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Familial Advanced Sleep Phase Syndrome
Kathryn J. Reid, PhD;
Anne-Marie Chang, BS, BA;
Margarita L. Dubocovich, PhD;
Fred W. Turek, PhD;
Joseph S. Takahashi, PhD;
Phyllis C. Zee, MD, PhD
Arch Neurol. 2001;58:1089-1094.
ABSTRACT
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Background The circadian rhythms of sleep propensity and melatonin secretion are
regulated by a central circadian clock, the suprachiasmatic nucleus of the
hypothalamus. The most common types of sleep disorders attributed to an alteration
of the circadian clock system are the sleep/wake cycle phase disorders, such
as delayed sleep phase syndrome and advanced sleep phase syndrome (ASPS).
Advanced sleep phase syndrome is characterized by the complaint of persistent
early evening sleep onset and early morning awakening. Although the complaint
of awakening earlier than desired is relatively common, particularly in older
adults, extreme advance of sleep phase is rare.
Objective To phenotypically characterize a familial case of ASPS.
Methods We identified a large family with ASPS; 32 members of this family gave
informed consent to participate in this study. Measures of sleep onset and
offset, dim light melatonin onset, the Horne-Ostberg morningness-eveningness
questionnaire, and clinical interviews were used to characterize family members
as affected or unaffected with ASPS.
Results Affected members rated themselves as "morning types" and had a significant
advance in the phase of sleep onset (P<.001) and
offset (P = .006) times. The mean sleep onset was
2121 hours for the affected family members and 0025 hours for the unaffected
family members. The mean sleep offset was 0507 hours for the affected members
and 0828 hours for the unaffected members. (Times are given in military form.)
In addition, the phase of the circadian rhythm of melatonin onset for the
affected family members was on average 3 hours earlier than for the
unaffected members.
Conclusions The ASPS trait segregates with an autosomal dominant mode of inheritance.
The occurrence of familial ASPS indicates that human circadian rhythms, similar
to those in animals, are under genetic regulation. Genetic analysis of familial
sleep and circadian rhythm disorders is important for identifying a specific
gene(s) responsible for the regulation of sleep and circadian rhythms in humans.
INTRODUCTION
ADVANCED SLEEP phase syndrome (ASPS) is characterized by persistent
advanced sleep onsets and awakenings that are earlier than desired.1, 2, 3 Individuals with ASPS
typically experience sleepiness in the early evening, when other people are
active, and early morning awakening, when most are still sleeping. Therefore,
individuals with ASPS sometimes find it difficult to maintain a normal social
and work life. It has been postulated that ASPS is a circadian rhythm disorder
in which the phase of the circadian rhythm of sleep and wake is advanced in
relation to the "normal timing," which is synchronized, to the external environment.2, 3
The search for genetic components to many complex behaviors is intensifying.
The recent completion of the Human Genome Project places researchers in a
better position to quickly discover genes responsible for some of these complex
behaviors. A familial approach is one technique used in the field of human
genetics in an attempt to find associations between behaviors and genes. To
do this type of research, it is important to identify and phenotypically characterize
families that exhibit these behaviors. Familial associations have been reported
in several sleep disorders. There is one reported case4
of delayed sleep phase syndrome, but as yet this family has not been fully
described. Restless legs syndrome, a condition in which patients experience
discomfort in the legs or limbs that is relieved by movement, appears to be
transmitted as an autosomal dominant trait.5
One sleep disorder in which the heritability is well established is narcolepsy.
Between 1% and 2% of narcoleptic probands have family histories of excessive
daytime sleepiness.6, 7 Furthermore,
human narcolepsy has been linked to a region of the major histocompability
complex (HLA) genes.8
More recently, the compound orexin has been linked to narcolepsy. Using a
narcoleptic dog model, Lin and colleagues9
recently showed that the hypocretin (orexin) receptor gene (Hcrtr2) may be responsible for narcolepsy. Chemelli and colleagues10 found that orexin knockout mice exhibit a phenotype
similar to that seen in narcoleptic patients and in dogs that have a mutation
of canarc-1, a canine narcolepsy gene.11
In comparison, ASPS appears to be a far more rare sleep/circadian rhythm
disorder, and until recently there were only 3 reported cases of ASPS.12, 13, 14, 15 More
recently, however, Jones and colleagues16 described
3 separate families with a familial preponderance of ASPS. Identification
of the familial nature of ASPS suggests a genetic basis for this syndrome.
