Lysosomal Storage Disease (LSD) is a rare disorder characterized by a deficiency or malfunction of lysosomal enzymes, which act as “intracellular scavengers,” leading to the accumulation of harmful substances and eventually to organ damage.
Mucopolysaccharidosis, Pompe disease, Gaucher disease, Fabry disease, Niemann-Pick disease, and Krabbe disease are representative, and the importance of early diagnosis is emphasized as irreversible damage cannot be avoided if treatment is missed.
In Korea, newborn screening tests for six LSDs have been covered by health insurance since January 2024, making early detection of the disease possible.
In just one year, more than a dozen children were diagnosed early across the country, and many of them were able to start treatment before the onset of the disease and develop normally. This is evidence that the diagnosis and treatment system is starting to work and signals a structural shift.
However, faster diagnosis does not mean that all problems have been solved.
The path from diagnosis to treatment is still fraught with structural limitations, including capacity gaps between hospitals, shortages of specialized personnel, and cuts to genetic testing. In particular, as most patients flock to large hospitals in the Seoul metro region, there are growing calls for policy complements to maintain and expand the precision diagnosis system.
Korea Biomedical Review interviewed Professor Chae Jong-hee of the Department of Clinical Genomics at Seoul National University Hospital and the director of the hospital’s Rare Disease Center about the changes in the field since the introduction of newborn screening, specific patient cases, and the achievements and challenges of the early diagnosis system.
Question: What are lysosomal storage diseases?
Answer: Lysosomes act as “intracellular scavengers,” breaking down and removing unwanted materials from the cell. Enzymes are needed to perform this function, and most lysosomal storage diseases start when these enzymes are not produced or function properly due to genetic abnormalities. When enzymes are deficient, harmful substances that should be broken down and released gradually accumulate in the cell, impairing the cell's function.
There are about 70 different LSDs reported to date, but only six or seven of them are treatable. Each disease has a very different clinical presentation depending on the deficient enzyme type and the organ in which the malfunctioning substance accumulates without breaking down. Therefore, irreversible damage can occur if not diagnosed and treated early, requiring specialized care.
Q: What is the number of LSD patients in Korea, and how many are diagnosed early?
A: Currently, there are no accurate statistics on the number of patients with rare diseases, including lysosomal storage disease (LSD), in Korea, but the number of LSD patients in clinical practice is estimated to be around 400 to 500. Based on the Rare Disease Management Act, the government is working to build data and register patients.
In the past, getting a diagnosis by visiting various hospitals was called “Diagnostic Odyssey,” but recently, the term “Diagnostic Journey” has been used to shed more positive light on the process, and a campaign is underway.
The diagnosis period has been significantly shortened compared to the past. While overseas, the average is about seven years, in Korea, it has been reduced to two to three years. In recent years, diagnosis has been made within a year and a half or as early as a few weeks if connected to the right specialist.
Advances in genomic diagnostic technology have played a decisive role in this change. At an institution like Seoul National University Hospital, where experience and technology have been accumulated, multidisciplinary care and precision medical technology are combined to provide fast and accurate diagnosis. Korea's diagnostic capabilities are recognized as one of the best in the world.
Q: What changes have you seen in diagnosis and treatment since the introduction of newborn screening for LSD in January last year?
A: In the case of early-onset Pompe disease, just one year after the introduction of newborn screening, six newborns were diagnosed early in the country, and four of them started treatment. This is significant because, with early diagnosis, appropriate and rapid treatment can be initiated, allowing for normal development without complications.
Two to three children each were diagnosed and treated early for Krabbe disease and mucopolysaccharidosis. This is more than just a number—each of these children could become a world-changing figure, like Wolfgang Amadeus Mozart or Steve Jobs. To see this kind of change in just one year is a remarkable achievement.
Q: How does confirmation work if the screening test is abnormal?
A: A positive lysosomal screening test does not always mean a diagnosis. There is a possibility of false positives, so most patients are retested. If the retest confirms the abnormality, they are quickly referred to a rare disease specialist for further testing and a final diagnosis.
Currently, rare disease specialty centers are designated by region nationwide. If an abnormality is found in the screening test, the patient is transferred to an easily accessible center for confirmatory testing. During this process, enzyme and genetic tests determine the disease.
Most hospitals operate a rapid diagnosis system that provides confirmation results within two to three weeks for diseases that can be diagnosed and treated early. Tests that used to take more than two months have been improved so that patients can receive results within one to two weeks if early intervention is necessary, taking into account screening results, family history, and current condition. In the case of Seoul National University Hospital's Rare Disease Center, a separate rapid diagnosis system is in place to provide enzyme tests or genetic diagnosis results within three to five days and seven days at the latest if the disease is strongly suspected.
Q: What are treatable LSDs, and how do you treat them?
A: Lysosomal storage diseases (LSDs) are mostly treatable with enzymatic therapies. Currently, treatments are available for mucopolysaccharidosis, Pompe disease, Gaucher disease, Fabry disease, and Niemann-Pick disease. In the case of Krabbe disease, once diagnosed, bone marrow transplantation is the mainstay of treatment before the onset of symptoms. However, recent advances in gene therapy are also being made.
Enzyme replacement therapy can be very effective. In Pompe disease, for example, patients with early-onset and infantile forms of the disease have benefited most from newborn screening. Major organs, such as the heart, are often damaged when symptoms appear. While treatments can prevent further damage, they can't restore lost function. This means that if treatment is delayed, the patient will have to live with a weak heart for the rest of their life.
However, suppose early-onset Pompe disease is diagnosed and genetically tested within the first two weeks of life, and enzyme therapy is administered immediately. In that case, the child has an excellent prognosis and can lead a nearly normal life.
