Lysosomal Disease Network

Status: Closed

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

Fabry disease is a rare genetic disease with deficient activity of enzyme a-galactosidase A. Deficient activity of this enzyme leads to accumulation of lipid-derived inclusions in different organs including kidney, heart and vessels. These inclusions can be found in the kidney even before birth. The earliest known clinical manifestation of Fabry kidney disease is typically appearance of excess protein in the urine which usually occurs in the second decade of life. However, our studies, as well as those of other investigators show evidence that kidney injury starts much earlier. Once excess protein is found in the urine, kidney function deterioration becomes progressive and most Fabry patients require kidney transplantation or hemodialysis in the third to fifth decade of life.

The research aims are:

1. To study the natural history of Fabry renal disease and measure renal function and renal structure in male and female patients diagnosed with Fabry disease. These patients would encompass the broad age range from childhood to adulthood and from normal renal function to moderate renal insufficiency [serum creatinine (SCr) ≤ 2.5 mg/dL (Chronic kidney disease or CKD3)]. 
    
2. To utilize the resultant cross-sectional information to determine the renal structural parameters or composite of parameters that most closely relates to the onset and progression of clinical renal disease in Fabry patients.

About this Study

This is an observational, cross-sectional study of 50-60 individuals diagnosed with Fabry renal disease who are undergoing a kidney biopsy deemed necessary for patient care. Those participating in this study will be evaluated once.

For the first visit, you will be asked to:

• Have a physical exam
• Provide information about the medications you are taking and information about your family history
• Give blood (1 to 2 teaspoons)
• Give a urine sample (random collection and overnight collection)

We will look at your clinically indicated kidney biopsy specimen so that we can collect information about your Fabry disease.

Targeted Enrollment

To be eligible to participate, you must:

• Have a diagnosis of Fabry disease who have had or will have a kidney biopsy and measures or estimates of glomerular filtration rate (GFR) as part of their clinical evaluation

You are not eligible to participate if:

• Are unwilling/unable to give informed consent, or sign the assent (if applicable) and parental consent
• Presence of other kidney disease

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

• University of Minnesota
  Cathy Bagne
  612-624-4688
  pinth001@umn.edu

Status: Recruiting

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

Mucopolysaccharidosis (MPS) types I, II, IV, VI and VII, are inherited diseases that result from the bodies inability to break down large sugar molecules that are by-products of metabolism. MPS affects most organs of the body and causes abnormalities in the liver, spleen, bones, and brain. We are studying the central nervous system (primarily the brain) so we can better understand the nature of the problems individuals with MPS I, II, IV, VI and VII have so we can find ways of better treating these problems. We would like to find out about the changes in the brain of individuals with MPS I, II, IV, VI and VII using data from MRI and neuropsychological tests. This is a longitudinal study so patients who enroll will need to be seen 3 times over 5 years. The longitudinal nature of the study allows us to make conclusions about how changes in some structures of the brain and changes in cognitive ability are related.

The research objectives are:

1. To identify abnormalities of brain (and central nervous system) structure and function in patients with MPS I, II, IV, VI and VII, regardless of how they are being treated or have been treated in the past; and to track disease progression over time.
2. To examine the degree to which independent variables (e.g., age at first treatment, severity of disease, types of medical abnormalities, mutation, medical events, and sensory abnormalities) have an impact on both functional and structural outcomes as well as on quality-of-life.
3. To identify, through longitudinal study, those measures that most accurately reflect the current disease state.

About this Study

This is a longitudinal study of 75-100 individuals with either MPS I, II, IV, VI and VII. Those participating in the study will be evaluated 3 times over 5 years. The primary site for this study is the University of Minnesota but there are an additional 6 centers in the United States and Canada that are also participating and will provide data for analysis. You will need to be able to travel to Minnesota or one of the participating centers in order to be a part of this study.

If you are already seen at the University of Minnesota Clinics as a part of the Bone Marrow Transplant program or Fairview-University Clinic, you will be asked to:

• Share data on neuropsychological testing that is a part of your clinical care program
• Share data on brain MRIs that are a part of your clinical care program
• Share data on your medical background

If you are not a University of Minnesota patient you will be asked to:

• Take a series of tests that measure cognitive, psychosocial and emotional functioning which may include:
  • Wechsler Abbreviated Scale of Intelligence
  • Hopkins Verbal Learning Test
  • Test of Variables of Attention
  • Vineland Adaptive Behavior Scales
  • Children's Health Questionnaire
• Have a brain MRI
• Share medical background as appropriate

For University of Minnesota research subjects not being seen for clinical evaluation:

• If eligible, transportation and one night of hotel will be covered
• Insurance will not be billed; MRI, and neuropsychological testing will have no cost to you.

Targeted Enrollment

To be eligible to participate, you must:

• Have a confirmed diagnosis of MPS I, II, IV*, VI, or VII*
  • MPS IV and MPS VII patients will be considered for enrollment in the study on an individual basis
• Be a child or adult aged 6-25 years

You are not eligible to participate in the brain MRI if:

• you have a pacemaker
• you have a programmable shunt
• you have other indwelling electronic devices
• you have orthodontic braces unless they are not made of metal
• you have other metal in the body other than titanium.
• you are unable to stay still in the MRI scanner
• you are pregnant

You are not eligible to participate in the neuropsychological testing if:

• you are too functionally impaired for testing

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

California

• UCSF Benioff Children's Hospital, Oakland
  Jo Ann Johnson, MPH, CCRC
  510-428-3885, ext 5421
  E-mail: jajohnson@mail.cho.org

Minnesota

• University of Minnesota, Minneapolis
  Ashley Wiesenburger, Project Coordinator
  612-301-1371
  E-mail: amwiesen@umn.edu

New York

• New York University, New York
  Swapnil Parmar 
  212-263-8344 
  E-mail: Swapnil.parmar@nyumc.org

Ontario

• The Hospital for Sick Children, Toronto, ON, Canada
  Mohammed Hussain
  416-813-7654 ext 2646
  E-mail: mohammed.hussain@sickkids.ca

Status: Recruiting

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

The purpose of this research study is to look at the brain and eye in patients with mucolipidosis type IV (MLIV). MLIV is a lysosomal storage disease that primarily affects the brain and the eyes. The disease is caused by a defect in a gene called MCLON1 that makes a protein called mucolipin-1. Patients with MLIV do not make enough normal mucolipin. The disease begins early in life and the neurological problems seem to stabilize later in life. On the other hand, the eye abnormalities usually progresses over time. The exact course of the disease has not been determined, and until now, no study has addressed this question carefully. 
 The research objectives are:

1. To learn about the natural history of cognitive function for individuals with mucolipidosis type IV.
2. To measure brain volume over time in individuals with mucolipidosis type IV

About this Study

This is a longitudinal study of 10 individuals with Mucolipidosis type IV. Those participating in this study will be evaluated once a year for five years. All visits will take place at the Baylor University Medical Center and will take at the most three days.

For each visit, you will be asked to:

• Have a neurological exam
• Give blood (1 to 2 tablespoons)
• Give a urine sample
• Have an electroencephalography (this test measures and records the electrical activity of your brain by sensors
• Fill out a feedback form about your life
• MRI (magnetic resonance imaging) of your head
• DNA Sample (taken from a piece of your skin or blood)- this will only happen at the first visit.
• Pregnancy test (if you are a women of childbearing potential)

Targeted Enrollment

To be eligible to participate, you must:

• Have a definitive diagnosis of Mucolipidosis Type IV based at least on a compatible history and significantly elevated blood gastrin levels will be considered as potential candidates for this study.
• The general health and well being of each candidate must be sufficient to allow travel to Baylor Institute of Metabolic Disease in Dallas, Texas, modest amount of blood drawing, performance of necessary neuromiaging studies and ophthalmological examinations under monitored sedation. The patient must be able to return to Dallas once a year for a follow up.
• Females of child bearing potential who have had a negative pregnancy test.

