Lysosomal storage diseases (LSD) are a group of over 70 diseases that are distinguished by lysomal dysfunction and mostly inherited as autosomal recessive traits with some being X-linked1. They are a heterogeneous group of rare multisystem genetic disorders that occur mainly in infancy and childhood2. We have previously looked at two of the most common types, Gaucher Disease and Fabry Disease. Here we will not look at any single LSD, rather we will take a more general look at not only the diseases, but also how such an array of diseases with a similar cause are not only diagnosed, but also treated.

LSD's can be caused by a various number of variants in various genes that affect different parts of the body.

LSDs can be caused by a various number of variants in various genes that affect different parts of the body.

Incidence and Prevalence

Let’s take a look at how common this rare genetic disease is. The group of diseases as a whole is quite common; it is estimated that 1 in 5,000 suffer from an LSD. However once we look at the individual diseases, they become much rarer ranging from 1 in 50,000 to 1 in 250,0001. Due to founder effects, the incidence of certain LSD’s can vary among certain ethnic groups as well. Aspartylglucosaminuria for example is estimated to be <0.2 in 100,000, but is common in the Finnish population at 2.3 to 3% 1. Differences in population types can also be observed with other LSD’s like Gaucher disease type I (Ashkenazi Jews), Tay-Sachs disease (Ashkenazi Jews), Pompe disease (Netherlands), and Fabry disease (Nova Scotia) among others1. With so many diseases affecting certain populations differently, effective diagnosis of LSD’s is prudent.

Diagnosis

LSD constitutes a wide range of diseases including a wide range of clinical symptoms that may contain organ dysfunction, neurological and skeletal disorders, that may vary depending on the kind of LSD. Traditionally, enzyme activity assays are conducted, followed by a second stage of diagnosis that entails molecular diagnosis through next generation sequencing (NGS) which is considered the gold standard for LSD3. NGS provides confirmation of enzyme activity assays and determination of mutation in the proband. It is demonstrated to be superior to other genotyping methods with false positives/negatives results not being identified4. It has also been demonstrated as being an effective prenatal diagnostic method without needing genetic pedigree information for LSD diagnosis including Gaucher’s disease5.

The effectiveness of NGS has helped to promote the idea of reversing the current status quo of LSD diagnostic testing, prioritizing NGS before an enzyme assay test. NGS can provide a diagnostic option for patients affected by certain conditions, which escape proper diagnosis by other methods so much so that clinicians are now considering genomic sequencing to replace conventional biochemical tests by improving newborn screening (NBS)2. Via both exome and targeted sequencing, NGS has been used to diagnose LSD’s as a first tier diagnostic tool2. The value of NGS as a first tier diagnosis tool is based on its ability for effective carrier screening studies of high-risk populations, like those mentioned above (Ashkenazi Jews, Finland, Nova Scotia, Netherlands). NGS is also capable of differentiating genetically heterogeneous diseases with overlapping phenotypes, like Pompe disease, limb-girdle muscular dystrophies, and Gangliosidosis2. This is more true with LSD which is composed of 70 different disorders. Conducting separate assays is not only costly but time consuming; making NGS a first tier diagnostic option would help in diagnosing at an earlier stage, which would then result in faster treatment. Also, there is also the possibility to diagnose before certain symptoms are present, treating the disease early, delaying loss of functions. A second option of waiting for early signs of the disease to occur before treatment is implemented is also an option, as could be the case if a disease is identified in early childhood but symptoms may not develop until adulthood2. Many countries have now been instituting several NBS programs in various countries across the world, including Pompe, Fabry, Gaucher, Karabbe, and Niemann-Pick2. Italy for example has NBS programs for Pompe, Fabry, Gaucher, and MPSI2.

Treatment

While there is no cure for LSD as a whole nor any individual LSD, various treatments are available for several of the diseases6. Let’s take a look at some of the treatments available giving hope to those affected by these diseases.

  • Fabry disease (GLA gene)
    One of the most popular medications is Fabrazyme that was developed by Sanofi as an enzyme replacement therapy (ERT) taken intravenously every 2 weeks that was first approved by the FDA in 20037. Agalsidase alfa is also an ERT that was developed by Takeda that is administered by a continuous intravenous infusion every two weeks8. Takeda also has a special program where it distributes its enzyme-replacement therapy medications to patients in underserved communities 9.