The present study phenotypically characterizes an additional case of familial
ASPS by describing the clinical characteristics, activity/rest measures, and
circadian phase in affected and nonaffected members of a large family with
ASPS.
SUBJECTS AND METHODS
SUBJECTS
Thirty-two members of a single family gave informed written consent
before participation in this study. This study was approved by the Institutional
Review Board of Northwestern University, Evanston, Ill. Subjects were interviewed
and examined by a sleep specialist physician (P.C.Z.).
PROCEDURE
Identification of the ASPS phenotype and diagnosis of affected and unaffected
family members were determined by physician interview using the American Sleep
Disorders Association's diagnostic criteria as a guideline. The Hamilton Depression
Rating Scale was administered to all subjects, and informative subjects also
completed a family history questionnaire. Sleep/wake schedules were measured
using wrist actigraphy and sleep diaries, the circadian preference was determined
from the Horne-Ostberg morningness-eveningness questionnaire, and the circadian
phase was determined from dim light salivary melatonin onset (DLMO). A family
pedigree was constructed to further characterize the heritability of the disorder.
SLEEP VARIABLES
The timing and characteristics of the rest/activity cycle were determined
by wrist actigraphy and sleep diaries. Subjects were asked to wear activity
monitors (Cambridge Neurotechnology LTD, Cambridge, England) on the wrist
of the nondominant hand. Activity data were analyzed using a computer program
(Rhythm Watch, version 2.41; Cambridge Technologies LTD) to plot actograms.
Subjects were also asked to maintain a sleep diary during the 2 weeks of actigraphy
measurement, recording bedtime, any awakenings during the night, and the final
wake time.
CIRCADIAN VARIABLES
Subjects completed the Horne-Ostberg questionnaire to determine their
circadian "chronotype." Scores between 70 and 86 are indicative of a morning-type;
between 59 and 69, a moderate morning-type; between 42 and 58, neither type;
between 31 and 41, a moderate evening-type; and between 16 and 30, an evening-type.17
Profiles of evening salivary melatonin level, a reliable marker of circadian
phase, were collected using salivettes at 30-minute intervals under dim light
conditions (<100 lux). Subjects were in dim light conditions from 1730
hours until bedtime. Sampling began at 1800 hours (central time) and was concluded
at each individual's desired bedtime, which varied between individuals. (Times
are given in military form.) Melatonin levels were measured using a direct
radioimmunoassay (Buhlmann Saliva; ALPCO, Windham, NH).18 Melatonin onset was defined as the time of the first sample
exceeding, by at least 2 SDs, the mean of all prior samples, without a subsequent
decline to below that level.
DIAGNOSIS OR CLASSIFICATION
Subjects who met the diagnostic clinical criteria for ASPS and had a
morning-type score on the Horne-Ostberg questionnaire and/or an advanced melatonin
onset (those with DLMO were considered to have an advanced melatonin onset
if the onset was 2 hours before that of "normal subjects" described in the
literature18) were considered to exhibit the
ASPS phenotype.
DATA ANALYSIS
Unpaired t tests were used to determine any
difference between affected and unaffected family members for self-reported
sleep onsets, offsets, and durations.
RESULTS
THE FAMILY PEDIGREE
A pedigree of the family, shown in Figure 1, was constructed from the physician interviews, sleep questionnaires,
and family histories. Thirty-two family members were studied. Eight family
members were diagnosed as being definitely affected, 4 as being possibly affected,
and 8 as being affected by history; 12 were unaffected. The members studied
ranged in age from 11 to 85 years. The age of onset (by history) varied from
as early as 8 years to early adulthood.
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Figure 1. The entire pedigree for the family
with advanced sleep phase syndrome. The arrow indicates the proband; squares,
males; circles, females; and slashes, deceased.
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The proband was an 85-year-old man with a history of going to sleep
in the early evening and awakening in the early morning for as long as he
could remember. He reported that his children and several other relatives
had a similar sleep pattern. The ASPS phenotype can be seen in 4 generations
of the proband's branch and in possibly 3 generations in an extended branch.
