The purpose of this 3 year, multi-site, non-randomized, prospective, observational study is to characterize the natural history of Alpers syndrome. This syndrome is a rare autosomal recessive disease caused by mutations in the polymerase gamma 1 gene (POLG), which is responsible for all mitochondrial DNA (mtDNA) replication. POLG mutations result in reduced levels of in mitochondrial DNA (mtDNA depletion), which, in turn, causes loss of mitochondrial functioning and gives rise to this disorder. Disease is characterized by seizures, liver degeneration, and progressive developmental regression (Harding, 1990). Typically, children develop normally over the first few months or years with the average age at onset of 2 - 4 years, but onset can be as late as the third decade. Alpers syndrome is thought to be a uniformly fatal disorder, but the rate of neurological degeneration, degree of liver involvement and age of death vary considerably. This disorder has been identified in diverse ethnic groups (Saneto et al., 2010). The study proposes to achieve the following specific aims:
Specific Aim 1 : To characterize the natural history of Alpers Syndrome stratified by POLG genotype, age of onset, sequence and timing of major symptom onset, severity and progression of organ involvement and symptom progression. If possible, to identify different phenotypes of Alpers Syndrome.
Specific Aim 2 : To examine possible associations between specific events in patient medical history and onset of Alpers, including viral illness, dehydration, fever, catabolic stress, including vaccination-related fever. In particular, we aim to answer the following questions:
Specific Aim 3 : To identify correlations between signs and symptoms of presentation of Alpers and disease severity and survival. This study is an extension of the NAMDC Clinical Registry. Patients with Alpers syndrome and their siblings will be followed for up to 2 years. Study data will include: results of tests performed as standard of care;detailed symptom information collected through diaries;neuro-developmental test results;medical history;and supplemental clinical information. At study conclusion, study data will be summarized and relevant subgroups of Alpers syndrome patients and/or their siblings will be compared using standard statistical methods in order to identify associations between genotype and phenotype and between medical history and disease course.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZNS1-SRB-S)
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Columbia University (N.Y.)
New York
United States
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Al-Gadi, Iman S; Haas, Richard H; Falk, Marni J et al. (2018) Endocrine Disorders in Primary Mitochondrial Disease. J Endocr Soc 2:361-373
Hirano, Michio; Emmanuele, Valentina; Quinzii, Catarina M (2018) Emerging therapies for mitochondrial diseases. Essays Biochem 62:467-481
Raghavan, Neha S; Brickman, Adam M; Andrews, Howard et al. (2018) Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol 5:832-842
Barca, Emanuele; Ganetzky, Rebecca D; Potluri, Prasanth et al. (2018) USMG5 Ashkenazi Jewish founder mutation impairs mitochondrial complex V dimerization and ATP synthesis. Hum Mol Genet 27:3305-3312
Shen, Lishuang; Attimonelli, Marcella; Bai, Renkui et al. (2018) MSeqDR mvTool: A mitochondrial DNA Web and API resource for comprehensive variant annotation, universal nomenclature collation, and reference genome conversion. Hum Mutat 39:806-810
Garone, Caterina; Taylor, Robert W; Nascimento, Andrés et al. (2018) Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet 55:515-521
Winawer, Melodie R; Griffin, Nicole G; Samanamud, Jorge et al. (2018) Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol 83:1133-1146
Zolkipli-Cunningham, Zarazuela; Xiao, Rui; Stoddart, Amy et al. (2018) Mitochondrial disease patient motivations and barriers to participate in clinical trials. PLoS One 13:e0197513
Mancuso, Michelangelo; McFarland, Robert; Klopstock, Thomas et al. (2017) International Workshop:: Outcome measures and clinical trial readiness in primary mitochondrial myopathies in children and adults. Consensus recommendations. 16-18 November 2016, Rome, Italy. Neuromuscul Disord 27:1126-1137
Bedoyan, Jirair K; Yang, Samuel P; Ferdinandusse, Sacha et al. (2017) Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab 120:342-349

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