Mission of Johns Hopkins Lysosomal Storage Disease Program

   Johns Hopkins Lysosomal Storage Disease Program is committed to offer a comprehensive and personalized clinical care for patients with lysosomal storage diseases. Lysosomal storage diseases (LSDs) are genetic disorders that are caused by specific enzyme deficiencies resulting in multi-systemic disease, presenting with neurological, renal, cardiovascular, gastro-intestinal, musculo-skeletal, ophthalmological and respiratory problems (fig.1). The LSD program provides diagnosis, management, treatment and monitoring of diverse treatments available for patients affected with LSD including enzyme replacement therapy, small molecule therapies, hematopoietic stem cell therapy and others.

   Johns Hopkins LSD program unites outstanding physicians from multiple specialties making up a broad and cooperative team devoted to offer excellence in patient care. Dr. Gustavo Maegawa MD, PhD coordinates the multi-disciplinary group from primary specialties as Pediatrics and Medicine, and their respective subspecialties. Our team has experience and resources to treat a wide range of complications commonly seen in these inherited metabolic diseases.    

   Based on the Johns Hopkins tradition on integrating clinical and basic research, teaching and patient care, LSD program are also involved in several clinical studies including clinical trials with the most advances therapeutic agents. The unique characteristics of the program is integrated approach to patients suffering from multi-systemic LSDs following Johns Hopkins founding principles of pursuit of excellence and innovation in patient care.

Johns Hopkins Landmarks and Contributions in Lysosomal Storage Disease

   Historically, Johns Hopkins has a long and contributing tradition in the field of LSDs. Dr. Victor A. McKusick MD, father of Modern Medical Genetics then Johns Hopkins University Professor of Medical Genetics performed elegant and important clinical observations in several types of LSDs. Dr. McKusick established and firstly reported the classifications of the different mucopolysaccharidosis (LSDs caused by accumulation of mucopolysaccharides resulting in multiple health problems) which stands until today. Metachromatic leukodystrophy, one of the most devastating LSD affecting predominantly the central nervous system (CNS) and peripheral nerves, had its biochemical defect (arylsulfatase A deficiency) identified by Drs. Michael M. Kaback MD and R. Rodney Howell MD from the Department of Pediatrics at Johns Hopkins. Lately, Dr. Kaback did pioneer and innovative work on the development of simple and reliable test for the diagnosis of Tay-Sachs disease, which also allowed the identification of carriers this LSD. Considering the high-incidence in individuals from specific ethnic groups, including Ashkenazi Jew and French-Canadian, the availability of test for carriers has had an enormous medical and social impact in the prevention of the infantile and fatal form of this neurological LSDs. In 1972, Dr. Hugo Moser MD, Johns Hopkins University Professor of Neurology and mostly known by his work in the diagnosis and treatment of peroxisomal disorders, identified the biochemical defect of Farber disease a LSD caused by ceramidase deficiency. Dr. Moser early on reported the initial failure of enzyme replacement therapy (ERT) to treat neurological complications of LSDs concluding that “…independent of the method by which exogenous hydrolase is administered and procedures to perturb the blood-brain barrier must be devised to enhance the entry of deficient enzyme into the CNS of patients…”. Dr. George Thomas PhD, former director of biochemical genetics laboratory at Kennedy Krieger Institute play an essential role in the identification of the biochemical defect of several LSDs including α-mannosidosis (α-mannosidase deficiency), mucolipidosis type II (sialidase deficiency), the deficiency of β-galactosidase in Morquio-like syndrome, (now MPS-IVB) and free sialic acid storage disease.

   More recently, Dr. Craig Montell PhD, Professor of Department of Biological Chemistry at Johns Hopkins, a senior neuroscientist, developed a fruit fly model for a LSD known as mucolipidosis type IV. Using this model, Dr. Montell’s group characterized cellular and molecular mechanisms of the neurodegeneration typically observed in patients with ML-IV, a LSD caused by defected lysosomal protein causing the severe early childhood neurodegenerative clinical phenotype of this disease. Dr. Gustavo H.B. Maegawa, MD, PhD, Assistant Professor and Attending Physician in the McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, is responsible for Johns Hopkins Lysosomal Storage Disease Program. Dr. Maegawa’s research is mainly committed to the development novel therapies for LSDs based on the molecular pathogenesis of LSDs. Dr. Maegawa methods are using patients LSDs cell lines to discover molecules that can attenuate or prevent events that can trigger the disease process in these devastating diseases.

