Elucidating lysosomal diseases

Lysosomal diseases comprise a family of inherited metabolic disorders that generally involve progressive neurological manifestations and that primarily affect children. Although individually rare, collectively the diseases are not uncommon.

Symptoms vary greatly among the specific disorders, and can be mild or severe. Neurological signs and symptoms can include developmental delay, movement disorders and seizures. Other symptoms might affect the orthopedic, gastrointestinal, dermatological, cardiac and ophthalmologic systems. Although most of these diseases were described in the 20th century, their natural histories are not yet fully understood.

Through the generosity of a benefactor, Mayo Clinic in Rochester, Minnesota, is launching a research initiative aimed at learning more about lysosomal diseases and possible new treatments. A uniform program is being put in place to obtain consent and biosamples from every patient seen at Mayo Clinic with a suspected lysosomal disease. Through gaining more genetic samples, Mayo Clinic researchers expect to learn more about the prognosis for patients with specific lysosomal diseases and to enhance the design of future studies.

"We now have an opportunity to build on our strengths and to more readily offer our patients the opportunity to be continuing partners in research," says Marc C. Patterson, M.D., chair of Child and Adolescent Neurology at Mayo Clinic's campus in Minnesota. "We're at a very exciting time for lysosomal disorders."

Breaking the brick wall

In collaboration with the National Institutes of Health (NIH), Mayo Clinic has been at the forefront of research into the genetics of lysosomal storage diseases as well as efforts to improve patient care. Dr. Patterson has researched these disorders for 25 years, and was part of an NIH team that in 1997 identified a genetic mutation that causes Niemann-Pick disease type C (NPC). Mayo Clinic researchers currently are conducting next-generation sequencing of the genes of people with a lysosomal disease.

"With the power of next-generation sequencing, we can often get to a diagnosis more rapidly. We have one of the world's best biochemical genetics labs here to support our clinical diagnoses and investigate the significance of mutations," Dr. Patterson says. "One of the challenges is that next-generation sequencing is finding many more variants of undetermined significance. This is sometimes a brick wall that we come up against."

Mayo Clinic scientists are using clustered regularly interspaced short palindromic repeats (CRISPR) technology to make targeted mutations in flies. "That allows us to have a very rapid turnaround and see if a mutation of undetermined significance will produce a phenotype in that animal model," Dr. Patterson says.

The current lack of data on lysosomal diseases inhibits studies of potential treatments. "It's difficult for us to design studies with meaningful outcomes," Dr. Patterson says. "Natural history and treatment go hand in hand."

Because lysosomal diseases typically progress over decades, researchers must go beyond identifying clinical features of the disorders and find biochemical, imaging or electrical biomarkers that can serve as study endpoints. Mayo Clinic's multidisciplinary approach promotes collaboration among neurologists, medical geneticists and other specialists who treat people with lysosomal diseases.

"One of our important collaborations will be with our radiologists," Dr. Patterson says. "They have developed exciting techniques such as elastography, which will allow us to determine if lysosomal storage stiffens the brain."

Improving diagnosis and treatment

The mainstay treatment in lysosomal disorders is enzyme-replacement therapy, which doesn't enter the nervous system and thus can improve systemic manifestations of the diseases but not underlying neurological disease. As a result of the lysosomal initiative, Mayo Clinic will enhance its efforts to find small molecules that can be active in the nervous system to prevent accumulation of substrate in lysosomes.

A diagnosis of lysosomal disease can be overlooked, particularly in teenagers and young adults where the symptoms might be subtle. "As with many genetic disorders, lysosomal disease has with very rare exceptions been recognized first in its really severe childhood forms," Dr. Patterson says. "But there's no question there's a hidden pool of patients who have been diagnosed, for example, with atypical early-onset dementias or who have psychiatric presentations that are treatment resistant."

Boy with mucopolysaccharidosis Boy with mucopolysaccharidosis

Photograph of a boy with mucopolysaccharidosis shows full lips, puffy tissues around the eyes and use of a hearing aid — all suggestive of the diagnosis.

He cites a patient who, as a teenage girl in an old order religious community, abruptly refused to do chores and exhibited other behavioral changes. "She had a metachromatic leukodystrophy, which presents as schizophrenia," Dr. Patterson says.

Clues to diagnosis of lysosomal disorder include:

  • Progressive cognitive problems, such as developmental regression in a child or dementia in a young adult
  • Enlargement of the liver or spleen
  • Characteristic facial features, particularly in people with a mucopolysaccharidosis
  • Cataracts, sensitivity to light or abnormal eye movements
  • Hearing problems
  • Myoclonus, dystonia or seizures

"If you have an unexplained constellation of neurological findings with or without systemic changes in the skin, viscera, heart or bones, think about a lysosomal disease as a possibility," Dr. Patterson says. "At Mayo Clinic we have a tremendous opportunity, thanks to the generosity of our benefactor, to develop new approaches to diagnosing and treating lysosomal diseases, and to create awareness."