You are not eligible to participate if:

• You refuse to sign the protocol consent form
• You are unable to travel to the Baylor University Medical Center in Dallas, Texas
• You are pregnant or nursing

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

• Baylor Research Institute
  Caren Swift
  214-820-4857
  E-mail: caren.swift@baylorhealth.edu

Status: Recruiting

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

Mucopolysaccharidoses (MPS) I, II, and VI are a group of rare, lysosomal storage diseases in which certain enzymes are missing that are normally required for breaking down specific complex carbohydrates.

Deficiencies in these enzymes result in the build-up of toxic substances in various tissues and cause damage to the body's organs. In the past, children diagnosed with MPS I, II, or VI frequently died in early to late childhood. Recent advances in treatments including hematopoietic cell transplantation (HCT) and enzyme replacement therapy (ERT) have been helping children with these disorders live into adulthood. The long term-course of the disease is now unknown. Unfortunately, severe skeletal disease persists for most individuals despite current therapies.

The purpose of this study is to document the progression of skeletal disease and identify biomarkers that either predict disease severity or could be used as therapeutic targets. This information is needed to:

1. determine long-term benefits and limitations of current treatments including HCT or ERT
2. direct development of further treatment options
3. improve clinical care for children affected by the disorder

About this Study

This is a longitudinal study of 50 children and adults with MPS I, II, and VI. Study participants will be evaluated every year for up to 3 years.

At the first visit, your child will be asked to:

1. Have a physical exam, including pubertal assessment by a doctor
2. Tell information about their medical history
3. Have measurements taken of their body
4. Give blood (3 teaspoons)
5. Give a urine sample
6. Be tested for their hand strength
7. Have bone mineral density tests to measure the strength of his/her bones (DXA scan or pQCT scan)
8. Have an x-ray of his/her left hand to show the age of the bones
9. Have an x-ray of their hips
10. Be tested for range of motion of shoulder, elbow, hips and knees
11. Answer questions about pain, physical function, and other quality of life concerns

Targeted Enrollment

To be eligible to participate, your child must:

• Have a diagnosis of MPS I, II, or VI
• Be able to travel to the study center for evaluations (Harbor-UCLA, University of Minnesota, or Children's Hospital Oakland)
• Be between 5 years and 18 years of age. To ensure a minimum of 2 study visits, your child should be at least 5 years old at the beginning of the study and no older than 16 years old.
• Speak English

Your child is not eligible to participate if:

• She is pregnant
• Your child has participated in another study within the past 12 months that would increase his / her radiation exposure to above 500 mrem (millirem of radiation) for the calendar year.
• S/he cannot comply with study procedures or have other factors that would limit participation as determined by the doctor.

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

California

• Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles
  Lynda Polgreen, M.D., M.S.
  Phone: 310-222-1961
  E-mail: lpolgreen@labiomed.org

• UCSF Benioff Children's Hospital, Oakland
  Ellen Fung, Ph.D., R.D., C.C.D.
  Phone: 510-428-3885 ext 4939
  E-mail: efung@mail.cho.org

Minnesota

• University of Minnesota
  Brad Miller, MD
  612-624-5409 
  E-mail: mille685@umn.edu

Status: Recruiting

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

Infantile-onset Pompe disease is an inherited disorder that is normally diagnosed within the first months of life. It is caused by lack of or defect in an enzyme (a special protein that carries out normal chemical reactions within the body) called acid alpha-glucosidase (GAA).  GAA normally breaks down glycogen (stored sugar) in lysosomes (the part of the cell that digests food and other chemicals). Pompe disease is one of many lysosomal storage diseases (LSDs). LSDs are diseases caused by the malfunction of the lysosome or one of their digestive enzymes. Patients with Pompe disease cannot break down lysosomal glycogen. This causes glycogen to build up and damage cells throughout the body, especially in the heart and muscles.

Current treatment for Pompe disease involves enzyme replacement therapy (ERT). In this treatment, the drug alglucosidase alfa (Myozyme) is put into your blood. The drug provides a form of the GAA enzyme to replace the enzyme that is missing or not working properly in the patient's blood. This treatment has allowed babies to live longer and achieve developmental milestones. 

In this study, researchers will learn about the patient's ability to tolerate ERT. Cross-Reactive Immunological Material (CRIM) is a measurement of natural GAA production. A patient's CRIM status (either positive or negative) is an important factor that affects how he or she responds to ERT with Myozyme. Children who produce some natural GAA are classified as CRIM+, while children who do not produce any natural GAA are classified as CRIM-.

Children who are CRIM+ generally tolerate ERT well. But, children who are CRIM-, and some children classified as CRIM+, have a poor response to ERT. Patients who have a poor response to ERT have complications because their body sees Myozyme as "foreign" and triggers an immune response to try to remove it from the body. Treatments are currently being developed to stop this immune response and prevent complications from ERT.

We will enroll patients with Infantile Pompe disease in this longitudinal natural history (observational) study. The specific aims of this study are:

1. To understand the developing natural history of Pompe disease, in both treated and untreated patients;
2. To evaluate the success of immunosuppressive therapy for CRIM- patients and CRIM+ patients who are risk for complications of ER

About this Study

This is a longitudinal natural history study of Infantile Pompe disease. We will regularly collect and review medical information regarding the diagnosis of Pompe disease, health information and response to ERT for up to 3 years.

Targeted Enrollment

To be eligible to participate, you must:

• Be an individual of any age diagnosed with one of the following conditions

  • Aspartylglucosaminuria
  • Fucosidosis
  • Galactosialidosis
  • alpha-mannosidosis
  • beta-mannosidosis
  • Mucolipidosis II
  • Mucolipidosis III
  • Schindler disease
  • Sialidosis

You are not eligible to participate if:

• You are not diagnosed with one of the nine glycoproteinoses listed above.

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

Duke University Medical Center
Joanne Mackey, Nurse Practitioner 
Phone: (919) 681-1945
E-mail: Joanne.Mackey@duke.edu

Status: Closed

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

The goal of this study is to determine if rates of Fabry disease are higher than previously thought in certain high risk patient populations. Specifically, we will screen large groups of patients with cryptogenic stroke, cardiac disease, and end stage renal disease to determine rates of undiagnosed Fabry disease. Secondarily, we are interested in developing and validating an easy to use, reliable test for Fabry disease from blood and urine.

Research question

In this study, we will learn the extent to which Fabry disease is under diagnosed in persons with heart disease, stroke of unknown cause and advanced kidney disease.

Background

Fabry disease is an inherited disorder with little or no activity of a particular enzyme that controls lipid build-up in such organs as kidney, heart and vessels. This build-up can cause nerve pain, skin changes, strokes, heart problems, digestive difficulties and symptoms, absent or decreased sweating, temperature and exercise intolerance, and kidney failure.

An early clinical symptom of Fabry kidney disease is excess protein in the urine which usually occurs when the affected person is in his or her 20s. The occurrence of undiagnosed Fabry in end stage renal disease, including dialysis and kidney transplant recipients is approximately 10-100x higher than that of the general population.

An accurate test is needed to identify and improve accuracy in diagnosis, especially in female Fabry patients, a previously underserved component of these at-risk groups.

About this Study

1. Through this pilot study we hope to be able to develop a cost-effective method for detecting Fabry disease from a single small collection of blood. 
2. At the University of Minnesota, we will perform a small study of Fabry Disease detection in patients with kidney disease who have undergone kidney transplant. 
3. At Baylor University Health Center and Massachusetts General Hospital, we will apply similar strategies to patients with strokes of unknown cause and heart disease, respectively.
4. There is no direct treatment involved. This is a pilot study involving screening testing for Fabry disease. However, if Fabry disease is diagnosed, referral to experts in the care of Fabry disease will be available.

For this screening visit, you will be asked to:

• Sign two forms: a study consent form which explains the study in detail and allows you to agree or not agree to participate and a HIPAA Authorization form which outlines the steps the study will take to maintain your confidentiality.
• Complete a contact information form with basic information about you.
• Complete a medical history form concerning your current health status, symptoms, dates of key medical events such as kidney transplantation, etc.
• Provide us with an up to date list of the medications you are currently taking.
• Have a 5 ml (one teaspoon) blood sample drawn in a tube that we provide to you or provide 10 ml (two teaspoons) of urine in a container that we provide to you to test for the presence of an enzyme or the gene for the enzyme that may indicate whether you have Fabry disease.

