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. 2013:11:87-92.
doi: 10.1007/8904_2013_226. Epub 2013 Apr 16.

Substrate Reduction Therapy in Four Patients with Milder CLN1 Mutations and Juvenile-Onset Batten Disease Using Cysteamine Bitartrate

M Gavin  1 , G Y Wen, J Messing, S Adelman, A Logush, E C Jenkins, W T Brown, M Velinov
Affiliations

Substrate Reduction Therapy in Four Patients with Milder CLN1 Mutations and Juvenile-Onset Batten Disease Using Cysteamine Bitartrate

M Gavin et al. JIMD Rep. 2013.

Abstract

Homozygous mutations in the gene CLN1 typically result in infantile-onset neuronal ceroid lipofuscinosis, a severe progressive neurological disorder with early death. The gene CLN1 encodes the enzyme palmitoyl protein thioesterase (PPT1), which is involved in lysosomal degradation of S-fatty acylated proteins. Cysteamine bitartrate (Cystagon) has been shown to reduce the storage material in PPT1 deficient cells. We report the results of a 7-year, open label, nonrandomized trial using Cystagon in four individuals with juvenile-onset NCL resulting from milder CLN1 mutations. The Cystagon doses were gradually increased with the goal of achieving 50 mg/kg bodyweight. The disease progression was monitored with parental questionnaires in four treated individuals and five untreated controls with the same CLN1 mutations. Mononuclear leukocytes from the treated individuals were examined for submicroscopic lysosomal storage inclusions. Cystagon treatment resulted in decreased storage material in peripheral leukocytes of the treated individuals. No severe side effects were noted. An allergic rash occurred in one of the individuals that required a dose reduction. The treatment did not result in overall attenuation of the disease progression. Slower progression of the disease was observed in two of the individuals when they were analyzed separately. However, slower progression in these individuals was also observed prior to starting the treatment. This effect may have been due to the higher Cystagon dose achieved in this group, but it could also have been coincidental. The apparent lack of toxicity of Cystagon may warrant further Cystagon trials in infantile NCL, possibly in conjunction with other developing therapies.

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Figures

Fig. 1
Fig. 1
Proportions of peripheral blood cells with NCL-specific inclusions identified on electron microscopy (EM) studies in three of the treated study participants are shown in relation to the Cystagon doses. Such EM studies were not done for participant 1-10. The ID number of each patient is shown on top of the graph. These studies demonstrate decrease in the NCL-specific inclusions with the Cystagon treatment
Fig. 2
Fig. 2
Disease severity scores (DSS) at different ages in the treated and control individuals. Average disease severity scores (DSS) are shown on the Y-axis and patients’ age in years are shown on the X-axis. The treated patients are indicated with black lines and the controls with gray lines. Lower scores show more advanced disease stage. (a) Results of all treated and control individuals combined. (b) Results in group 1. (c) Results in group 2. (d) Results in group 3. Only the results in group 1 show lower disease severity/progression in the Cystagon treated individuals (see text for further explanation)
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