Prevalence of Lysosomal Storage Disorders FREE

Lysosomal storage disorders (LSDs) represent a group of at least 41 distinct genetic diseases, each one resulting from a deficiency of a particular lysosomal protein or, in a few cases, from nonlysosomal proteins, that are involved in lysosomal biogenesis. Most LSDs are inherited in an autosomal recessive manner, with the exception of Fabry disease and mucopolysaccharidosis (MPS) type II, which show X-linked recessive inheritance.

The number of LSDs is steadily increasing as new disorders are characterized biochemically and genetically. A deficiency of cathepsin K has recently been described that results in an LSD called pyknodysostosis.¹ In the last 2 years, infantile neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, has been shown to result from a deficiency of palmityl protein thioesterase,^2- 3 and classic late-infantile NCL has been shown to result from a deficiency of a carboxypeptidase.⁴ Many LSDs have been classified into clinical subtypes (such as the Hurler-Scheie definition of MPS type I or the infantile-, juvenile-, and adult-onset forms of Pompe disease), but it is clear that most LSDs have a broad continuum of clinical severity and age of presentation.

With the advent of molecular biology and the characterization of many of the LSD genes, it is now recognized that the range of severity may in part be ascribed to different mutations within the same gene. However, genotype-phenotype correlations do not always hold. In Gaucher disease, for example, there are sometimes substantial differences in the clinical manifestation of the disease between siblings and, in some instances, one sibling is severely affected while another is virtually free of disease.⁵ Other factors, including genetic background and environmental factors, presumably play a role in disease progression.

Although each LSD results from mutations in a different gene and consequent deficiency of enzyme activity or protein function, all LSDs share a common biochemical characteristic in that the disorder results in an accumulation of normally degraded substrates within lysosomes. The particular substrates stored and the site(s) of storage vary, although the substrate type is used to group LSDs into broad categories, including MPSs, lipidoses, glycogenoses, and oligosaccharidoses.⁶ These categories show many clinical similarities within groups as well as significant similarities between groups. Common features of many LSDs include bone abnormalities, organomegaly, central nervous system dysfunction, and coarse hair and facies.

There have been a number of reports on the prevalence of particular disorders in select populations. Of note is the level of Gaucher disease and Tay-Sachs disease in the Ashkenazi Jewish population, reported to be 1 per 855 and 1 per 3900, respectively.^5,7 Prevalences as high as 1 per 18,500 for aspartylglycosaminuria in the Finnish population⁸ and 1 per 24,000 for MPS type III in the Netherlands⁹ have also been reported. In addition, there have been a number of limited studies on the prevalence of some LSDs in different countries.^10- 15 However, in general, these studies have not been comprehensive and have not covered all LSDs. As the development of therapies for this group of disorders proceeds and the possibilities for neonatal screening are explored, it becomes important to obtain accurate values for prevalence of the disorders. These data will be required to accurately assess the cost of these disorders to public health care systems and will be a key factor in the adoption of screening and treatment programs for LSDs.

In this article, we present a summary of all LSD diagnoses in Australia for the period 1980 through 1996.

In this study, patients diagnosed as having an LSD have a reduced level of 1 or more lysosomal proteins, which leads to the storage of substrate within their lysosomes and results in the development of clinical problems and a subsequent reduction in their quality of life.

Retrospective data on the enzymatic diagnosis of LSDs, both from patient referrals and prenatal diagnoses for the period January 1, 1980, through December 31, 1996, were collected from the National Referral Laboratory, Department of Chemical Pathology, Women's and Children's Hospital, Adelaide, Australia, and from the Division of Chemical Pathology, Royal Brisbane Hospitals, Brisbane, Australia. All diagnoses were performed at these 2 centers and this represents all enzymatic analyses performed in Australia during this period. No data were collected on the diagnosis of pyknodysostosis, glycogen-storage disease type II-B, or the various forms of Batten disease, which are currently not diagnosed enzymatically in Australia.

Data on the number of births in Australia were collected from the Australian Bureau of Statistics (Canberra). Data were compiled according to disorder, year of diagnosis, and age of patient (including prenatal diagnoses), and correlated with Australian birth rates for each year. Instances in which there were 2 or more affected siblings were identified.

Incidence rates were calculated by dividing the number of postnatal diagnoses by the number of births during the study period. Prevalence rates were calculated by dividing the number of postnatal plus prenatal diagnoses by the number of births during the study period. The total number with prenatal diagnoses who were not live-born were not included in the denominator because this figure was not accurately known and would not have made a significant difference to the prevalence figures. Carrier frequency was calculated by dividing the prevalence value by 4 and finding the square root. Carrier frequency for X-linked disorders was equal to the prevalence values because the incidence of carrier births should equal the prevalence of affected births for these disorders.