Persons found to have a positive test result for Fabry would then be contacted to advise additional follow up, and to suggest that their at risk relatives including children, siblings or parents also be tested. We anticipate asking about 500 persons to participate in this pilot study.

Targeted Enrollment

To be eligible to participate, you must:

• Be between the ages of 18-70;
• For Kidney Group: Either be on dialysis, or have received a kidney transplant.
• For Cardiovascular Group: Either have coronary artery disease, rhythm or conduction abnormality, cardiomyopathy or valvular disease.

You are not eligible to participate if:

• You are unwilling or unable to give consent to participate.

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

Kidney Group:

• University of Minnesota, Pediatric Nephrology Studies
  Michael Mauer, MD or Cathy Bagne, BS.,CCRP, project coordinator
  Phone 612-626-2922 or 612-624-5900
  E-mail  Dr. Mauer mauer002@umn.edu  Cathy Bagne pinth001@umn.edu

Cardiovascular Group

• Baylor Research Institute
  Caren Swift
  214-820-4857
  E-mail: caren.swift@baylorhealth.edu

Status: Recruiting

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

The gangliosidosis family of disorders (Tay-Sachs, Sandhoff, late-onset Tay-Sachs and GM1 gangliosidosis diseases) are fatal genetic conditions with no known treatment. Tay-Sachs and Sandhoff diseases presenting early in life are characterized by rapid neurological decline and early death. Late-onset Tay-Sachs disease occurs in patients beginning in their early twenties and is characterized by progressively poorer motor coordination, psychotic behaviors, and a decreased life expectancy. In this study we look at how people with any of the gangliosidosis diseases change over time with respect to cognitive functioning and disease progression.

The main research questions are:

1. To define and characterize disease progression, paying particular attention to the variability of the disease.
2. For late-onset Tay-Sachs disease, we will examine if there are any detectable correlations between changes in behavior and cognitive function, and changes in specific brain structures.

About this Study

This longitudinal study plans to enroll 52 participants. Forty-two participants are infants or juveniles who have a gangliosidosis disease; 10 are adults with the late-onset form of disease. Each participant will be evaluated every year for 5 years.

Subjects with Tay-Sachs or Sandhoff disease will be asked to:

• Release medical records that report the results of any clinical assessments that measure the evolution of symptoms over time.  Specifically, this may include, but is not restricted to, evaluation of motor control, gain or loss of developmental milestones, hyperacusis (acute hearing), seizures, macrocephaly (brain size), ocular (eye) exam, personal interactions, and reflexes.  We will also look for biomarker measures, such as, for example, enzyme activity levels.
• Provide release of information regarding neurodevelopment and neurobehavior testing.

Subjects with late-onset Tay-Sachs disease will visit the University of Minnesota yearly for:

• Cognitive and behavioral testing
• Head MRI
• Release of medical records that report the results of any clinically relevant assessments such asthose mentioned above for infantile or juvenile Tay-Sachs/Sandhoff patients (and additionally including evaluation of muscle tone and coordination).

Targeted Enrollment

To be eligible to participate, you must:

• Participants must have a documented gangliosidosis disease.
• Participants must be able to complete appropriate neuropsychological and neurobehavioral tests.
• Late-onset gangliosidosis subjects must be able to tolerate a head MRI.

You are not eligible to participate if:

• You do not wish to participate

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

University of Minnesota, Minneapolis, MN
Evelyn S. Redtree, M.S.
Phone: 612-625-0974
E-mail: eredtree@umn.edu

Status: Closed to Recruitment

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

Mucopolysaccharidosis I (MPS I) is a hereditary disease involving deficiency of an enzyme (a type of protein in the body). This enzyme is needed to break down a type of substance called glycosaminoglycans or GAGs, which are found throughout the body. Normally, the body uses enzymes to break down and recycle GAG in cells. In individuals with MPS I, the missing or insufficient enzyme prevents the proper recycling process, and as a result, cells do not perform properly and may cause progressive damage throughout the body, including the heart, bones, joints, 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 GAG. Excess GAG in the central nervous system leads to cognitive decline, spinal cord compression, hearing, and vision difficulties. As patients get older, they have continuous worsening in their thinking, memory, and behavior that eventually leads to complete dependence on others for their care. Patients with the most severe form of MPS I develop slowing in cognitive development that usually appears after age one and thereafter accelerates. By age 3 years, most of these children fall into the range of mental retardation as defined by standard intelligence tests (Shapiro and Balthazor 2000).

Enzyme replacement therapy (ERT) recently became available for the treatment of MPS I patients. This is a way to give back a manufactured form of the enzyme (called laronidase or Aldurazyme) that MPS I patients are missing due to the disease. However, given in the usual way, ERT does not reach the brain or spinal cord to help with the damage caused there by excess storage. For this reason, an intrathecal approach (injecting the enzyme directly into the cerebral spinal fluid, which is the fluid that surrounds the brain and spinal cord) was studied in dogs with MPS I. The treatments brought the GAG storage in the brain to normal levels (Kakkis et al., 2004, Dickson et al., 2007). Based on the results in MPS I dogs, a pilot trial of intrathecal injections of enzyme was started and is ongoing in human patients to treat spinal cord compression.

The study proposed here will examine the effects of intrathecal injections of enzyme on cognition in MPS I patients. The objectives of the study are to demonstrate the long-term safety of intrathecal enzyme replacement and to determine whether signs of cognitive impairment in MPS I can be reversed or at least stabilized.

Subjects will undergo neuropsychological testing, radiologic imaging of the brain, physical examinations, and biochemical tests involving blood draws (about a tablespoon of blood per visit) at screening and throughout the study. Treatments with the enzyme will be done by inserting a needle into the lower back (after numbing medicine is given). A small amount (roughly 2 teaspoons) of cerebral spinal fluid (CSF) will be taken out for tests at each of these spinal taps. The amount of CSF removed is replaced in large part by the treatment.

About this Study

Study design

This is a pilot study that will last up to 24 months. During these 24 months, subjects will make 12 study visits to Harbor-UCLA Medical Center. These visits will occur at screening, at Day 0, and 1, 2, 3, 6, 9, 12, 15, 18, 21 and 24 months later. At each visit, subjects will be evaluated for symptoms of MPS I, cognitive decline, and, if applicable, receive injections of Aldurazyme. In addition to the study visits at this site, subjects will make up to 5 study visits (screening, month 6, 12, 18 and 24) to the University of Minnesota for neuropsychological testing and an magnetic resonance imaging (MRI) study of the brain.

Subjects enrolled in the study will be randomly assigned (like the flip of a coin) to one of two groups: the treatment group or the control group. The Treatment Group will receive injections of Aldurazyme and have samples of their CSF drawn for testing starting at Day 0 and repeated at months 1, 2, 3, 6, 9, 12, 15, 18 and 21 (10 treatments total) The Control Group will receive injections of Aldurazyme and have samples of their CSF drawn for testing starting at Month 12 and repeated at Months 15, 18 and 21 (4 treatments total). We plan to enroll sixteen subjects in total.

At every visit, a subject will have a physical exam, neurological evaluation, walk test, and some subjects will be photographed or videotaped (if they have agreed to this). Before receiving Aldurazyme, you will have blood drawn.

