Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study

Abstract

Summary Background Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease caused by mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1). PPT1-deficiency causes lysosomal ceroid accumulation leading to INCL pathogenesis. Previously, we reported that phosphocysteamine and N-acetylcysteine mediated ceroid depletion in cultured cells from INCL patients. We conducted a pilot study to determine whether a combination of cysteamine bitartrate and N-acetylcysteine is beneficial for these patients. Methods Patients (6-month to 3-years old) with any combination of 2 of the 7 most lethal PPT1 mutations were admitted. All patients were recruited from physician referrals and the PPT1 mutations were analyzed prior to admission. Patients were evaluated by electroretinography(ERG), brain MRI and MRS, electroencephalography (EEG), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Patients received oral cysteamine bitartrate (60mg/kg/day) and N-acetylcysteine (60mg/kg/day) and were evaluated every 6 to 12 months until they showed isoelectric EEG attesting to a vegetative state or were too sick to travel. Outcomes were compared with the reported INCL natural history. In two cases, the disease progression was compared with that of a sibling who was above the age limit for inclusion into the protocol. Findings Between March, 2001, and June, 2011, we recruited 10 children with INCL but one was lost to follow-up after the first visit. Thus, a total of 9 patients (5 females and 4 males) were studied. At the first follow-up visit, peripheral leukocytes in all 9 patients showed virtually complete depletion of GRODs and 7 of 9 patients manifested less irritability and/or improved alertness based upon parental and physician observations. Evaluation by Denver scale showed acquisition of no new developmental skills and retinal function assessed by ERG progressively declined. Most notably, average time to isoelectric EEG (indicating vegetative state) was significantly longer in our patients compared to that previously reported. MRI studies demonstrated signal abnormalities similar to previous reports. Brain volume and NAA declined steadily, but no published quantitative MRI or MRS studies of INCL patients are available for comparison on these measures. There were no adverse events related to therapy other than a mild gastrointestinal discomfort in 2 of 9 patients, which was eliminated when the liquid preparation of cysteamine bitatrate was replaced with capsules. Interpretation The objectively demonstrated benefits in our study are the depletion of GRODs and delay of isoelectric EEG in all patients; in addition, several subjective benefits were suggested, all of which warrant further study. Nevertheless, this report systematically and quantitatively documents the natural history of 9 INCL patients with the most lethal CLN1/PPT1 mutations and thereby provides a benchmark for evaluating future experimental therapies. Fu...

MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis

“…We have demonstrated that, among the regions that we measured separately, atrophy begins earliest and proceeds fastest in the cerebrum, with the thalamus lagging slightly behind; there is later involvement of the cerebellum and then the brainstem. Although our patients had a variety of different gene mutations, the pattern and rate of atrophy that we observed did not appear to vary by genotype, in agreement with previous reports that these particular gene mutations are clinically indistinguishable 16, 19 .…”

“…We would have liked to have compared our quantitative atrophy measurements to previous reports on the natural history of volume loss in INCL 16, 25 to evaluate the treatment benefits of cysteamine bitartrate and N-acetylcysteine; in particular we would have liked to determine whether the treatment resulted in any delay in atrophy onset or any slowing of the rate of atrophy. However, since all previous studies evaluating atrophy in INCL used qualitative scoring without correspondence to any particular absolute or fractional volume loss, we could not determine the effect of the treatment on brain atrophy.…”

“…Recruitment and inclusion criteria for this study have been described in detail elsewhere 16 (ClinicalTrials.gov number NCT00028262). A total of 10 patients were recruited for the study, 9 of whom initiated treatment after the baseline study and returned for follow-up; the other patient dropped out of the study after the baseline evaluation and did not undergo treatment.…”

“…The intention was to compare to the natural history and to future treatment interventions using behavioral and developmental assessments, and quantifiable measures such as electroencephalography, electroretinography, MRI derived brain volume measurements, MRS, and quantification of intralyosomal ceroid deposits. An overview of the study results has been published recently 16 ; the current report details the MRI derived brain volume measurements.…”

Progress in the Development of Small Molecule Therapeutics for the Treatment of Neuronal Ceroid Lipofuscinoses (NCLs)

“…Decrease in the number and size of GRODs was observed after the first posttreatment follow-up and in the subsequent follow-up GROD levels were undetectable indicating that the treatment had beneficial effects in patients. 5 …”