For the period January 1980 through December 1996, there were 470 LSD-affected individuals diagnosed in the Australian population. In addition, there were 75 positive LSD prenatal diagnoses for affected fetuses, yielding a total of 545 diagnoses (Table 1). There was no significant increase in the rate of either clinical diagnoses or prenatal diagnoses during the study period (Figure 1). These diagnoses represent 27 different LSDs, whereas there were 10 LSDs for which there were no diagnoses in Australia during this period (Table 2). The prevalence of these disorders ranged from 1 per 57,000 for Gaucher disease to 1 per 4.2 million for sialidosis. The prevalence of LSDs as a group was calculated to be 1 per 7700 live births. When prenatal diagnoses were not considered, the incidence for LSDs was 1 per 9000 live births. Mucopolysaccharidosis, a particularly well-defined subgroup of LSDs, had a combined prevalence of 1 per 22,500 and represented 35% of all LSDs. Carrier frequencies were calculated from the prevalence values and ranged from 1 per 119 for Gaucher disease to 1 per 1027 for sialidosis (Table 1). Comparison of the number of LSD diagnoses in the different states of Australia (Table 3) indicates similar prevalence values in all major population centers. The exceptions, Australian Capital Territory, Northern Territory, and Tasmania, are all low-population areas that use genetic services in neighboring states and, as such, would have had some patients recorded in those states.

We determined the median age of the patients at diagnosis for each LSD and report these together with the low and high values for each disorder (Table 4). Although for some disorders, the number of diagnoses was not high enough to make these data statistically significant, it still gives an indication of the range of ages at which these disorders can present. Most disorders (18/27) had more than 10 diagnoses in this period. These data demonstrate that certain disorders, in particular Fabry disease, can present relatively late in life, with a mean age at diagnosis of 28.6 years, although for some individuals diagnosis was made in the first year of life. Clinicians should note the wide range of the clinical spectrum presenting in these disorders. In some LSDs, including Krabbe disease, MPS type I, Pompe disease, and Sandhoff disease, the median age at diagnosis was younger than 1 year, although the range of ages in each disorder still reflected a considerable variation in the clinical spectrum.

Of the 470 clinical diagnoses, there were 79 individuals who had 1 or more affected siblings. There were 4 families with twins, 9 families with an index case 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 individuals were adults (older than 18 years) when the disease was diagnosed.

The prevalence values for individual LSDs clearly define these as rare genetic disorders. Gaucher disease was the most common, with a prevalence of 1 per 57,000 births. However, when taken as a group, LSDs are far more common, with a prevalence of 1 per 7700 births. Each year in Australia there are, on average, 28 LSD diagnoses made, with an additional 4 to 5 prenatal diagnoses. Although exact national figures for the number of MPS referrals are unavailable, in South Australia, 150 to 250 urine screening tests for MPS are performed each year to diagnose MPS, on average, in 1 patient. White-cell enzymology, which is performed for most other LSDs, is performed on 400 to 450 patients per year nationally, resulting in an average of 18 diagnoses. These estimates suggest considerable overlap between clinical features of LSDs and other conditions, but may also indicate the presence of additional as yet undefined LSDs. Although prenatal diagnosis is possible for most LSDs, no practical prenatal screening tests are available for any LSD.

The life expectancy of a patient with an LSD depends on the particular disorder, the severity, and the treatment available. In MPS, this can range from lethal fetal hydrops to an almost-normal life expectancy.¹⁶ In most, if not all, disorders, there is a strong correlation among age at diagnosis, severity, and life expectancy. The difference between the median age (2.7 years) and average age (9.7 years) at diagnosis of an LSD in Australia reflects the relatively few adult patients who have an almost-normal life expectancy. Based on the average age at diagnosis of 9.7 years and an average of 28 affected individuals born each year, we estimate that there are currently about 270 individuals with an undiagnosed LSD and possibly up to twice that number of patients with a diagnosed LSD in Australia.

That there were only 2 centers involved in the enzymatic diagnosis of LSDs greatly facilitated the collection of data for this study; as a consequence, we have a high level of confidence that few diagnoses were missed. Our confidence is supported by the state-by-state breakdown of the prevalence values for the LSDs, with the 5 major population centers showing similar prevalence data. Had 1 or more states missed a significant number of cases, this would present as uneven prevalence values among states. In addition, there was no significant variation in the number of diagnoses made per year during the study period; this would suggest that the patient identification rate is constant and close to 100% for these disorders. It is possible, however, that there are some individuals at the less-severe end of the clinical spectrum of some disorders, particularly in the adult population, in whom an LSD was not diagnosed. Gaucher disease is likely in this group. Similarly, we observed that there was no increase in the rate of prenatal diagnoses for the period of the study; this again reflects the steady rate of diagnosis of these disorders.