Targeted Enrollment

To be eligible to participate, you must:

1. The presence of MPS I disease as documented by low α-L-iduronidase activity
2. Age six years or older.
3. The presence of acquired cognitive deficits as demonstrated by:
   1. A score of one standard deviation below mean on IQ testing or in one domain of neuropsychological function (language, memory, or non-verbal ability), OR
   2. Documented historical evidence of a decline of greater than one standard deviation on sequential testing, OR
   3. A score between 0.75 and 1 standard deviation below the mean, AND the cognitive deficit affects daily performance.
4. The decline in function is not explainable by other neurological or psychiatric factors.
5. Subject and/or guardian willing and able to provide written informed consent.
6. Negative urine pregnancy test at screening (non-sterile females of child-bearing potential only)
7. Currently using two acceptable methods of birth control as determined by the investigator and willing to continue to use acceptable birth control during their participation in the study (non-sterile females of child-bearing potential who are sexually active only)
8. Willing and able to comply with study procedures. For example, the subjects must be able to complete written and computer-based testing. The subjects must be able to lie still in the MRI scanner for at least 40 minutes without sedation.

You are not eligible to participate if:

1. The subject has undergone hematopoietic stem cell transplantation
2. Recent initiation of intravenous Aldurazyme® therapy with less than 6 months of therapy. Subjects who have been receiving Aldurazyme® therapy for more than 6 months, and those who have never received Aldurazyme® therapy, will be allowed to enroll
3. Pregnant or lactating, or considering pregnancy
4. Receipt of an investigational drug or procedure within 30 days of enrollment
5. A condition, medical or other, that prevents participation in the study, including severe auditory or visual impairment, significant lumbar pathology, lumbar catheter, or recent major surgery within 6 weeks that would preclude their ability to participate.
6. Infusion reactions to intravenous Aldurazyme® therapy that require ongoing medical treatment, special prophylaxis or altered rate or dose of enzyme administration
7. The subject has severely impaired spinal CSF flow, demonstrates by failure of appearance of 99m Technetium-DTPA in the basal cisterns by 4 hours after intralumbar administration.
8. The subject has problems with blood clotting, as identified by a platelet count of less than 50,000, an INR of 1.5 or greater, or a PTT that is 1.5 times the upper limit of normal for the laboratory from which it was drawn.

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

California

• Children's Hospital & Research Center, Oakland
  Jacqueline Madden, PNP 
  Phone: 510-428-3885 x5745
  E-mail: jmadden@mail.cho.org

• Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
  Leonor Rovai 
  Phone: 310-222-4145
  E-mail: lrovai@labiomed.org

Status: Closed to Recruitment

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

LINCL is a lysosomal storage disease. In lysosomal storage diseases, some cells are not able to perform their natural recycling function. TPP-I is important for brain cell survival, and it may have a role in the protection of cells from apoptosis (cell death).

Batten disease affects 1 in 12,500 to 100,000 live births each year, making it the most common neurodegenerative (deterioration and loss of brain cells) disease of childhood.

Symptoms of Neuronal Ceroid Lipofuscinoses (NCLs) include:

• Mental retardation with decreasing mental function
• Blindness or vision problems, usually by age 4-6 years
• Seizures
• Deteriorating motor development

LINCL manifests itself at age 2 to 4 years of age. The major symptoms that bring children to medical attention are seizures, the loss of ability to coordinate voluntary movement, and myoclonus (a sudden twitching of muscles or parts of muscles, without any rhythm or pattern). Seizures are often the first symptom, but the time of onset and the appearance of all of the symptoms vary among individuals.

Patients with the condition generally become dependent on a wheelchair between 4 and 6 years of age. Towards the late stages of the disease, feeding becomes very difficult, resulting in poor weight gain. Death occurs by age 8 to 12. There is currently no proven treatment for LINCL other than management of symptoms.

About this Study

In this study, researchers will study the genetic correlations of central nervous system manifestations of the disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL), a form of Batten Disease. The study will compare genetic mutations of the disease to established scales, magnetic resonance imaging (MRI), and routine clinical evaluations. Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL), is a form of Batten disease. LINCL is an autosomal recessive disease, meaning the patient has two copies of an abnormal gene called CLN2. This genetic mutation leads to an absence of the lysosomal protein (tripeptidyl peptidase I, TPP-I).

We anticipate that we will be able to capture an 18 months genotype - phenotype progression assessment for n=16.

The clinical protocol is designed to study the natural disease process of Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL), a fatal, autosomal recessive disorder of the central nervous system.

Subjects for this study (n=16) will be recruited from direct referrals to the Principle Investigator with the help of relevant foundations and support parts.

Each individual will undergo 1 baseline evaluation that includes:

• General assessment (history, physical exam, vital signs, respiratory rate, temperature and weight, neurological assessment);
• Ophthalmological assessment (eye exam);
• General blood tests (chemistry, hematology and coagulation);
• Genetic testing of blood for CLN2 genomic analysis;
• Urine analysis;
• MRI/MRS assessment;
• Lumbar puncture (spinal tap);
• Developmental psychological assessment consisting of 3 scales:
  • Weill Cornell LINCL scale,
  • Standardized CHQ and ITQOL quality of life scales, and
  • Mullen scale. 

The subjects will be re-assessed in a similar fashion at 18 months. Timeline of screening below.

Targeted Enrollment

Subjects are eligible to participate if:

1. There is a definitive diagnosis of LINCL, based on clinical phenotype and genotype.
2. The subject is between the age of 3 and 18 years.
3. The subject has not previously have participated in a gene transfer or stem cell study.
4. Parents of study participants agree to comply in good faith with the conditions of the study, including attending all of the required baseline and follow-up assessments, and both parents or legal guardians must give consent for their child's participation.

Subjects are not eligible to participate if:

1. There is a presence of other significant medical or neurological conditions that would disqualify the subject from participation in this study (for example, malignancy, congenital heart disease, liver or renal failure).
2. Subjects do not have adequate control of seizures.
3. Subjects have a condition, such as heart disease, that would put them at risk for anesthesia or subjects have a history of major risk factors for hemorrhage.
4. Subjects cannot participate in MRI studies.
5. Subjects are currently participating in any other FDA approved Investigational New Drug study.
6. Subjects have a history of prolonged bleeding or abnormal platelet function or if the subject is taking aspirin.

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

Subjects for this study will be recruited from direct referrals to the Principle Investigator with the help of relevant foundations and support parts.

• Weill Cornell Medical College 
  Mary Yeotsas
  Phone: 646-962-4563
  E-mail: mey2003@med.cornell.edu

Table I - Timeline of the screening clinical study (1, 19)

Footnotes for Table I

R= test required; O= test optional

Parameters listed are mandatory for the study; additional parameters will be evaluated at the discretion of the physician assessing the individual.

(2) The "general assessment" will be used to make the diagnosis of LINCL on clinical grounds plus CLN2 genomic analysis; prior genomic analysis will be accepted

(3) General - medical history, physical exam, vital signs (blood pressure, heart rate, respiratory rate, temperature)

(4) CBC - hematocrit, hemoglobin, white blood count, differential, platelets

(5) ESR - erythrocyte sedimentation rate

(6) Clotting - prothrombin time, partial throm­boplastin time

(7) Chemistry - sodium, potassium, chloride, total CO2, blood urea nitrogen (BUN), glucose, magnesium, uric acid, phosphate,creatinine, alanine amino trans­ferase (ALT), aspartate amino trans­ferase (AST),­ cal­cium, serum total protein, albumin, alkaline phosphatase, bili­rubin (total)

(8) Future (serum) - serum sample frozen for future use

(9) Urinalysis - appearance, specific gravity, pH, protein, glu­cose, ketones, bilirubin, hemoglobin, number and type of cells, characterization of sediment

(10) EKG - electrocardiogram. Subject's previous EKG results will be accepted within six months of screening in the event that cardiac history is present. If no cardiac history is found, an EKG will not be necessary. If an EKG is necessary, it will be reviewed by pediatric cardiologist.

(11) Posterior-anterior and lateral. Subject's previous chest x-ray results will be accepted within six months of screening unless there has been a significant change in his/her clinical scenario.

(12) Ophthalmology - routine ophthalmologic exam performed by a board certified ophthalmologist. Anesthesia may be administered depending on the ability of the subject to remain still as the doctor performs the tests. The eye exam will include eye dilation, color photos, electroretinogram (ERG), fluorescein angiography and a possible optical coherence tomography (OCT).