The pattern of affected individuals in the proband's branch is consistent
with a genetic model of segregation of a single autosomal dominant gene.
The ASPS status of some individuals in an extended branch of the family
is considered to be possibly affected. The oldest member of this branch is
an elderly woman who by history is affected, but because of her poor health,
accurate characterization of the disorder was not possible. However, we do
consider her to be affected by history. Her daughter is self-reported as affected,
and her granddaughter is a teenager and is advanced compared with other adolescents
in the general population, but does not strictly meet the American Sleep Disorders
Association criteria for ASPS.
Data from the completed interviews, the Hamilton Depression Rating Scale
(mean [± SD] score, 2.4 [± 2.7]), and sleep questionnaires do
not indicate that the ASPS phenotype is associated with a high prevalence
of affective disorder or other types of sleep disorders, such as narcolepsy,
sleep apnea, restless legs syndrome, or periodic leg movements. Results from
a clinical sleep study indicated that 1 subject does have sleep apnea.
SLEEP/WAKE PATTERNS
Representative profiles of wrist activity records for affected subjects
can be seen in Figure 2, left. The
wrist activity monitoring clearly shows that family members affected with
ASPS have early sleep onsets and offsets. The average subjective sleep onsets,
offsets, and durations were calculated for 10 individuals and are shown in Table 1. Relative to unaffected subjects,
affected subjects had, on average, sleep onsets nearly 3 hours earlier and
sleep offsets nearly 3 hours earlier. The mean sleep duration was
not significantly different between the 2 groups.
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Figure 2. A, Subject 2. B, Subject 3. C,
Subject 10. Representative samples of wrist activity records (left) and evening
dim light salivary melatonin profiles (right). The arrows indicate dim light
melatonin onset. Data points are timed with each individual's local time zone.
Times are given in military form.
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Table 1. Average Subjective Sleep Onsets, Offsets, and Durations for
5 Affected and 5 Unaffected Subjects*
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CIRCADIAN PHASE
Horne-Ostberg Questionnaire of Diurnal Preference
Scores on the Horne-Ostberg questionnaire are shown in Table 2. All affected individuals were morning types, while none
of the unaffected individuals were morning types.
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Table 2. Horne-Ostberg Morningness-Eveningness Questionnaire Results
for 10 Family Members*
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Dim Light Melatonin Onset
Dim light melatonin onset values were collected via saliva sampling
from 4 affected and 1 unaffected family member from the proband's branch of
the family (Figure 2, right). Although
no statistical analysis of these findings can be carried out due to the limited
number of samples in each group, the mean DLMO for the affected subjects was
much earlier (1830 hours) than that of the unaffected subject (2200 hours).
There was an advance in the DLMO of the affected individuals of approximately
3 hours compared with that of the unaffected family member. The phase
of melatonin onset for the individuals with ASPS was advanced when compared
with that seen in the normal population.18
COMMENT
We have identified a large family with ASPS in which an affected member
is present in every generation, suggesting that the ASPS phenotype segregates
as a single gene with an autosomal dominant mode of inheritance (Figure 1). Analysis of sleep diary and activity
records indicates that affected family members have significantly earlier
sleep onsets and offsets than unaffected members. The results are consistent
with those of published reports12, 13, 14
of individual cases of ASPS. However, there was no significant difference
between the 2 groups in sleep duration. This is consistent with ASPS criteria
and published reports12, 16, 19
of polysomnographic recordings that show no difference in the duration and
architecture of sleep between affected and unaffected individuals. These results
suggest that ASPS is not likely due to a disruption of sleep homeostasis or
sleep architecture, but rather represents an alteration of the circadian timing
of sleep propensity.
When we examined subjective circadian measures (Horne-Ostberg morningness-eveningness
questionnaire scores), the results indicated that all family members who were
considered affected with ASPS also scored as morning-type on the questionnaire,
whereas the unaffected members scored as moderate evening types or fell into
neither category. Morning-type on this questionnaire has generally been associated
with an advance in other circadian rhythms, including core body temperature
and performance levels.20, 21 A
link has also been suggested between diurnal preference, as determined by
the Horne-Ostberg questionnaire, and a polymorphism located in the 3'
flanking region of the human CLOCK gene.22 (CLOCK is a basic helix-loop-helix
transcription factor that, when mutated, alters the circadian period.) It
could be suggested that a genetic component of diurnal preference could be
passed on through a family similar to the one described herein.
