Cystagon to Treat Infantile Neuronal Ceroid Lipofuscinosis
Condition: Infantile Neronal Ceroid Lipofuscinosis
MeSH terms: Neuronal Ceroid-Lipofuscinoses
Intervention: Cystagon
Intervention MeSH terms: Cysteamine
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 6 Months
Maximum age: 3 Years
Healthy volunteers: No
Keywords: Palmitoyl-Protein Thioesterase; Lysosomes; Batten Disease; Encephalopathy; Progressive Neurodegeneration; CLN 1; Infantile Neuronal Ceroid Lipofuscinosis; Cystagon

Summary:

      This study will examine the effectiveness of a drug called Cystagon in treating infantile
      neuronal ceroid lipofuscinosis (INCL), a progressive neurological disease affecting children.
      At around 11 to 13 months of age, patients develop slowed head growth, mild brain atrophy
      (wasting), electroencephalographic (EEG) changes and retinal deterioration, with symptoms
      worsening over time. The disease results from an enzyme deficiency that causes fatty
      compounds called ceroid to accumulate in cells. In laboratory experiments, Cystagon has
      helped remove ceroid from cells of patients with INCL.

      Children with INCL between 6 months and 3 years of age may be eligible for this study.
      Participants take Cystagon daily by mouth every 6 hours. They are admitted to the NIH
      Clinical Center for a 4- to 5-day period every 6 months for the following tests and
      evaluations:

        -  Review of medical history, including a detailed record of seizures, physical
           examination, blood tests and clinical photographs. For the initial baseline studies,
           examinations may also be scheduled with pediatric neurology, ophthalmology and
           anesthesia services.

        -  Magnetic resonance imaging (MRI) of the brain MRI uses a powerful magnet, radio waves,
           and computers to provide detailed images of the brain without the use of X-rays. The
           patient lies on a table that slides inside a donut-shaped machine containing a magnetic
           field. The child requires general anesthesia for the procedure.

        -  Electroretinogram (ERG) measures the function of the retina, the light-sensitive tissue
           in the back of the eye. To record the flash ERG, a special contact lens is placed on the
           eye s surface and the eye is stimulated with flashes of light. Infants and very young
           children require general anesthesia for the procedure.

        -  Visual evoked potential (VEP) measures the function of the visual pathway from the eye
           to the brain. To record the VEP, five electrodes are placed on the scalp and the eye is
           stimulated with flashes of light. Infants and very young children must be anesthetized
           for the procedure.

        -  Electroencephalogram (EEG) measures brain electrical activity, using electrodes placed
           on the scalp. The test is useful in defining seizures. The child may need to be sedated
           to keep still during the test.

        -  Skin biopsy A small piece of skin is removed (usually from the upper arm or shoulder)
           under local anesthetic to grow cells in the laboratory. This procedure is done at the
           start of the study and is repeated after 1 year if therapy results are promising.

      Children s condition may improve, stabilize or worsen during this study. Life may be
      prolonged without significant improvement in quality. The information gained from the study
      may help scientists develop more potent drugs to treat INCL.
    

Eligibility criteria:

        -  INCLUSION and EXCLUSION CRITERIA:

        Only patients between 6 months and 3 years of age will be admitted in this study. Parents
        or caregivers of patients recruited to the study will be provided with a copy of the
        protocol and the consent form to review prior to their coming to the NIH. They will be
        encouraged to call either Dr. Levin or Dr. Mukherjee to discuss any questions they may have
        concerning the protocol prior to enrollment in the study.

        The proposed age range (6 mo to 3 yrs) was chosen because these children are expected to
        have a mild to moderate neurological deficiency but are well enough to be cared for at home
        by the family. Therefore, these patients should not require extensive medical or nursing
        care during their stay at the Clinical Center. Moreover, the patients are locally cared for
        by neurologists and pediatricians on a regular basis, and such care will continue when the
        patients return home.

        The rigid age exclusion criteria will be used because the majority of INCL patients have
        more frequent seizures, complete retinal blindness and significant cerebral atrophy beyond
        3 years of age. Dr. Santavuori (one of our consultants who is now deceased), who had the
        most extensive experience with these patients, believed that the neurological degeneration
        after age 2 might not be reversible. While Dr. Santavuori s speculation is well taken, we
        feel that since to date there has not been any effective treatment to slow the progression
        of neuronal death in INCL, and since our preliminary results show that Cystagon slows the
        progression of neurodegeneration, we feel that a combination of Cystagon plus N-Ac with its
        anti-apoptotic and neuro-protective effects may show some added benefits over Cystagon
        therapy alone.

        In our initial protocol we restricted the admission of patients that carried two lethal
        mutations in the PPT1 gene. The purpose of including only those patients who carry specific
        PPT1 mutations

        (L10X, R151X, R164X, W296X, R122W, c.169insA and E184K) was to establish that the
        beneficial effects of the combination therapy because a patients who had any two of these
        mutations manifested the most severe disease phenotype. Because of the uniform
        manifestation of the disease it was easier to determine any beneficial effects of the
        combination drug therapy.

        Subsequently, our protocol was approved for treatment of INCL patients with any two
        mutations in the PPT1 gene. Our protocol has been previously amended to include all INCL
        patients regardless of the PPT1 mutations they carry.

        Patients with intractable seizures that cannot be controlled by two or fewer antiepileptic
        medications will not be accepted for this study. Patients who cannot take nourishment
        orally or who are in a vegetative state will not be enrolled in this study even if the 6
        months to 3 year age criterion is met.

        Both male and female patients are eligible for enrollment in this study.