in the neo- tient identification rate is constant and ease in Australia. The Ashkenazi Jewish natal screening programs for phenylke- close to 100% for these disorders. It is pos- population in Australia is estimated to be tonuria and other genetic diseases, would sible, however, that there are some indi- 105 000 and is concentrated in Victoria provide the option for prenatal diagno- viduals at the less-severe end of the clinical and New South Wales. Despite this, we sis for many more families carrying these spectrum of some disorders, particularly see no increase in the prevalence of ei- disorders. In addition, early detection in the adult population, in whom an LSD ther Gaucher disease or Tay-Sachs dis- would maximize the efficacy of current was not diagnosed. Gaucher disease is ease in these states compared with other and proposed therapies for LSDs. The ef- likely in this group. Similarly, we ob- states in Australia. This may be the re- ficacy of these therapies, particularly for served that there was no increase in the sult of outbreeding from the Jewish com- those LSDs involving central nervous sys- rate of prenatal diagnoses for the period munity into the general population. A tem and bone pathologies, will rely heavily of the study; this again reflects the steady screening program for the detection of on the early diagnosis and treatment of rate of diagnosis of these disorders. Tay-Sachs disease carriers in the Jewish the disorder, before the onset of irrevers- To calculate incidence, prevalence, and community was commenced in 1994; ible disease. A further consideration, criti- carrier frequency values, we needed to however, this would have had only a cal to bone marrow transplant therapy, make certain assumptions. We as- minimal effect on this study, which cov- is that early diagnosis of the LSD will al- sumed that the rate of postnatal diagno- ered the period 1980 to 1996. low clinicians to take advantage of the win- sis was equivalent to the birth rate for The cost to the community, in particu- dow of opportunity presented by the natu- each disorder. If the postnatal diagnosis lar the health care system, of individuals rally suppressed immune system of the was less than the birth rate, as a result with LSDs is significant. We have calcu- neonate to maximize the chances of a suc- of undiagnosed early death, then our es- lated the medical costs for a patient with cessful engraftment. Early intervention has

Downloaded From: https://jamanetwork.com/ on 09/30/2021 PREVALENCE OF LYSOSOMAL STORAGE DISORDERS

the potential to reduce costs associated common: estimates of incidence levels 6700. Further epidemiological studies are with LSDs. Studies into the development range from a global incidence for all forms required for this group of disorders. 18 of neonate screening for LSDs are currently of 1 per 12 500 to 1 per 78 000 for all Funding/Support: This study was supported in part 17 19 in progress. forms in Germany. In Finland, where by the South Australian Health Commission and the Recently, there have been several there is a particularly high level, inci- Women’s and Children’s Hospital Research Founda- tion, Adelaide; and the National Health and Medical advances made in the understanding of dence values of 1 per 13 000 for infantile Research Council of Australia, Canberra. NCLs, a group of at least 4 disorders clas- and 1 per 21 000 for juvenile forms have Acknowledgment: We acknowledge the many refer- 20 ring pediatricians for clinical diagnoses; Sharon Chin, sified by age at onset. Previously, these dis- been reported. Clearly, NCLs are going Peter Clements, PhD, Beverley Fong, Vivian Muller, orders were diagnosed histopathologi- to contribute importantly to the overall Paul Nelson, Dace Petersons, and Greta Richardson for chemical diagnoses performed in Adelaide; Robert cally rather than enzymatically and, prevalence of LSDs. A rate of 1 per 50 000 Barns, PhD, and David Morris for chemical diagnoses consequently, we have no incidence data births for NCLs would alter the preva- performed in Brisbane; and Janice Fletcher, MD, available. However, NCLs are relatively lence of LSDs from 1 per 7700 to 1 per and Nicolla Poplawski, MD, for cost analyses of treatments.