  • Gaucher disease (GBA gene)
    There are currently various treatment options for Gaucher disease. Surgical procedures can include bone marrow transplant or spleen removal which has become a last resort option since the inception of enzyme replacement therapies10. Other medications include Zavesca marketed by Actelion, and Cerdelga and Cerezyme both developed by Sanofi which are oral medications. Cerdelga interferes in the production of fatty substances 10 while Cerezyme replaces the enzyme glucocerebrosidase. Osteoporosis drugs can also be taken to help in rebuilding bone weakened by Gaucher disease10.

  • Pompe disease (GAA gene)
    The current treatments offered by doctors include supportive care and an ERT, alglucosidase alfa2 that was first approved by the FDA in 2006 that is currently manufactured by Sanofi under Lumizyme.

  • Krabbe disease (GALC gene)
    Currently for most cases, only palliative and supportive care is available. Patients that are diagnosed early before symptoms arise or in cases of later onset may be treated with hematopoietic stem cell transplant (HSCT) therapy11.

  • Metachromatic leukodystrophy (ARSA and PSAP genes)
    The current treatment available focuses on preventing nerve damage, slowing progression of the disorder, preventing complications and supportive care. The medication currently used only targets the symptoms such as behavioral problems, seizures, gastrointestinal issues, infection and pain12.

  • Mucopolysaccharidosis (IDUA, IDS, SGSH, NUGLU, HGSNAT, GNS, GALNS, GLB1, ARSB, GUSB genes)
    The two main treatments include hematopoietic stem cell transplant (HSCT) and ERT that replaces the missing enzyme. HSCT is dependent on timing; it is most effective early in the disease prior to two years of age13. The current available enzyme replacement therapy medication that is injected into a vein through an IV once per week is Aldurazyme, manufactured by BioMarin Pharmaceutical, Inc13.

The full extensive list of medications are not listed in this blog post, rather this is meant to show that there is progress being made in the development of treatment options for the various LSD’s. New treatment options are also being developed as well. Clinical trials are also in progress for LSD’s like Gaucher disease 10; experimental gene therapy trials for Krabbe disease11, Fabry disease1, Pompe disease1, Sanfilippo syndrome 1 among others; clinical trials including gene therapy, enzyme replacement therapy, and substrate reduction therapy for Metachromatic leukodystrophy12; and gene transfer clinical trial for Mucopolysaccharidosis14.

The challenge with LSD’s, is due to them being multisystem disorders with heterogeneous genetic profiles and overlapping clinical symptoms. Progress in identifying, diagnosis, and treatment has steadily been increasing over the years. However, there is still much effort that researchers and clinicians must put forth in order to help those with this common rare disease.

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References

  1. Platt, Frances M.; d’Azzo, Alessandra; Davidson, Beverly L.; Neufeld, Elizabeth F.; Tifft, Cynthia J. Lysosomal Storage Diseases. Nature Reviews Disease Primers. 4 (1): 1–25 (2018).
  2. La Cognata, Valentina, et al. Highlights on Genomics Applications for Lysosomal Storage Diseases. Cells 9.8: 1902 (2020).
  3. Meikle, Peter J., Michael J. Fietz, and John J. Hopwood. Diagnosis of lysosomal storage disorders: current techniques and future directions. Expert review of molecular diagnostics 4.5: 677-691 (2004).
  4. Meikle, Peter J., Michael J. Fietz, and John J. Hopwood. Diagnosis of lysosomal storage disorders: current techniques and future directions. Expert review of molecular diagnostics 4.5: 677-691 (2004).
  5. Mokhtariye, Armin, et al. Diagnostic Methods for Lysosomal Storage Disease." Reports of biochemistry & molecular biology 7.2: 119 (2019).
  6. WebMD. What Are Lysosomal Storage Disorders?
  7. Fabrazyme. Fabrazyme Agalsidase Beta.
  8. Takeda. Product Monograph
  9. Fabry Disease News. Charitable Program by Takeda Helps Patients Worldwide Gain Treatment
  10. Mayo Clinic. Gaucher Disease
  11. Healthline. Krabbe Disease
  12. Mayo Clinic. Metachromatic leukodystrophy
  13. US Department of Health and Human Services. Mucopolysaccharidosis type I.).
  14. US National Library of Medicine. Clinical Trials