In addition, our objective measure of circadian phase, DLMO, clearly
showed that members of this family with the ASPS phenotype have an earlier
DLMO than either the unaffected family member or unaffected individuals described
in the literature.18, 23
Since there are only a few reported cases of ASPS, it would appear to
be a relatively rare disorder. However, several factors, such as the lack
of complaints from these individuals and the lack of recognition of this condition
by health care professionals, may explain this low incidence of reported cases.24 Several of the participants interviewed in this study
were accustomed to their advanced schedule and were surrounded by many members
of their family who were similarly affected. In addition, individuals with
ASPS found that social pressures, such as work schedules, adhered to this
advanced phase and were, therefore, resigned to the timing of their sleep/wake
schedule. However, it is unlikely that the advanced sleep phase is merely
a result of social conditioning within a family unit. Interviews reveal that
several members of the same family unit are affected with ASPS; however, there
are spouses and siblings within the same family unit, living in the same house,
who do not exhibit the advanced sleep phase.
Identification of the ASPS phenotype may have been influenced by the
effects of marriage to individuals with a delayed sleep phase ("night owls").
This was the situation in individuals from the extended branch whose spouses
were reported to be night owls. Another consideration in regard to accurate
identification of the affected status in this familial case of ASPS is the
broad age range of its members. Changes in circadian timing and in the timing
of sleep are associated with age.25, 26
Specifically, there is generally an advance in sleep/wake behavior for older
people and a delay in teenagers.25, 26, 27
When the teenaged affected family members were compared with the rest of the
population in their own age group, they were advanced. However, they did not
meet the American Sleep Disorders Association criteria when sleep onsets and
offsets were assessed.1 Research diagnostic
criteria of ASPS need to be established and defined, perhaps taking into account
age. This is most crucial for the accurate characterization of circadian phase
syndromes. With this in mind, in the present study, we used the American Sleep
Disorders Association criteria as a guideline for determining the phenotype
of ASPS, but we also used other tools, such as morningness-eveningness preference
and melatonin onset, as more stringent measures of circadian phase. Individuals
with an advanced sleep phase also displayed an advance in other circadian
rhythms, indicating that this condition is best described as advanced circadian
phase syndrome.
This family, along with the 3 families identified by Jones and colleagues,16 suggests that not only is ASPS familial in some cases
but that it may be more prevalent than previously believed. The results reported
for this family and those of Jones et al appear to be consistent and segregate
in a similar pattern: the sleep onsets and Horne-Ostberg questionnaire scores
are similar. Although Jones et al do report a DLMO of on average 1 hour earlier
than ours, this could be the result of a later period of dim light exposure
before sampling in our studies. We have yet to determine whether there are
changes in period in members of this family like that reported in a single
case by Jones et al.
Taken together, the results from the present study indicate that ASPS
may in some cases be a familial disorder that appears to segregate as a single
gene with an autosomal dominant mode of inheritance. Identification of families
with alterations in circadian sleep phase is expected to play an important
role in identifying the gene(s) responsible for regulation of human sleep
and circadian rhythms.
AUTHOR INFORMATION
Accepted for publication September 29, 2000.
This study was funded by grant DAAG55-98-1 from the Army Research Office,
Durham, NC.
We thank Teepu Siddique, MD, for his invaluable advice; Gloria Park
for performing the melatonin measurements; and Rosemary Ortiz for administrative
assistance.
From the Departments of Neurobiology and Physiology (Drs Reid, Turek,
and Takahashi and Ms Chang) and Molecular Pharmacology and Biological Chemistry
(Dr Dubocovich), the Transportation Center (Dr Reid), the Center for Circadian
Biology and Medicine (Drs Reid, Turek, Takahashi, and Zee), and the Howard
Hughes Medical Institute (Dr Takahashi), Northwestern University; and the
Department of Neurology, Northwestern University Medical School (Dr Zee),
Chicago, Ill.
Corresponding author and reprints: Kathryn J. Reid, PhD, Department
of Neurobiology and Physiology, Northwestern University, Hogan Hall 2-160,
2153 N Campus Dr, Evanston, IL 60208 (e-mail: k-reid{at}northwestern.edu).
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