REFERENCES 1. Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pyk- 7. Petersen GM, Rotter JI, Cantor RM, et al. The Tay- 1993. Pediatr Neurol. 1994;11:295-297. nodysostosis, a lysosomal disease caused by cathep- Sachs disease gene in North American Jewish popu- 14. Michelakakis H, Dimitriou E, Tsagaraki S, Giou- sin K deficiency. Science. 1996;273:1236-1238. lations: geographic variations and origin. Am J Hum roukos S, Schulpis K, Bartsocas CS. Lysosomal stor- 2. Vesa J, Hellsten E, Verkruyse LA, et al. Mutations Genet. 1983;35:1258-1269. age diseases in Greece. Genet Couns. 1995;6:43-47. in the palmityl protein thioesterase gene causing in- 8. Arvio M, Autio S, Louhiala P. Early clinical symp- 15. Coelho JC, Wajner M, Burin MG, Vargas CR. Se- fantile neuronal ceroid lipofuscinosis. Nature. 1995; toms and incidence of aspartylglycosaminuria in Fin- lective screening of 10,000 high-risk Brazilian pa- 376:584-587. land. Acta Paediatr. 1993;82:587-589. tients for the detection of inborn errors of metabo- 3. Hellsten E, Vesa J, Olkkonen VM, Jalanko A, Pel- 9. van de Kamp JJ, Niermeijer MF, von Figura K, Gies- lism. Eur J Pediatr. 1997;156:650-654. tonen L. Human palmityl protein thioesterase: evi- berts MA. Genetic heterogeneity and clinical variabil- 16. Neufeld EF, Muenzer J. The mucopolysacchari- dence for lysosomal targeting of the enzyme and dis- ity in the Sanfilippo syndrome (types A, B, and C). Clin doses. In: Scriver CR, Beaudet AC, Sly WS, Valle D, turbed cellular routing in infantile neuronal ceroid Genet. 1981;20:152-160. eds. The Metabolic and Molecular Basis of Inherited lipofuscinosis. EMBO J. 1996;15:5240-5245. 10. Lowry RB, Applegarth DA, Toone JR, MacDon- Disease. Vol 2. 7th ed. New York, NY: McGraw-Hill 4. Sleat DE, Donnelly RJ, Lackland H, et al. Associa- ald E, Thunem NY. An update on the frequency of mu- Book Co; 1995:2465-2494. tion of mutations in a lysosomal protein with classical copolysaccharide syndromes in British Columbia. Hum 17. Meikle PJ, Brooks DA, Ravenscroft EM, et al. Di- late-infantile neuronal ceroid lipofuscinosis. Science. Genet. 1990;85:389-390. agnosis of lysosomal storage disorders: evaluation of a 1997;277:1802-1805. 11. Ozand PT, Gascon G, al Aqeel A, Roberts G, Dhalla lysosome-associated membrane protein LAMP-1 as a 5. Beutler E, Grabowski GA. Gaucher disease. In: M, Subramanyam SB. Prevalence of different types of diagnostic marker. Clin Chem. 1997;43:1325-1335. Scriver CR, Beaudet AC, Sly WS, Valle D, eds. The lysosomal storage diseases in Saudi Arabia. J Inherit 18. Rider JA, Rider DL. Batten disease: past, present, Metabolic and Molecular Basis of Inherited Disease. Metab Dis. 1990;13:849-861. and future. Am J Med Genet Suppl. 1988;5:21-26. Vol 2. 7th ed. New York, NY: McGraw-Hill Book Co; 12. Krasnopolskaya KD, Mirenburg TV, Aronovich EL, 19. Claussen M, Heim P, Knispel J, Goebel HH, 1995:2641-2670. et al. Diagnosis and prevention of lysosomal storage Kohlschutter A. Incidence of neuronal ceroid- 6. Hopwood JJ, Brooks DA. An introduction to the ba- diseases in Russia [published erratum appears in J In- lipofuscinoses in West Germany: variation of a method sic science and biology of the lysosome and storage herit Metab Dis. 1994;17:111]. J Inherit Metab Dis. for studying autosomal recessive disorders. Am J Med diseases. In: Applegarth DA, Dimmick JE, Hall JG, eds. 1993;16:994-1002. Genet. 1992;42:536-538. Organelle Diseases. New York, NY: Chapman & Hall; 13. Czartoryska B, Tylki Szymanska A, Gorska D, Saw- 20. Santavuori P. Neuronal ceroid-lipofuscinoses in 1997:7-35. nor Korszynska D. Lipidoses detected in Poland through childhood. Brain Dev. 1988;10:80-83.

Nonviolence is the answer to the crucial political and moral questions of our time; the need for man to overcome oppression and violence without resorting to oppression and violence. Man must evolve for all human conflict a method which rejects revenge, aggression and retaliation. The foundation of such a method is love. —Martin Luther King, Jr (1929-1968)

Downloaded From: https://jamanetwork.com/ on 09/30/2021