Sondra W Levin1, Eva H Baker2, Wadih M Zein3, Zhongjian Zhang4, Zenaide M N Quezado5, Ning Miao6, Andrea Gropman7, Kurt J Griffin8, Simona Bianconi4, Goutam Chandra4, Omar I Khan9, Rafael C Caruso10, Aiyi Liu11, Anil B Mukherjee12. 1. Program on Developmental Endocrinology and Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA; Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD, USA. 2. Department of Radiology and Imaging Sciences, NIH Clinical Center, NIH, Bethesda, MD, USA. 3. National Eye Institute, NIH, Bethesda, MD, USA. 4. Program on Developmental Endocrinology and Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA. 5. Department of Anesthesiology, NIH Clinical Center, NIH, Bethesda, MD, USA; Department of Anesthesiology, Children's National Medical Center, Washington, DC, USA. 6. Department of Anesthesiology, NIH Clinical Center, NIH, Bethesda, MD, USA. 7. National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA; Department of Neurology, Children's National Medical Center, Washington, DC, USA. 8. Program on Developmental Endocrinology and Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA; Sanford Research/University of South Dakota Medical Center, Sioux Falls, SD, USA. 9. National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA. 10. National Eye Institute, NIH, Bethesda, MD, USA; Department of Psychology, Princeton University, Princeton, NJ, USA. 11. Biostatistics and Bioinformatics Branch, Eunice Kennedy-Shriver NICHD, NIH, Bethesda, MD, USA. 12. Program on Developmental Endocrinology and Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA. Electronic address: mukherja@exchange.nih.gov.
Abstract
BACKGROUND: Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative lysosomal storage disease caused by mutations in the gene (CLN1 or PPT1) encoding palmitoyl-protein thioesterase-1 (PPT1). We have previously reported that phosphocysteamine and N-acetylcysteine mediate ceroid depletion in cultured cells from patients with this disease. We aimed to assess whether combination of oral cysteamine bitartrate and N-acetylcysteine is beneficial for patients with neuronal ceroid lipofuscinosis. METHODS: Children between 6 months and 3 years of age with infantile neuronal ceroid lipofuscinosis with any two of the seven most lethal PPT1 mutations were eligible for inclusion in this pilot study. All patients were recruited from physician referrals. Patients received oral cysteamine bitartrate (60 mg/kg per day) and N-acetylcysteine (60 mg/kg per day) and were assessed every 6-12 months until they had an isoelectric electroencephalogram (EEG, attesting to a vegetative state) or were too ill to travel. Patients were also assessed by electroretinography, brain MRI and magnetic resonance spectroscopy (MRS), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Children also underwent physical and neurodevelopmental assessments on the Denver scale. Outcomes were compared with the reported natural history of infantile neuronal ceroid lipofuscinosis and that of affected older siblings. This trial is registered with ClinicalTrials.gov, number NCT00028262. FINDINGS: Between March 14, 2001, and June 30, 2012, we recruited ten children with infantile neuronal ceroid lipofuscinosis; one child was lost to follow-up after the first visit and nine patients (five girls and four boys) were followed up for 8 to 75 months. MRI showed abnormalities similar to those in previous reports; brain volume and N-acetyl aspartic acid (NAA) decreased steadily, but no published quantitative MRI or MRS studies were available for comparison. None of the children acquired new developmental skills, and their retinal function decreased progressively. Average time to isoelectric EEG (52 months, SD 13) was longer than reported previously (36 months). At the first follow-up visit, peripheral leukocytes in all nine patients showed virtually complete depletion of GRODs. Parents and physicians reported less irritability, improved alertness, or both in seven patients. No treatment-related adverse events occurred apart from mild gastrointestinal discomfort in two patients, which disappeared when liquid cysteamine bitartrate was replaced with capsules. INTERPRETATION: Our findings suggest that combination therapy with cysteamine bitartrate and N-acetylcysteine is associated with delay of isoelectric EEG, depletion of GRODs, and subjective benefits as reported by parents and physicians. Our systematic and quantitative report of the natural history of patients with infantile neuronal ceroid lipofuscinosis provides a guide for future assessment of experimental therapies. FUNDING: National Institutes of Health.
BACKGROUND:Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative lysosomal storage disease caused by mutations in the gene (CLN1 or PPT1) encoding palmitoyl-protein thioesterase-1 (PPT1). We have previously reported that phosphocysteamine and N-acetylcysteine mediate ceroid depletion in cultured cells from patients with this disease. We aimed to assess whether combination of oral cysteamine bitartrate and N-acetylcysteine is beneficial for patients with neuronal ceroid lipofuscinosis. METHODS:Children between 6 months and 3 years of age with infantile neuronal ceroid lipofuscinosis with any two of the seven most lethal PPT1 mutations were eligible for inclusion in this pilot study. All patients were recruited from physician referrals. Patients received oral cysteamine bitartrate (60 mg/kg per day) and N-acetylcysteine (60 mg/kg per day) and were assessed every 6-12 months until they had an isoelectric electroencephalogram (EEG, attesting to a vegetative state) or were too ill to travel. Patients were also assessed by electroretinography, brain MRI and magnetic resonance spectroscopy (MRS), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Children also underwent physical and neurodevelopmental assessments on the Denver scale. Outcomes were compared with the reported natural history of infantile neuronal ceroid lipofuscinosis and that of affected older siblings. This trial is registered with ClinicalTrials.gov, number NCT00028262. FINDINGS: Between March 14, 2001, and June 30, 2012, we recruited ten children with infantile neuronal ceroid lipofuscinosis; one child was lost to follow-up after the first visit and nine patients (five girls and four boys) were followed up for 8 to 75 months. MRI showed abnormalities similar to those in previous reports; brain volume and N-acetyl aspartic acid (NAA) decreased steadily, but no published quantitative MRI or MRS studies were available for comparison. None of the children acquired new developmental skills, and their retinal function decreased progressively. Average time to isoelectric EEG (52 months, SD 13) was longer than reported previously (36 months). At the first follow-up visit, peripheral leukocytes in all nine patients showed virtually complete depletion of GRODs. Parents and physicians reported less irritability, improved alertness, or both in seven patients. No treatment-related adverse events occurred apart from mild gastrointestinal discomfort in two patients, which disappeared when liquid cysteamine bitartrate was replaced with capsules. INTERPRETATION: Our findings suggest that combination therapy with cysteamine bitartrate and N-acetylcysteine is associated with delay of isoelectric EEG, depletion of GRODs, and subjective benefits as reported by parents and physicians. Our systematic and quantitative report of the natural history of patients with infantile neuronal ceroid lipofuscinosis provides a guide for future assessment of experimental therapies. FUNDING: National Institutes of Health.
Authors: Tyler B Johnson; Jacob T Cain; Katherine A White; Denia Ramirez-Montealegre; David A Pearce; Jill M Weimer Journal: Nat Rev Neurol Date: 2019-03 Impact factor: 42.937
Authors: Jonathan B Rosenberg; Alvin Chen; Stephen M Kaminsky; Ronald G Crystal; Dolan Sondhi Journal: Expert Opin Orphan Drugs Date: 2019-11-27 Impact factor: 0.694