(13) Neurological assessment - Level of consciousness, speech, language, cranial nerves, motor strength, motor tone, reflexes, upper extremity sensation, lower extremity sensation, gait, romberg, nystagmus, coordination. The neurological assessment will be done by two blinded, independent pediatric neurologists, based on videotaped footage of subjects.

(14) Lumbar puncture (spinal tap) - A needle is carefully inserted into the spinal canal low in the back. Samples of CSF are collected. This will be performed under anesthesia. CSF will be analyzed for biomarkers of LINCL. The MRI will be performed before the spinal tap in order to check for increased intracranial pressure due to a space occupying mass. If a mass causing increased intracranial pressure is observed, a spinal tap will not be performed due to the additional risks involved.

(15) Magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) - see section A.4 for details; all studies will be carried out on the same scanner located in the New York Presbyterian Hospital. The scanner is a 3.0 Tesla whole body system with an included head coil. MRS data obtained from this will be for information only for method development.

(16) The Child Health Questionnaire™ (CHQ) or Infant Toddler Quality of Life Questionnaire (ITQOL) will be administered to at least one parent/legal guardian at the designated visits. The ITQOL was developed for use in infants and toddlers at least 2 months of age up to 5 years. The CHQ is a family of generic quality of life instruments that have been designed and normed for children 5-to-18 years of age.

(18) The acceptable "time windows" for the assessment days are as follows:

(a) except CLN2 genomic analysis, which may be evaluated at any point prior to assessment date.

Status: Closed

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

Tay-Sachs disease belongs to the hexosaminidase family of disorders and is caused by an error in the gene responsible for making a protein called "hexosaminidase A enzyme." Individuals who do not make this enzyme cannot break down or degrade a different substance called GM2 ganglioside (Tay-Sachs disease is also known as GM2-gangliosidosis) so it accumulates in all cells and tissues of the body, but particularly the brain, leading to damage. Over time, this damage causes a loss of basic functions controlled by the brain such as the ability to sit up and roll over; excessive drooling; and seizures.

Up to now there have been no comprehensive assessments of the natural history of Tay-Sachs disease and how it progresses. This study is a two-year pilot study that will record clinical measurements from Tay-Sachs patients to create a comprehensive index for Tay-Sachs disease that can be used to measure the effectiveness of any future therapy.

The objectives of this study are:

1. To define and characterize disease state in Tay-Sachs patients through the collection of medical record data including biomarker analysis, MRI, Quality of Life reports, and ophthalmology.
2. To use the data collected above to create a natural history of disease progression, including the effects of any secondary therapies/treatments such as bone marrow transplant.
3. To use the natural history data to create a disease specific stage and severity index which can be used to evaluate the effectiveness of any future disease-specific therapies.

About this Study

This is a two-year pilot study that will recruit as many Tay-Sachs patients as possible. However, given the rarity of the disease we expect to enroll only 5-7 patients.

Those participating in the study must agree to release all of their medical records to the researchers and continue to release records for the length of the study.

Data may be collected from deceased patients as well through the retrospective collection of medical records.

Targeted Enrollment

To be eligible to participate, you must:

• Have a confirmed diagnosis of Tay-Sachs disease
• Be willing to participate

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

University of Minnesota
Brenda Diethelm-Okita
Phone: 612-625-1594
E-mail: dieth001@umn.edu

Status: Closed

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

Mucopolysaccharidosis (MPS) syndromes are disorders caused by a lack of enzymes needed to break down certain carbohydrates in the body's cells. MPS has been linked to heart problems. There are currently no proven markers of heart and artery health for patients with MPS. The main purpose of this study is to test the ease and convenience of a non-invasive measurement of artery function in patients with MPS I, MPS II and MPS VI compared to healthy control subjects. This is an observational study, which means that there is no treatment in this study.

The research questions are:

1. Is the artery health of MPS I, II and VI patients different from healthy controls?
2. Is the artery health of patients with MPS VI patients different that of patients with MPS I and II

About this Study

This is an observational study of 60 individuals with MPS I, II and VI between the ages of 3 and 18. Those participating in this study will be seen for a one-time, one-hour study visit. Participants will be enrolled at the University of Minnesota in Minneapolis, Minnesota and Children's Hospital of Orange County in Orange, California.

In this study, researchers will:

• Take a blood pressure reading
• Measure your (or the patient's) height, weight, and the distance around your waist
• Measure your (or the patient's) vascular health using ultrasound (sound waves that help researchers view organs and structures inside the body)
• Ask questions about your (or the patient's) current health and past medical history
• Review medical records for diagnosis and previous laboratory information

Targeted Enrollment

To be eligible to participate, you must:

1. Be between the ages of 3 and 18 years old
2. Have a diagnosis of MPS I, II or VI.

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

California

• Children's Hospital of Orange County
  Raymond Wang, MD
  Phone: 714-532-8732
  E-mail: rawang@choc.org

Minnesota

• University of Minnesota
  Cameron Naughton
  Phone: 612-625-3623
  E-mail: naug0009@umn.edu

Status: Recruiting

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

For Diseases:

Type 1 Gaucher Disease (GD1)

Background

The purpose of this study is to measure blood and brain chemicals related to oxidative stress (an imbalance between the production of potentially harmful by products of metabolism and the ability of the body to detoxify the harmful effects through neutralization by antioxidants) and inflammation in healthy volunteers and individuals with Type 1 Gaucher disease (GD1). We want to learn if these levels are abnormal in patients with GD1. We will also examine if there is a change in these blood and brain chemicals in GD1 patients after treatment with oral N-acetylcysteine (NAC). NAC is available both as a prescription medication and as a natural product and has antioxidant and anti-inflammatory effects. NAC has been used for many years for the treatment of lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis. The findings from this study may add to our understanding of how GD1 causes tissue damage and could lead to better treatment options.

About this Study

This study is being carried out in 3 clinics (University of Minnesota, New York University, University of Miami). Patients who are not receiving care in any of the 3 clinics may also enroll by contacting University of Minnesota directly (see below). We will enroll people with Type 1 Gaucher disease as well as healthy volunteers who will serve as a control group. We anticipate enrolling approximately 50 people in total. Healthy volunteers will have 3 study visits over the course of 3 months. Procedures will include review of medical history, blood sample collection at each visit, and a brain scan (MRI) at the third visit. Volunteers will not be treated with NAC or with a placebo. GD1 patients will have 7 study visits over the course of 9 months. Procedures include review of medical history, blood sample collection at each visit (multiple draws from an IV catheter at Visit 6), neurological exams, pain and fatigue questionnaires, and MRI scans (Visits 3 and 6). In addition, GD1 patients will be given oral NAC to be taken twice a day beginning at Visit 3 for 90 days. All MRI scans will be done at the University of Minnesota in Minneapolis meaning that study participants from the New York and Miami sites will have to be willing to travel to Minneapolis twice during the study. Patients not receiving care in any of the 3 clinics will need to come to Minneapolis three times during the study. Participants will be reimbursed for expenses related to travel to Minneapolis. Other visits will take place at the clinic where the patient receives care for his/her GD1.

Targeted Enrollment

To be eligible to participate, if:

1. You are 18 years of age or older.
2. In the opinion of the investigators, you can understand and cooperate with requirements of the study and are then able and willing to provide written informed consent.
3. In the opinion of the investigators, you are medically stable meaning that manifestations of Gaucher disease or any other illness you may have are controlled and not frequently changing in severity.
4. You are being treated for GD1, and you are stable on a specific Gaucher treatment (ERT and/or SRT therapy) at a specific dose (for eg. on a units/kg basis) for at least 2 years. If you had a change in therapy i.e. a change in dose or switch from one drug to another, you can be enrolled after at least 6 months have elapsed since the change and is considered stable in the opinion of the clinician providing care to the patient.
5. You are a healthy participant and of an age that permits matching with GD1 enrollees.
6. Participants are willing to not take any of these antioxidants: coenzyme Q-10, vitamin C, or vitamin E for 3 weeks prior to and during the course of the study.