Q: How does patient monitoring and management proceed after an LSD diagnosis?
A: There is a set monitoring protocol for all lysosomal storage diseases (LSDs). Neurological and physical examinations, MRI scans and follow-ups, and enzyme level checks are performed regularly according to criteria set by experts in the field. An organized system ensures that abnormalities are detected and lead to early treatment.
These procedures are called “surveillance protocols” or “monitoring protocols." Depending on the nature of the disease, specific tests are required at six-month, one-year, and two-year intervals. The results of these tests can help refine when and how to start treatment and allow for a more personalized approach.
These protocols and guidelines are constantly being revised based on medical evidence, so healthcare providers must keep up with the latest research and learn about the latest advances.
Q: Is Korea's current rare disease treatment environment sufficient to follow these protocols and guidelines?
A: At Seoul National University Hospital, more than 500 medical workers are involved in the outpatient care of rare disease patients, and the Children's Hospital, in particular, operates like a children's rare disease center because most patients have rare or complex diseases.
Although the treatment is well organized, its multidisciplinary nature leads to a manpower shortage and overworked medical staff. In particular, about 75% of pediatric rare diseases are diagnosed in infancy and early childhood. Still, there is an overwhelming shortage of manpower to diagnose and treat them.
Despite the high capacity for care, the structural foundation to sustain it is weak. Despite government policies and support, barriers that are hard to see on the ground remain.
Rare diseases are not financially rewarding, which tends to discourage younger physicians from entering the field. Both care and research require long-term experience, but the outcomes are difficult to quantify, and the profitability is low, making it difficult for hospitals to invest heavily.
Many rare diseases begin in childhood, but the number of pediatricians is declining, and fewer are entering the field. The workforce base is becoming increasingly fragile.
The issue of genetic testing is also sensitive. While there are some issues of overuse, cuts to tests that are reasonably ordered by national accrediting bodies will disrupt diagnosis, especially if a screening test is positive. Genetic testing is an essential step.
In the field, the number of LSD patients detected by screening is increasing rapidly. However, there is still a shortage of available specialists. Even though there are designated base institutions for each region, the treatment is concentrated in large hospitals in the metropolitan area or among a few specialists.
There is also a paradoxical situation where the number of false positives is increasing, which requires resources to confirm them, leaving relatively little time for diagnosis and treatment of severe patients. Therefore, expanding screening tests alone is not enough; overhauling the diagnostic system, training specialized personnel, and resolving capacity gaps between regions are also needed.
Q: What improvements are needed to improve early diagnosis and access to treatment for LSDs?
A: The most important thing is the systematic accumulation of experience and data to improve early diagnosis and access to treatment for lysosomal storage diseases (LSDs). Data on a national level, including the number of positive screening tests, the proportion that leads to actual diagnosis, the age of onset, and the clinical course of diagnosed patients, must be collected and analyzed.
It is also essential to establish a patient genetic database. Once the number of cases is sufficiently accumulated, it will be possible to develop protocols that prioritize the detection of common genetic variants in Korea, reducing the burden of testing on patients and wasting medical resources.
Currently, Seoul National University Hospital is planning to screen some newborns for rare diseases and metabolic diseases, including LSD, and the Center for Rare Diseases is continuing to systematically collect and analyze genetic and clinical data of LSD patients through multidisciplinary collaboration with the Department of Clinical Genomics.
Through these data-driven activities, we aim to analyze the types of diseases, treatments, and management flows most frequently visited over the past two years and lead to discussions on improving policies.
Hospitals should not be limited to providing medical treatment. Based on the data, they should also extend the scope of analysis to problems at the point of care and suggest directions for improvement. Seoul National University Hospital has been designated the National Rare Disease Central Support Center for operating rare disease centers by region until 2023. It has experience supporting regional rare disease centers nationwide and establishing an efficient network through cooperation.
Q: How accessible are rare disease treatments in Korea?
A: In Korea, access to orphan drugs, especially costly ones, is relatively good, although not all newly developed and expensive drugs are introduced quickly. Health insurance coverage standards are in the middle of the pack globally, and patient burden is not high compared to other developed countries.
One thing to consider, however, is that insurance for high-priced orphan drugs in South Korea operates on a “post-payment refund system.” In this system, patients pay the full cost of treatment first and receive reimbursement from the insurance organization after a specific period, which can be a burden of tens of millions of won in the case of costly drugs.
To compensate for this limitation, devices that reduce the burden of upfront payment, such as advance payment systems, have been discussed recently. As the introduction of high-priced drugs is expected to increase in the future, institutional responses and flexible insurance systems will continue to be needed.
Q: What would you like to share with patients and families undergoing the diagnosis and treatment process?
A: The scariest moment in lysosomal storage disease (LSD) is when you are diagnosed. The early-onset form of the disease requires lifelong treatment, and the late-onset form is burdened by the uncertainty of not knowing when symptoms will appear. However, sophisticated monitoring protocols are already in place for late-onset disease to catch early signs and start treatment at the right time. With expert counseling and follow-up care, it can be managed reliably.
Most importantly, it's important to remember that this is not the end of the road. Even if you're uncomfortable with the current treatment, medicine is constantly evolving, and there are likely to be more convenient and effective treatments in the future. For now, staying positive and supportive as a family is the most important thing. Ultimately, the process will greatly support both the child and the family.
It is also not uncommon for many parents to give up trying for a second child because they are worried about the risk of relapse. Prenatal genetic counseling is essential because LSD is a chromosomally recessive disorder with many X-linked conditions. Nowadays, prenatal diagnosis and pre-implantation genetic testing are available, so it is possible to have a healthy next child. Please take advantage of consulting with a specialist.