Apnea, Obstructive Sleep
Description
Obstructive sleep apnea is a common, chronic, complex disease associated with serious cardiovascular and neuropsychologic sequelae and with substantial social and economic costs (Palmer et al., 2003).
Clinical FeaturesStrohl et al. (1978) described 2 males and their father with severe hypersomnolence and obstructive sleep apnea. A third son, although asymptomatic, was shown to have upper-airway obstruction during sleep. Electromyographic recordings of genioglossal muscle activity showed loss of tonic activity in early stages of sleep when sleep apnea occurred. (The bilateral genioglossus muscles play a crucial role in the normal mechanism for maintaining a patent oropharyngeal lumen, especially during sleep in the supine position, for they are the muscles that force the tongue forward during inspiration.) The asymptomatic son showed loss of tonic activity during rapid-eye-movement sleep, the period when upper-airway obstruction occurred. A fourth son died in his sleep at age 30 years and a daughter of the asymptomatic brother (member of the third generation) died at age 4 months from presumed sudden-infant-death syndrome. The tongue may be responsible for airway obstruction in this seemingly hereditary syndrome. Daytime somnolence was striking in these persons and narcolepsy (161400) had been diagnosed in some. When the subjects slept, observers described restless movements, loud snorts and snoring, and long periods of apnea.
Manon-Espaillat et al. (1988) described a family in which sleep apnea was associated with partial complex seizures and anosmia and segregated in an autosomal dominant pattern. Both the proband and his affected father had seizure disorder; in addition, the proband and his brother were colorblind. The authors designated this 'familial sleep apnea plus' syndrome.
Guilleminault et al. (1995) conducted a mail survey of first-degree relatives of 157 subjects with obstructive sleep apnea syndrome and friends who were approximately the same age who were not relatives of the index case. A more extensive investigation was performed on first-degree relatives of the index group living in the San Francisco Bay area or vicinity. The latter investigation indicated that, when first first-degree relatives were compared with friends, the complaint of daytime tiredness, sleepiness, or both with the presence of a high and narrow (ogival) hard palate sharply differentiated between friends and relatives. Disproportionate craniofacial anatomy, as indicated by cephalometric x-ray films, was common in familial groups with OSAS. They concluded that craniofacial familial features can be a strong indicator of risk for the development of OSAS.
Mojon et al. (2002) found a high prevalence of sleep apnea syndrome in patients with nonarteritic anterior ischemic optic neuropathy (NAION; 258660), which supported previous case reports suggesting that such an association existed. This association might explain why approximately 75% of all patients with NAION discovered visual loss upon first awakening or when they first used vision critically after sleeping. The authors stated that sleep apnea syndrome may play an important role in the pathogenesis of NAION.
Svatikova et al. (2003) found that plasma levels of serum amyloid A1 (SAA1; 104750) were more than 2-fold greater in patients with moderate to severe obstructive sleep apnea compared with subjects with mild obstructive sleep apnea or healthy controls regardless of gender. The authors concluded that elevated SAA1 may contribute to any increased risk for cardiovascular and neuronal dysfunction in patients with obstructive sleep apnea.
InheritanceRostand (1978) observed an affected man with an affected son and brother, suggesting autosomal dominant inheritance.
Douglas et al. (1993) did a prospective study of first-degree relatives of 20 consecutive nonobese patients with the sleep apnea/hypopnea syndrome. They concluded that there is an increased frequency of abnormal breathing during sleep in relatives.
Teculescu et al. (1994) found evidence for a 'familial factor' in habitual snoring.
Redline and Tishler (2000) reviewed the data suggesting that there are 'strong genetic underpinnings' for obstructive sleep apnea hypopnea syndrome. They cited an estimate of 40% of the variance in the apnea hypopnea index being explained by familial factors. They suggested that genetic factors associated with craniofacial structure, body fat distribution, and neural control of the upper airway muscles interact to produce the OSAS phenotype.
MappingAlong with male gender, obesity is the most common characteristic of OSA in adults. To identify susceptibility loci for OSA, Palmer et al. (2003) performed a 9-cM genome scan in 66 white pedigrees ascertained on the basis of either an affected individual with laboratory-confirmed OSA or a proband who was a neighborhood control individual. Multipoint variance component linkage analysis was performed for the OSA-associated quantitative phenotypes apnea-hypopnea index (AHI) and BMI. Candidate regions on chromosomes 1p (lod score 1.39), 2p (lod score 1.64), 12p (lod score 1.43), and 19p (lod score 1.40) gave the most evidence for linkage to AHI. BMI was also linked to multiple regions, most significantly to markers on 2p (lod score 3.08), 7p (lod score 2.53), and 12p (lod score 3.41). Extended modeling indicated that the evidence for linkage to AHI was effectively removed after adjustment for BMI, with the exception of the candidate regions on 2p (adjusted lod score 1.33) and 19p (adjusted lod score 1.45). After adjustment for AHI, the primary linkages to BMI remained suggestive but were roughly halved. The results suggested that there are both shared and unshared genetic factors underlying susceptibility to OSA and obesity and that the interrelationship of OSA and obesity in white individuals may be partially explained by a common causal pathway involving one or more genes regulating both AHI and BMI levels.
Molecular GeneticsKadotani et al. (2001) studied apolipoprotein E4 (107741) in relation to sleep apnea because apoE4 is a risk factor for Alzheimer disease (AD; 104300) and cardiovascular disease, and sleep-disordered breathing occurs in AD patients and increases the risk for cardiovascular disease. Using nocturnal polysomnography to evaluate the apnea-hypopnea index in 791 middled-aged adults, they found that the probability of moderate to severe sleep-disordered breathing was significantly higher in participants with apoE4, independent of age, sex, body mass index (BMI), and ethnicity. These effects increased with the number of apoE4 alleles carried. In a study of 1,775 individuals, Gottlieb et al. (2004) found an age-dependent association between the APOE4 allele and obstructive sleep apnea. APOE4 carriers younger than 65 years had an odds ratio of 3.08 for sleep apnea, whereas APOE4 carriers 65 years of age or older had an odds ratio of 1.25. The association was stronger in those with hypertension or cardiovascular disease. Among 18 older adult APOE4 carriers with obstructive sleep apnea, O'Hara et al. (2005) found an association between greater numbers of respiratory events and lower memory performance. No association was found in 18 older adult noncarriers with sleep apnea. The authors suggested that sleep apnea may partly account for the association of the E4 allele and cognitive decline in community-dwelling older adults and postulated that hypoxia may have a role in neuronal vulnerability to oxidative stress.
Gozal et al. (2007) found that the APOE E4 allele was more common in nonobese children with obstructive sleep apnea compared to controls, and particularly in those who developed neurocognitive deficits.