You are not eligible to participate if you:

1. Have a medically unstable condition as determined by the investigators during the initial screening process.
2. Have a concurrent disease; medical condition; or an extenuating circumstance that, in the opinion of the investigator, might compromise subject safety, study compliance, completion of the study, or the integrity of the data collected for the study.
3. Are pregnant or lactating (breast feeding) or of child-bearing age, and are not using acceptable forms of contraception.
4. Have a history of asthma that is presently being treated.
5. Are enrolled in another interventional study.
6. Have an allergy to N-acetylcysteine.
7. Cannot or are unwilling to have blood drawn.
8. Are unable to undergo MRI scanning including, but not limited to, the inability to remain still in an MRI scanner for more than 30 minutes, claustrophobia, presence of paramagnetic (metal) substances or pacemakers in body, weight over 300 lbs.
9. Are unable to adhere to the study protocol for any reason.

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

• University of Minnesota
  Reena Kartha, PhD
  Phone: 612-626-2436
  E-mail: rvkartha@umn.edu
• New York University
  Michele Ford
  Phone: 212-263-6981
  E-mail: Michele.Ford@nyumc.org
• New York University
  Marissa Ferraris
  Phone: 212-263-0139
  E-mail: Marissa.Ferraris@nyumc.org

Status: Recruiting

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Neuroinflammation and oxidative stress have been shown to be present in persons with mucopolysaccharidosis type I (MPS I), but their effect on disease severity and disease progression is unknown. The study intends to employ brain magnetic resonance spectroscopy (MRS), a non-invasive technique, along with analysis of neuroinflammation and oxidative stress biomarkers in the blood, to measure and determine the level of oxidative stress and neuroinflammation and their impact on clinical variability in MPS I patients.

For Diseases:

Mucopolysaccharidosis Type I (MPS I)

Background

MPS I is a genetic disorder with deficient breakdown of the material called glycosaminoglycans in lysosomes. Lysosomes are found in almost every single human cell, acting like a waste disposal system to help break unwanted materials down. MPS I is categorized into three different types depending on the patient’s mutation and symptoms. Regardless of MPS I type, patients can experience cognitive, attention, and behavioral issues which can get worse over time. Many patients experience orthopedic, cardiac, pulmonary, brain, and dental issues too. If a patient has the most severe type of MPS I, Hurler syndrome, they will undergo a hematopoietic stem cell transplant. The purpose of this study is to learn more about the brain in patients with MPS I and see if there is inflammation and other stresses in these individuals.

The research questions are:

1. Is there inflammatory and oxidative stress in patients with MPS I?
2. If inflammation and oxidative stress are present, does it reflect disease severity?
3. Is there an association between inflammation, oxidative stress, and glial cell activation?

About this Study

This is a cross-sectional prospective study of 30 individuals. Ten individuals with Hurler syndrome, ten with the more attenuated form of MPS I, and ten will be healthy volunteer controls will be recruited. The study includes individuals six years of age and older. The study is one year long. Participants will be seen for only one visit. The study will examine the brain using magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) along with a blood draw. At the study visit, participants will undergo an unsedated brain MRI/MRS; this will last about 60 minutes. They will also have a blood draw where up to 2 tablespoons of blood will be collected.

Targeted Enrollment

To be eligible to participate, you must:

• MPS I participants must meet all of the following:
  • Diagnosis of MPS I
  • 6 years of age or older at time of screening
• Healthy control participants must meet all of the following:
  • Absence of a neurological disorder
  • 6 years of age or older at time of screening

You are not eligible to participate if:

• Any surgically implanted pacemaker
• Any indwelling electronic device, including programmable shunts
• Orthodontic braces, unless non-metallic
• Other implanted metal in the body other than titanium
• An inability or unwillingness to complete an MRI/MRS because of low cognitive function or behavioral dysregulation
• Pregnancy

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

Minnesota

• University of Minnesota, Minneapolis
  Study Coordinator: Ashley Schneider, RD, LD
  Phone: 612-301-1371
  E-mail: amwiesen@umn.edu

Status: Recruiting

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

For Diseases:

Fabry disease

Background

Fabry disease is a rare genetic disease caused by mutations in the GLA gene, which result in a deficiency of a metabolic enzyme, alpha-galactosidase A. When this enzyme is absent or in low abundance, glycosphingolipid (a type of fat) accumulates within the blood vessels and a number of tissues and organs, leading to impaired function. Because Fabry disease is X-linked, it most profoundly affects males; however, females who carry the aberrant allele (copy of the gene) also have symptoms. Symptoms of Fabry disease begin in childhood. Among the most common and serious effects of Fabry disease are its effects on the kidney. Proteinuria (protein in the urine) is often the first sign of kidney involvement. Renal (kidney) insufficiency due to Fabry disease (Fabry nephropathy) may worsen throughout life.

There is a strong need for a sensitive, non-invasive biomarker to detect early Fabry nephropathy. Such a marker could enable physicians to categorize patients based on Fabry nephropathy risk, which may lead to beginning treatment at the right time, as well as adjusting treatment doses appropriately.

Podocytes are special kidney cells with a crucial role in preventing escape of protein from blood to the urine. Biopsy studies of Fabry disease patients suggest that podocyte injury occurs early and is progressive (gets worse) with increasing age in young Fabry disease patients. It is also known that podocyte injury and loss lead to irreversible kidney lesions in late stages of Fabry nephropathy. Because injured podocytes are discarded into the urine, a manifestation known as podocyturia, quantification (measuring the number) of urine podocytes could serve as a non-invasive and sensitive biomarker useful to predict Fabry nephropathy risk and to guide Fabry disease treatment.

The research questions are:

1. Is the severity of podocyturia related to the clinical severity of Fabry nephropathy (greater urine albumin and protein excretion and lower glomerular filtration rate)?
2. Does severity of podocyturia predict clinical progression (more symptoms) of Fabry nephropathy (greater urine albumin and protein excretion and lower glomerular filtration rate) over time

About this Study

This is a longitudinal study of 58 individuals with Fabry disease. Those participating in this study will provide a urine sample after enrollment. Data related to renal function, including urine albumin and protein excretion and estimated glomerular filtration rate, will be gathered from electronic medical records. There is no gender or age limitation for enrollment into this study.

For the baseline visit, you will be asked to:

• Fill out a questionnaire
• Give a urine sample (some patients)

We will look at your medical records every year for up to 5 years so that we can collect information about your medical history to find relationships between your medical history and the number of urine podocytes in the urine sample you provided.

Targeted Enrollment

To be eligible to participate, if:

1. Have been diagnosed with Fabry disease

You are not eligible to participate if you:

1. Have had a kidney transplant
2. Use investigational drug(s)

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

Georgia

• Emory University, Atlanta
  Study Coordinator: Dawn Laney, MS, CGC, CCRC
  Phone: 404-778-8518 
  E-mail: dawn.laney@emory.edu

Minnesota

• University of Minnesota, Minneapolis
  Study Coordinator: Cathy Bagne, BS, CCRP
  Phone: 612-624-4688
  E-mail: pinth001@umn.edu

Washington

• University of Washington, Seattle
  Study Coordinator: Cindy Tower
  Phone: 206-686-5464
  E-mail: cmschnei@uw.edu

Status: Recruiting

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

For Diseases:

Krabbe Disease

Background

The estimated incidence of Krabbe Disease is 1/100,000 live births. It is believed that 80-90% of affected children will have the early infantile form of the disease. Other forms of the disease however occur throughout life. Initial symptoms typically include irritability, poor feeding, poor head control, stiffness, loss of milestones, fisted hands, and arching. The only treatment for Krabbe Disease is bone marrow transplantation and we are studying how this treatment affects survival and quality of life and how the disease itself affects development and quality of life.

The research questions are:

1. How transplantation impacts survival and quality of life
2. How Krabbe Disease affects development and quality of life

About this Study

Follow-up calls will be made to surviving study participants every 4 months. Participants will be scored in areas such as, developmental stage, medical complications, and impact on family structure. 