What are Lysosomal Storage Diseases?

   Lysosomal storage diseases are caused by the malfunction enzymes that normally degrade several substances in the cells of the body. These enzymes are found in sac-like structures inside cells called lysosomes. Lysosomes function as recycling units of each cell, which contains hundreds of thousands of them. Lysosomes harbor specific enzymes that breakdown several substances, including proteins, sugars and lipids into simple products that the cell then utilizes to build renewal these substances (fig.1). Lysosomes and other related structures called endosomes are also essential for the transport or “trafficking” of different substances inside each cell. Each of these lysosomal enzymes has specific substances that they are capable of degrading. In the case of deficient enzyme of one of these enzymes, buildup of one and other substances occur resulting initially in dysfunctional lysosomes and then the whole cell. This then is reflected in the malfunction of several and body's cells forming different organs and systems resulting in serious and progressive health problems.

Figure 1. Principles to understand Lysosomal Storage Diseases.
(click on the figure for larger image)

   Lysosomal storage diseases (LSDs) are genetic diseases caused by specific enzyme deficiencies that result in the buildup of undegraded substance inside cell organelles called lysosomes, which are sac-like structures present in very cell in our body. Lysosomes are recycling units, i.e. they are responsible for breaking down lipids, sugars and proteins into small units that can be re-utilized by the cell. Lysosomes and related endosomes are responsible for intracellular trafficking that is essential for cell function. The figure shows a blood cell from a normal individual and from a patient with a LSD, showing the enlargement of several lysosomes containing the undegraded substance. This ultimately results in the impairment of lysosomal function and consequently cell function in multiple organs and systems. Therefore, LSDs manifest as systemic diseases in patients with multiple and progressive neurological, renal, cardiovascular, gastro-intestinal, musculo-skeletal, ophthalmological, cutaneous and respiratory problems.

Almost 60 LSD have been described known lysosomal storage diseases. Some common LSD include:

Fabry disease – known as X-linked genetic disease but affect both male and females with kidney, heart and pulmonary problems, chronic pain and s typical skin sign

Gaucher disease – progressive LSD causing enlargement of spleen, liver and bone lesions. Some forms affect also the brain causing sever neurological problems

Mucopolysaccharidosis (I-VII) – result from accumulation of mucopolysaccharides in causing progressive damage multiple organs and systems including heart, bones, joints, eyes, respiratory system and central nervous system. While the disease may not be apparent at birth, signs and symptoms develop with age as more cells become damaged by the accumulation of cell materials

Niemann-Pick C disease – results in progressive neurological condition along with enlargement of the spleen and liver, as well as lung disease

Pompe disease - an often fatal is presented in infancy with storage disease in which glycogen builds up mainly in the heart, initially also known as acid maltase deficiency. If it manifests in childhood and adulthood, Pompe can cause progressive shoulder, hips and respiratory muscles

Metachromatic leukodystrophy and Krabbe disease – devastating LSD that result in progressive and neurodegerative diseases. When presented in adulthodd are associated with neuropathies and psychiatric problems.

Tay-Sachs disease - a LSD causing severe and progressive causing degeneration of the brain in infants and nerve (pain and tactile sensation problems) and psychiatric problems in adolescence and adults

   The LSD are genetic disorders are rare. However taking together LSD incidence has shown recently to be 1/2,000-3,000 live-births. Some specific LSD can occur more often in certain ethnic groups including Ashkenazi Jew (Gaucher, Niemann-Pick A, mucolipidosis-IV, Tay-Sachs), French-Canadian (Tay-Sachs), Cajun (Tay-Sachs), infantile neuronal lipofuscinosis (Finland). Because these diseases follow several patterns of inheritance, a person's risk of passing this condition on to his or her children depends on the disease and the individual's family background. 

Is any treatment available for patients with LSDs?