To calculate incidence, prevalence, and carrier frequency values, we needed to make certain assumptions. We assumed that the rate of postnatal diagnosis was equivalent to the birth rate for each disorder. If the postnatal diagnosis was less than the birth rate, as a result of undiagnosed early death, then our estimates of incidence values would be low. This is unlikely because all unexpected child deaths in Australia result in postmortem examinations, including histopathology studies. We also assumed that the parents of affected individuals were heterozygous for the disorders (with the exception of X-linked disorders). If this were not the case, then our estimates of carrier frequency would be low; however, homozygous parents, in what are predominantly childhood disorders, are not common and, as such, would have little effect on our carrier frequency estimates.

The Australian population is predominantly of British extraction, with a significant contribution from other European countries and, to a lesser extent, Asian countries. As such, this population would be comparable with that of most Anglo-Celtic countries. Therefore, these results could be extrapolated to the white non-Hispanic populations in the United States, Canada, and the United Kingdom. However, a higher proportion of Ashkenazi Jews in a community may increase the prevalence of Gaucher disease and Tay-Sachs disease.

Although no data are available on the ethnic background of those diagnosed as having an LSD, we see no evidence that the Ashkenazi Jewish population contributed significantly to the figures for either Gaucher disease or Tay-Sachs disease in Australia. The Ashkenazi Jewish population in Australia is estimated to be 105,000 and is concentrated in Victoria and New South Wales. Despite this, we see no increase in the prevalence of either Gaucher disease or Tay-Sachs disease in these states compared with other states in Australia. This may be the result of outbreeding from the Jewish community into the general population. A screening program for the detection of Tay-Sachs disease carriers in the Jewish community was commenced in 1994; however, this would have had only a minimal effect on this study, which covered the period 1980 to 1996.

The cost to the community, in particular the health care system, of individuals with LSDs is significant. We have calculated the medical costs for a patient with severe MPS I who has not had a bone marrow transplant to be approximately Aust $80,000 (US $56,000) per year, based on hospital admissions, hospital procedures, and outpatient visits during a 2.5-year period. In addition, such a patient would require full-time nursing home care while attending a special school, further increasing the cost to the community. Bone marrow transplantation costs, on average, Aust $41,000 (US $29,000). Enzyme replacement therapy for Gaucher disease currently costs between Aust $140,000 and $250,000 (US $98,000-$175,000) per year, although the cost for enzyme replacement therapy should decrease as more efficient enzyme production systems are developed. Given that some of the affected individuals are at the less-severe end of the clinical spectrum, the total cost to the community for individuals with an LSD in Australia is thought to be in the tens of millions of dollars per year. Although it is useful to determine the cost of these disorders to the community, in particular to the health care system, this represents only a fraction of the real cost, in human terms, of these disorders.

There were 39 families with more than 1 affected child; this highlights the need for early diagnosis of these disorders because in most cases, there were 2 affected children born before the first was diagnosed as having an LSD. Early detection of LSDs, such as that possible in the neonatal screening programs for phenylketonuria and other genetic diseases, would provide the option for prenatal diagnosis for many more families carrying these disorders. In addition, early detection would maximize the efficacy of current and proposed therapies for LSDs. The efficacy of these therapies, particularly for those LSDs involving central nervous system and bone pathologies, will rely heavily on the early diagnosis and treatment of the disorder, before the onset of irreversible disease. A further consideration, critical to bone marrow transplant therapy, is that early diagnosis of the LSD will allow clinicians to take advantage of the window of opportunity presented by the naturally suppressed immune system of the neonate to maximize the chances of a successful engraftment. Early intervention has the potential to reduce costs associated with LSDs. Studies into the development of neonate screening for LSDs are currently in progress.¹⁷

Recently, there have been several advances made in the understanding of NCLs, a group of at least 4 disorders classified by age at onset. Previously, these disorders were diagnosed histopathologically rather than enzymatically and, consequently, we have no incidence data available. However, NCLs are relatively common: estimates of incidence levels range from a global incidence for all forms of 1 per 12,500¹⁸ to 1 per 78,000 for all forms in Germany.¹⁹ In Finland, where there is a particularly high level, incidence values of 1 per 13,000 for infantile and 1 per 21,000 for juvenile forms have been reported.²⁰ Clearly, NCLs are going to contribute importantly to the overall prevalence of LSDs. A rate of 1 per 50,000 births for NCLs would alter the prevalence of LSDs from 1 per 7700 to 1 per 6700. Further epidemiological studies are required for this group of disorders.