Targeted Enrollment

To be eligible to participate, if:

• Be an individual affected by Krabbe Disease or you must be a family member of someone affected by Krabbe Disease.

You are not eligible to participate if you:

• You are unaffected by Krabbe Disease or do not have a family member affected by Krabbe Disease

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

New York

• University at Buffalo, Buffalo
  Amy Barczykowski, MS
  Phone: 716-829-6101
  E-mail: alp38@buffalo.edu

Status: Recruiting

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Fabry disease is a rare genetic disease with deficient activity of enzyme a-galactosidase A. Deficient activity of this enzyme leads to accumulation of lipid-derived inclusions in cells of different organs including kidney, heart and vessels. These inclusions can be found in the kidney even before birth. The earliest known clinical manifestation of Fabry kidney disease is typically appearance of excess protein in the urine which usually occurs in the second decade of life. However, our studies, as well as those of other investigators show evidence that kidney injury starts much earlier.

Patients with Fabry disease, especially males, are at greater risk to develop kidney failure. Although the earliest clinical symptom of Fabry kidney disease is usually excess loss of protein in the urine starting in the second decade of life, microscopic examination of kidney biopsies from Fabry patients performed by us and other investigators indicate that kidney injury actually starts much earlier than the appearance of protein in the urine. Enzyme replacement therapy may help to stabilize kidney function; however, it cannot reverse excess protein loss into the urine, and may not prevent progression of kidney failure if therapy is started late in the disease. The effect of enzyme replacement therapy on long-term kidney function is not clear, and is what we are focusing our efforts on studying further.

For Diseases: Fabry Disease

Background

We know that Fabry clinical renal disease risk increases with increasing age, especially in males. However, progression with age of Fabry lesions in glomeruli, the filters of the kidney, occurs only in critical cells, the podocytes, for prevention of protein loss, suggesting an important role of these cells in the development of clinically serious Fabry nephropathy. Increased foot process width (FPW) of podocytes is a marker of podocyte injury. Podocyte FPW also increased with increasing age during in Fabry disease in childhood and FPW correlated strongly and directly with urinary protein excretion in young Fabry patients in our studies. Importantly, this progression in podocyte injury was not detectable by standard pathological assessments, but was easily identified by our special electron microscopic measurements.

The research questions or study aims are:

1. To evaluate the effects of age of institution of enzyme replacement therapy (ERT) on podocyte and other renal cell Fabry lipid, (globotriaosylceramide or GL-3) clearance in children and adults with Fabry disease. 
   Hypothesis: ERT instituted at younger age is more effective in reducing podocytes, distal tubular cells, and arterial smooth muscle GL-3 levels than in older Fabry patients.
2. To evaluate the effects of age of institution of ERT on podocyte numbers in children and adults with Fabry disease. 
   Hypothesis: Earlier institution of ERT will stabilize podocyte number while later ERT institution, especially in adults with urine protein may not prevent a progressive decline in podocyte numbers and other associated kidney markers including glomerular sclerosis, tubule-interstitial injury and GFR loss.
3. To test whether clearance of globotriaosylceramide or GL-3 from podocytes and other renal cell inclusions is dependent on ERT dose. 
   Hypothesis: Whereas lower dose ERT may effectively clear globotriaosylceramide or GL-3 from endothelial and meningeal cells, it will be less effective in clearing globotriaosylceramide or GL-3 from other cells in the kidney, i.e., and distal tubular cells, and arterial smooth muscle cells
4. To test whether clearance of podocyte GL-3 and other renal cell inclusions is dependent on gender. 
   Hypothesis: Affected cells will be cleared of globotriaosylceramide or GL-3 equivalently in females and males.

About this Study

This is an observational, cross-sectional study of 50-60 individuals diagnosed with Fabry renal disease who are undergoing a kidney biopsy deemed necessary for patient care. Those participating in this study will be evaluated once for a baseline visit, and then at subsequent or follow up visits after starting ERT at varying intervals, or as deemed clinically necessary by their physician or care provider.

For the study visit, you will be asked to:

• Have a physical exam
• Provide us with a full medical history and family medical history
• Provide information about the medications you are currently taking
• Have blood samples collected to be stored as de-identified samples of serum and plasma (1 to 2 teaspoons), and to be used for future Fabry research.
• Have three urine samples collected (2 random collections and 1 overnight collection). The overnight collection will be stored as de-identified urine samples, and will be used for future Fabry research.
• Allow us to look at your clinically indicated kidney biopsy specimen and your GFR results so that we can collect information about your Fabry disease.

At subsequent study visits, the same procedures as described above will be performed as a follow up to the initial or baseline visit. The interval between these visits will be determined by the provider.

Targeted Enrollment

To be eligible to participate, you must:

1. Have a diagnosis of Fabry disease and have had or will have a kidney biopsy and measures or estimates of glomerular filtration rate (GFR) as part of their clinical evaluation.

You are not eligible to participate if:

1. You are unwilling/unable to give informed consent, or sign the assent (if applicable) and parental consents.
2. There is evidence or the presence of another kidney disease.

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

This is a study that requires a pre-diagnosis of the genetic disorder called Fabry. Usually referrals and contacts are made through the genetic MD who has diagnosed this disease in the patient.

Additional information can be obtained through:

University of Minnesota
Dept. of Pediatric Nephrology
MMC 391
Mpls, MN 55455.

The individuals to contact are:

Dr. Michael Mauer
612-626-2720
E-mail: mauer002@umn.edu

Chester Whitley, PhD.  MD, 
Department of Pediatrics, and Institute of Human Genetics, 
612-625-7422
E-mail: whitley@umn.edu, or www.LysosomalDiseaseNetwork.org

Cathy Bagne, BS, 
Project Coordinator
612-624-4688 
E-mail: pinth001@umn.edu.

Status: Closed to Enrollment

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

Background

This study is an extension of our current study, "Intrathecal Enzyme Replacement for Cognitive Decline in Mucopolysaccharidosis Type I," study number MIRC-002. MIRC-002 is in progress, and several subjects have received treatment over a two-year period. However, the majority of the subjects who have completed the current study are interested in continuing to receive treatment and we also feel that a longer study period would allow us to better determine the long-term safety and efficacy of the treatment.

Mucopolysaccharidosis I (MPS I) is a hereditary disease involving deficiency of an enzyme (a type of protein in the body). This enzyme is needed to break down a type of substance called glycosaminoglycans or GAGs, which are found throughout the body. Normally, the body uses enzymes to break down and recycle GAG in cells. In individuals with MPS I, the missing or insufficient enzyme prevents the proper recycling process, and as a result, cells do not perform properly and may cause progressive damage throughout the body, including the heart, bones, joints, 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 GAG. Excess GAG in the central nervous system leads to cognitive decline, spinal cord compression, hearing, and vision difficulties. As patients get older, they have continuous worsening in their thinking, memory, and behavior that eventually leads to complete dependence on others for their care. Patients with the most severe form of MPS I develop slowing in cognitive development that usually appears after age one and thereafter accelerates. By age 3 years, most of these children fall into the range of mental retardation as defined by standard intelligence tests (Shapiro and Balthazor 2000).

Enzyme replacement therapy (ERT) recently became available for the treatment of MPS I patients. This is a way to give back a manufactured form of the enzyme (called laronidase or Aldurazyme) that MPS I patients are missing due to the disease. However, given in the usual way, ERT does not reach the brain or spinal cord to help with the damage caused there by excess storage. For this reason, an intrathecal approach (injecting the enzyme directly into the cerebral spinal fluid, which is the fluid that surrounds the brain and spinal cord) was studied in dogs with MPS I. The treatments brought the GAG storage in the brain to normal levels (Kakkis et al., 2004, Dickson et al., 2007). Based on the results in MPS I dogs, a pilot trial of intrathecal injections of enzyme was started and is ongoing in human patients to treat the cognitive impairment that occurs in this disease.

