Cyclic Vomiting Syndrome

A number sign (#) is used with this entry because of evidence that cyclic vomiting syndrome can be caused by mutation in the mitochondrial transfer RNA-leucine gene (MTTL1; 590050).

Clinical Features

Cyclic vomiting syndrome has long been recognized (Lombard, 1861; Gee, 1882). It is characterized by recurrent, explosive bouts of vomiting punctuated by periods of normal health. Affected individuals have stereotypical episodes with rapid onset, most often during the night or in the early morning, a high peak frequency of vomiting every 10 to 15 minutes, associated with nausea, retching, abdominal pain, lethargy, anorexia, pallor, and a rapid complete resolution. Median age at onset is 5 years, and median age at resolution of symptoms is 10 years (Haan et al., 2002).

In a review of 214 children with cyclic vomiting syndrome, Li et al. (1999) found that 176 (82%) met the criteria for migraine-related CVS, having either a family history of migraine or subsequent development of migraine, and 38 (18%) did not. Comparison of clinical features between the 2 groups showed that those without associated migraine had more severe episodes than those with migraine. Patients with associated migraine had more symptoms of abdominal pain, headache, social withdrawal, photophobia, and triggering events. Patients with associated migraine showed a significantly better response to antimigraine therapy than those without migraine. Li et al. (1999) concluded that cyclic vomiting syndrome is related to migraine in the vast majority of cases.

Haan et al. (2002) reported a family in which 4 members spanning 3 generations had cyclic vomiting syndrome. Age at onset was 13 to 15 years, slightly later than is typical for cyclic vomiting syndrome. Accompanying features were variable, and included increased yawning, diarrhea, diaphoresis, and photophobia, but no headache. Three women and 1 man were affected. The maternal inheritance suggested a mitochondrial disorder, but extensive metabolic studies of the proband showed no abnormalities.

Cyclic Vomiting Syndrome Plus

A subset of patients with cyclic vomiting syndrome have coexisting neuromuscular disorders, including cognitive delay, myopathy, or seizure disorders. Boles et al. (2003) referred to this subset as 'cyclic vomiting syndrome-plus.' They found that 48 (86%) of 57 families demonstrated probable or possible maternal inheritance. Non-CVS manifestations included growth retardation (59%), GI dysmotility (71%), exercise intolerance (45%), migraine headaches (40%), vital sign fluctuations (30%), endocrinopathies (25%), and psychiatric disorders (25%). Boles et al. (2003) postulated a maternally inherited propensity towards dysautonomia, of which CVS is only one of several potential clinical manifestations.

Inheritance

Boles et al. (2005) provided further clinical evidence for maternal inheritance in both isolated CVS and CVS-plus. Clinical interviews with 80 unrelated patients, including 44 individuals with isolated CVS and 23 with CVS-plus, and their families showed that disease manifestations were far more common in matrilineal compared to nonmatrilineal relatives. In both groups, affected matrilineal relatives had high incidences of dysautonomic-related conditions, including migraine and irritable bowel syndrome, as well as depression and hypothyroidism. Maternal inheritance was suggested in 54% and 52% of individuals with isolated CVS and CVS-plus, respectively.

Molecular Genetics

In 4 members of an Italian family with cyclic vomiting syndrome, Salpietro et al. (2003) identified a mutation in the MTTL1 gene (590050.0001). The youngest affected member, a 5-year-old boy, had 70% mutant mtDNA in peripheral blood. The boy's mother, maternal aunt, and maternal grandmother, who were all affected, had 35%, 30%, and 25% mutant mtDNA, respectively. There was a positive correlation between amount of mutant mtDNA and clinical severity. The 3 adults were affected by the syndrome during childhood and developed migraine headaches as adults.