Cyclic vomiting syndrome (CVS) is a disabling condition characterized by multiple severe and distinct episodes of nausea, vomiting, lethargy and variable other symptoms separated by asymptomatic intervals. Although CVS is generally believed to be a (predominantly) childhood variant of migraine, its etiology and pathogenesis are poorly understood. Several features of CVS, including a maternal bias in inheritance, suggest that mitochondrial DNA (mtDNA) sequence variations/mutations may be involved in its etiology. A significant subset of children with CVS have additional neuromuscular disease manifestations including cognitive dysfunction and epilepsy. Maternal inheritance of migraine and/or various neuromuscular disorders and lactic acidosis are present in ten children with CVS followed by the investigators, strongly suggesting that mtDNA mutations are involved in at least some cases. An inherited complex mtDNA rearrangement was found in one. Preliminary results using temporal temperature gradient gel electrophoresis (TTGE) found heteroplasmic sequence variations in the mtDNA D-loop in 2 additional CVS cases. TTGE is a novel mutation detection assay which was developed for use with mtDNA by the PI and collaborators. TTGE is sensitive and cost effective relative to other methods and for the first time permits the screening of large groups of patients for mutations throughout the entire mtDNA. Since mtDNA sequence variations are postulated to be more likely involved among CVS sufferers with additional neuromuscular disease manifestations, in the first sub-study 50 of these individuals will be screened by TTGE for all sequence variations throughout the mtDNA. The incidence of CVS cases caused by mtDNA sequence variations will be determined in a second sub-study in which the mtDNA in an unbiased group of 100 CVS sufferers will be screened. All sequence variations found in CVS sufferers will be compared against those found upon an identical screening of 100 control individuals, and any of interest will be sequenced. Pathogenicity of suspected mutations will be determined in rho negative cybrids. An extensive amount of clinical and laboratory data will be collected in all patients, allowing for the comparison of CVS sufferers with and without mtDNA mutations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS040462-03
Application #
6529559
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Tagle, Danilo A
Project Start
2000-09-01
Project End
2006-08-31
Budget Start
2002-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$186,375
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Boles, Richard G; Powers, Amy L R; Adams, Kathleen (2006) Cyclic vomiting syndrome plus. J Child Neurol 21:182-8
Wang, Qingxue; Boles, Richard G (2006) Individual human hair mitochondrial DNA control region heteroplasmy proportions in mothers and children. Mitochondrion 6:37-42
Boles, Richard G; Adams, Kathleen; Li, B U K (2005) Maternal inheritance in cyclic vomiting syndrome. Am J Med Genet A 133A:71-7
Wang, Qingxue; Ito, Masamichi; Adams, Kathleen et al. (2004) Mitochondrial DNA control region sequence variation in migraine headache and cyclic vomiting syndrome. Am J Med Genet A 131:50-8
Boles, Richard G; Chaudhari, Divya; Soderkvist, Jan et al. (2003) Quantification of mitochondrial DNA heteroplasmy by temporal temperature gradient gel electrophoresis. Clin Chem 49:198-200
Boles, Richard G; Adams, Kathleen; Ito, Masamichi et al. (2003) Maternal inheritance in cyclic vomiting syndrome with neuromuscular disease. Am J Med Genet A 120A:474-82