The study proposed here will continue to examine the effects of intrathecal injections of enzyme on cognition in MPS I patients. The objectives of the study are to demonstrate the long-term safety of intrathecal enzyme replacement and to determine whether signs of cognitive impairment in MPS I can be reversed or at least stabilized. Subjects will undergo neuropsychological testing, radiologic imaging of the brain, physical examinations, and biochemical tests involving blood draws (about a tablespoon of blood per visit) at screening and throughout the study. Treatments with the enzyme will be done by inserting a needle into the lower back (after numbing medicine is given). A small amount (roughly 2 teaspoons) of cerebral spinal fluid (CSF) will be taken out for tests at each of these spinal taps. The amount of CSF removed is replaced in large part by the treatment.

About this Study

The study will last up to 5 years. Subjects must have completed the original study, MIRC-002, in order to enter this study. There will be a study visit to Harbor-UCLA Medical Center (the main site), or Children's Hospital Oakland (an alternate site), every three months. At each visit, subjects will be evaluated for symptoms of MPS I, cognitive decline, and receive injections of Aldurazyme. In addition to the study visits at this site, subjects will visit the University of Minnesota yearly for neuropsychological testing and a magnetic resonance imaging (MRI) study of the brain. In the future, other study sites may be opened.

At every visit, a subject will have a physical exam, neurological evaluation, walk test, and some subjects will be photographed or videotaped (if they have agreed to this). Before receiving Aldurazyme, you will have blood drawn.

Targeted Enrollment

To be eligible to participate, you must:

1. The subject has completed the MIRC-002 study of intrathecal enzyme replacement therapy for cognitive decline in mucopolysaccharidosis I
2. Age six years or older.
3. Subject and/or guardian willing and able to provide written informed consent.
4. Negative urine pregnancy test at screening (non-sterile females of child-bearing potential only)
5. Currently using two acceptable methods of birth control as determined by the investigator and willing to continue to use acceptable birth control during their participation in the study (non-sterile females of child-bearing potential who are sexually active only)
6. Willing and able to comply with study procedures. For example, the subjects must be able to complete written and computer-based testing. The subjects must be able to lie still in the MRI scanner for at least 40 minutes without sedation.

You are not eligible to participate if:

1. The subject has undergone hematopoietic stem cell transplantation
2. Recent initiation of intravenous Aldurazyme® therapy with less than 6 months of therapy. Subjects who have been receiving Aldurazyme® therapy for more than 6 months, and those who have never received Aldurazyme® therapy, will be allowed to enroll
3. Pregnant or lactating, or considering pregnancy
4. Receipt of an investigational drug or procedure within 30 days of enrollment
5. A condition, medical or other, that prevents participation in the study, including severe auditory or visual impairment, significant lumbar pathology, lumbar catheter, or recent major surgery within 6 weeks that would preclude their ability to participate.
6. Infusion reactions to intravenous Aldurazyme® therapy that require ongoing medical treatment, special prophylaxis or altered rate or dose of enzyme administration
7. The subject has severely impaired spinal CSF flow, demonstrates by failure of appearance of 99m Technetium-DTPA in the basal cisterns by 4 hours after intralumbar administration.
8. The subject has problems with blood clotting, as identified by a platelet count of less than 50,000, an INR of 1.5 or greater, or a PTT that is 1.5 times the upper limit of normal for the laboratory from which it was drawn.

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

California

• Children’s Hospital & Research Center, Oakland
  Jacqueline Madden, PNP 
  Phone: 510-428-3885 x5745
  E-mail: jmadden@mail.cho.org

Minnesota

• Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
  Nathalia Patritti
  Phone: 310-781-3682
  E-mail: ncressey@labiomed.org

Status: Recruiting

Study Summary

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.

The purpose of this clinical trial is to evaluate the use of a combination of a medication called miglustat and a ketogenic diet (we call this the "Syner-G regimen") for treatment of the gangliosidoses, to learn if this combination will provide improved clinical outcomes compared to what we currently know about the natural course of the disease.

For Diseases:

• Gangliosidoses
• Tay-Sachs disease
• Sandhoff disease
• GM1 Gangliosidosis

Background

The gangliosidoses are a group of inherited genetic conditions in which a gene defect causes an enzyme deficiency.  GM1 gangliosidosis is caused by mutations to the gene that codes for the lysosomal enzyme beta-galactosidase, leading to deficiency of beta-galactosidase enzyme.  Without the beta-galactosidase enzyme to break it down, a fatty compound called GM1 ganglioside accumulates in brain and nerve cells and other tissues, leading to progressive mental and physical deterioration.

The GM2 gangliosidoses are caused by mutations to genes that lead to a deficiency in activity of an enzyme called beta hexosaminidase A. This enzyme is needed to break down a fatty compound inside the body's cells called GM2 ganglioside.  For patients with GM2 gangliosidosis, the GM2 ganglioside builds up in the body's cells, including brain and nerve cells, and this in turn causes symptoms of mental and physical deterioration.  GM2 gangliosidosis diseases include Tay-Sachs disease and Sandhoff disease.

For more detailed information, search for this study on ClinicalTrials.gov using its I.D. number NCT02030015. Visit: https://clinicaltrials.gov/ct2/search/index.

The research questions are:

The purpose of the study is to determine if a combination therapy using miglustat and the ketogenic diet for patients with a gangliosidosis disease will:

1. Improve overall survival for participants with infantile or juvenile gangliosidoses when compared to survival data reported in previous studies of the natural history of these diseases.
2. Improve neurodevelopmental clinical outcomes (outcomes involving development of the brain and central nervous system) for participants with infantile or juvenile gangliosidoses compared to information available in the medical literature.

About this Study

This is a clinical trial evaluating a planned total of 30 infant or juvenile individuals with a documented gangliosidosis disease. Those participating in this study will be evaluated at baseline, and then every 12 months until the study is over in five years. The study visits will take place at the University of Minnesota in Minneapolis, Minnesota. Some limited funding may be available to assist with the cost of travel and lodging during these visits. Standard clinical evaluations will be billed to the patient's health insurance as part of standard clinical care.

For each visit to the University of Minnesota, each participant will be asked to:

• Undergo neurodevelopmental testing to evaluate his/her neurodevelopmental status (the status of current brain development). This testing will be done by a pediatric neuropsychologist who specializes in evaluating patients with gangliosidosis diseases.
• Undergo neurological evaluation by a neurologist at the University of Minnesota who works with the study staff, to see if the participant has any seizures or movement disorders.
• Have a clinical assessment performed by Chester B. Whitley, MD, PhD, a geneticist and co-investigator in this clinical trial.
• Have a pharmacotherapy consultation (to discuss the use of pharmaceutical drugs as therapy) with Jeanine R. Jarnes Utz, the principal investigator in this clinical trial.
• Work with the ketogenic diet team at the University of Minnesota, who will help the participant transition to the ketogenic diet and who will work with the participant's local ketogenic diet team to provide the participant's caregivers with the education they need in order to successfully manage this diet.

Targeted Enrollment

To be eligible to participate, you must:

• Be an individual with one of the following gangliosidosis diseases:
  • Tay-Sachs Disease, infantile onset
  • Tay-Sachs Disease, juvenile onset
  • Sandhoff Disease, infantile onset
  • Sandhoff Disease, juvenile onset
  • GM1 Gangliosidosis, infantile onset
  • GM1 Gangliosidosis, juvenile onset
• Be aged 17 years or less
• Work closely with the University of Minnesota ketogenic diet team, and with a local ketogenic diet team, which must include a ketogenic dietician and a neurologist trained in the ketogenic diet.

You are not eligible to participate if:

1. You have a desire to not participate.
2. You are older than 17 years of age.
3. You have severe renal impairment.
4. You are a post-pubertal female who is pregnant, or who is unwilling to use highly-effective methods to prevent pregnancy.
5. You are a breast-feeding female.
6. You have an allergy to miglustat or any of the components within the drug product.

How to participate

In order to participate in a study, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation.

Minnesota

• University of Minnesota, Minneapolis, MN
  Study Coordinator: Evelyn Redtree, M.S.
  Phone: 612-625-0974
  E-mail: eredtree@umn.edu