  • The treatment of LSDs can be divided in supportive/symptomatic and specific treatment (fig.2).
  • Both treatment modalities complement each other and together they aim the best quality-of-life for the affected patients and their families.
  • Supportive treatment involves multi disciplinary care of different specialties. Usually the multiple problems LSD patients develop have a symptomatic/supportive treatment to address the secondary effects of the accumulation of substance in lysosomes. Several specialties, including cardiology, anaesthesia, orthopedics, otorhinolaryngology, ophthalmology and neurology, neurosurgery, as well as many paramedical groups including for example physiotherapy, occupational therapy, nutrition, audiology, speech therapy and psychology, will all have an important role in determine the clinical outcome and quality of life for patients with LSDs.

Figure 2 - Different Types of Treatment for Lysosomal Storage Diseases.

   In general the supportive/symptomatic treatment treats the secondary effects of lysosomal enzyme deficiency. The specific treatment approaches addresses either the accumulated substance (surgical procedures and substrate reduction therapy, SRT) or defective lysosomal enzyme by gene therapy (replacing the altered gene that generates a defective enzyme) or by enzyme augmentation therapy. This therapy is based on providing the normal enzyme through enzyme replacement therapy (ERT) or hematopoietic stem cell that provides donor cells that produce the normal that is taken by the patients disease cells with enlarged and dysfunctional lysosomes. A novel type of treatment is focus on enhancing the activity of the deficient enzyme that can still have a small but still insufficient enzyme activity.

Enzyme-augmentation therapy

Hematopoietic stem cell transplantation (HSCT)

  • The aim is to use donor derived cells as a source of enzyme.
  • The cell source can come from bone marrow or umbilical cord, donor macrophages can infiltrate diverse patients’ tissues including the central nervous system. These donor-cells secrete normal lysosomal enzyme (able to breakdown the accumulated substrate) which is uptake by patients cells, reaching directly their enlarged lysosomes and cleaning them as the defect. 
  • When done before patient with sever from of disease starts to develop neuroregression, HSCT has shown to be efficacious in one specific LSDs, MPS type 1 and a treatment algorithm is described. However, it has not proven to have the same result in most LSDs. In addition, in medical literature, most data available is anecdotal or a small case series. In Krabbe disease and metachromatic leukodystrophy, initial benefit has demonstrated, preventing the fulminant course of these neurodegenerative diseases.

Enzyme-replacement therapy (ERT)

  • Six LSDs are treated with ERT – Gaucher disease, Fabry disease, mucopolysaccharidoses types I, II and VI
  • ERT was originally developed for Gaucher disease type 1 (without neurological problems) using glucocerebrosidase purified from human placentas. The development of recombinant enzyme produced in cultured cells increased the scale of the production. The major limitation of ERT is its inability to treat neurological symptoms of most LSDs since the ERT agent is unable to cross the blood-brain barrier, which is a physiological barrier located in blood vessels located in the brain and spinal cord
  • Patients on ERT required to receive the recombinant enzyme diluted in normal saline intravenously every 1 or two weeks.
  • The response to ERT can be noted by 6-12 months evaluating different clinical outcomes. Some patients develop infusion-related reactions which consists of

Substrate Reduction Therapy (SRT)

  • SRT is based on reducing the production of the accumulating substance of a deficient lysosomal enzyme in LSDs
  • Miglustat is the only one SRT agent is available and FDA-approved for patients who are unable to tolerate ERT for Gaucher disease
  • It reduces the production of several SRT agents
  • In patients with Niemann–Pick type C disease, miglustat demonstrates stabilization of disease progression, and is now licensed in Europe for the treatment of this disease
  • The most common side effect of miglustat is weight loss, tremors and chronic diarrhea

Enzyme enhancement therapy

  • In most LSDs, the disease only brings health problems once the enzyme works below 10–15% of normal enzyme
  • Enzyme-enhancement therapy is based on a molecule on enhancing the activity of the deficient enzyme. Increasing residual enzyme activity by only a few percentage may have profound clinical effects.
  • The drugs are still on clinical trials are available for this type of treatment. 
  • Enzyme enhancement therapy is based on a small molecule that is capable of rescuing these mutant proteins so that they can be delivered to the lysosome where they can express their residual enzyme activity

What are the limitations of the current treatment for LSDs?

