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.

Neuronal ceroid lipofuscinosis (NCLs) are the most common (1 in 12,500) heritable progressive encephalopathies of children. Infantile NCL (INCL) is caused by lysosomal palmitoyl-protein thioesterase (PPT) deficiency. PPT catalyzes the hydrolysis of thioester linkages in S-acylated polypeptides and its deficiency causes abnormal accumulation of these polypeptides, leading to INCL. Since thioester bonds are susceptible to nucleophilic attack, drugs with nucleophilic properties may have therapeutic potential for INCL. Accordingly, we tested several compounds with nucleophilic properties (i.e., cysteamine, phosphocysteamine and N-acetylcysteine) and found that these drugs disrupt thioester linkages in a model high-energy thioester substrate, [(14)C] palmitoyl~CoA, releasing [(14)C] palmitic acid. As a positive control, we used hydroxylamine, a compound that specifically cleaves thioester linkages. Among the drugs tested, we characterized phosphocysteamine in further detail because: (i) INCL is a lysosomal storage disease and phosphocysteamine is reported to concentrate in the lysosomes; (ii) we found that phosphocysteamine functions at a low pH in cleaving thioester linkages; (iii) it crosses the blood-brain barrier; (iv) it prevents apoptosis in INCL lymphoblasts and (v) it is relatively nontoxic. Furthermore, our laboratory studies have shown that phosphocysteamine not only disrupts thioester linkages in S-acylated polypeptides in cultured cells from INCL patients but also mediates the depletion of intracellular ceroid deposits and prevents their reaccumulation. For the last 31/2 years we have been conducting a clinical trial to determine whether Cystagon is beneficial for INCL patients. So far, we have treated 6 Caucasian patients (3 females & 3 males). Our preliminary results indicate that Cystagon slows down the rapid neurodegeneration characteristic of INCL. Moreover, our patients have not developed epileptic seizures, a common complication of this disease. In fact, before the initiation of Cystagon treatment the EEG of one patient revealed epileptic foci, which were not detected in repeat EEG tests six months after treatment with this drug. The most dramatic effect of Cystagon is the complete clearance of lysosomal ceroids in WBCs within six months of therapy. In parallel with these studies, using an animal model of INCL we tested the effects of Cystagon alone and a combination of Cystagon and N-acetylcysteine (Mucomyst), which manifests anti-apoptotic and neuroprotective properties. Our preliminary results show that this combination therapy delays the development of neurological symptoms, reduces apoptosis and maintains the brain volume in these mice for a longer period of time compared with those treated with Cystagon alone. These preliminary results prompt us to propose a combination therapy with Cyatagon plus Mucomyst for INCL patients. Since INCL is a fatal disease and Mucomyst, has anti-apoptotic and neuroprotective effects, and since Mucomyst, like Cystagon, has a proven record of safety, we propose to test a combination of these two drugs in 20 INCL patients. In this population of 20 patients we will include those who are currently enrolled in our ongoing INCL-Cystagon study (#01-CH-0086).

• Santavuori P. Neuronal ceroid-lipofuscinoses in childhood. Brain Dev. 1988;10(2):80-3. Review.
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• INCLUSION CRITERIA:

Only patients between 6 months and 3 years of age will be admitted in this study.

Patients should not require extensive medical or nursing care during their stay at the Clinical Center.

Patients who have a genetic diagnosis and carry any combination of two of the following specific PPT mutations: L10X, R151X, R164X, W296X, R122W, c.169insA and E184K.

Both male and females patients are eligible for enrollment in this study.

EXCLUSION CRITERIA:

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.