  • The ERT is not able to treat neurological problems
  • The decision to start ERT for Fabry disease, Gaucher disease (type I) and late onset Pompe disease is based on patients symptoms or deterioration of those over time in each affected patient. The treatment decision is made in conjunction with patient and their family members 
  • Early initiation of treatment for mucopolysaccharidosis MPS-I, MPS-II and MPS-VI results in clinical benefit for patients with these conditions 
  • Although, ERT is not effective for neurological problems, it may bring significant improvement in the quality of life of patients with severe clinical forms of MPS1, MPS2 and neuronopathic Gaucher disease
  • Pregnancy is not considered a contraindication for ERT in nonneuronopathic Gaucher disease type I and Fabry disease. At the present time, no study or reports evaluating the ERT during pregnancy in mucopolysaccharidosis MPS-I, MPS-II and MPS-VI
  • For MPS1, specific criteria for offering HSCT and ERT are well-established

Johns Hopkins Lysosomal Storage Disease Program 

Comprehensive Services

   As LSDs are multi-systemic and complex diseases, the Johns Hopkins LSD program is committed to offer the best medical experts in the field pursing the excellence in health care and quality of life for LSD patients and their families. 

   All the specific treatments described above are available at Johns Hopkins LSD Program, which also have opportunities to patients to enroll in several ongoing clinical trials on different ERT and small molecule agents. The comprehensive and integrative services available at Johns Hopkins Lysosomal Storage Disease Program includes:
Consultation and clinical evaluation
Diagnostic testing and counseling
Interactions with referring physicians involved in patients primary health-care 
Coordination of Multi-disciplinary Management
Infusion of Centers for Enzyme Replacement Therapy
Hematopoietic Stem Cell Therapy
Monitoring of treatment clinical and biochemical response
Surveillance of LSD related complications
Patient education
Opportunities for participation in translational and clinical trials
Multidisciplinary Experts involved in Management

   The Johns Hopkins Lysosomal Storage Disease Program is directed by Gustavo H.B. Maegawa MD, PhD, physician-scientist from McKusick-Nathans Institute of Genetic Medicine (IGM) and Department of Pediatrics of The Johns Hopkins School of Medicine. Dr. Maegawa also conducts basic research in his laboratory aiming to understand molecular mechanisms of LSD and develop new therapeutic approaches. Dr. Maegawa coordinates the necessary multi-disciplinary and personalized for affected patients and their families. Dr. Maegawa also collaborates with LSD centers throughout the United States and around the world to bring advances from basic research to clinical care. Dr. Maegawa participates in the elaboration of several health-care guidelines for several LSDs. The Johns Hopkins LSD program is a multidisciplinary team includes specialists from Johns Hopkins from Cardiology, Endocrinology, Hematology/oncology, Neurology, Nephrology, Neurosurgery, Nutrition, Orthopedics, Otolaryngology, Organ Transplant, Pain Management, Pulmonology, Radiology, Surgery and Urology.

Johns Hopkins Lysosomal Storage Disease Program
Johns Hopkins Hospital
600 N Wolf Street – Blalock 1008
Baltimore, MD 21287

Gustavo H.B. Maegawa MD, PhD FACMG
Director, Lysosomal Storage Disease Program
McKusick-Nathans Institute of Genetic Medicine
The Johns Hopkins University School of Medicine
733 N. Broadway - Rm. 409
Baltimore, MD 21205
p 443-287-3505/ f 410-502-5677
email: gmaegaw1@jhmi.edu

For referrals: 
Dana Goins
Sr. Medical Office Coordinator
Phone: 410-502-2122
Fax: 410-614-9246

For Clinical Studies:
Gustavo H.B. Maegawa MD, PhD FACMG
Director, Lysosomal Storage Disease Program
McKusick-Nathans Institute of Genetic Medicine
The Johns Hopkins University School of Medicine
733 N. Broadway - Rm. 409
Baltimore, MD 21205
p 443-287-3505/ f 410-502-5677
email: gmaegaw1@jhmi.edu

For questions on appointments 
Nancy B. Smith, PAC, MPA
Phone: 410-614-7021
Fax: 410-614-9246

Johns Hopkins Lysosomal Storage Disease Clinic Location
Harriet Lane Clinic
David M. Rubenstein Child Health Building
200 North Wolfe Street
Baltimore, Maryland 21287