This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g. "circadian_phase_misalignment#Misalignment Between Endogenous Circadian Phase and the Imposed Sleep-Wake Schedule", the key conformance target and rate-limiting step).
ARM SELECTION IS THE CURATOR'S FIRST DECISION, and the two arms are not interchangeable. Enter at #Intrinsic Core Clock Period or Phase Lesion only when the endogenous oscillator itself is altered - familial advanced sleep phase syndrome (PER2 S662G, CSNK1D T44A), familial delayed sleep phase disorder (CRY1 gain-of-function). Enter at #Loss or Mistiming of Photic Entrainment Input when the oscillator is normal and the light signal that should reset it is absent or arriving at the wrong time - non-24-hour sleep-wake rhythm disorder in total blindness, jet lag disorder, shift work disorder. A disorder may legitimately carry both (evening light exposure reinforcing an already-delayed phase in delayed sleep phase syndrome), but the arms should be curated as separate nodes, not merged.
WHAT DOES NOT CONFORM. Misalignment is a claim about the relationship between an internal phase and an external schedule; a sleep complaint alone does not establish it. Chronic insomnia disorder, where hyperarousal prevents sleep at any phase, does not conform, and the discriminator is diagnostic rather than theoretical: in a circadian disorder, sleep is normal in structure and duration when the person is allowed to sleep at their own phase. Shortened or fragmented sleep with a normal, entrained phase belongs elsewhere. Advanced or delayed sleep timing that is a preference rather than a disorder is likewise out of scope - the module models the pathological case in which the phase cannot be moved to meet the schedule.
DRUG-TARGET PATTERN. Melatonin receptor agonists (tasimelteon, melatonin) ACTIVATE #Shifted or Free-Running Endogenous Circadian Phase, supplying at a fixed clock time the phase-setting signal that light normally provides. The cleanest demonstration is in totally blind patients with non-24-hour sleep-wake rhythm disorder, where the photic route is absent altogether and a timed melatonin-receptor signal entrains the pacemaker on its own - and where withdrawal of the drug loses entrainment again, which is the evidence that the agonist substitutes for the missing input rather than curing the lesion. Appropriately timed bright light acts on the same node through the intact photic route, and is the corresponding non-pharmacological intervention.
SCOPE BOUNDARIES. Distinct from orexin_arousal_instability (state instability at any time of day, with a normal clock) and from sleep_disordered_breathing_intermittent_hypoxia (sleep is correctly timed but destroyed by respiratory events). It is also distinct from glymphatic_dysfunction, which is gated by sleep state rather than by circadian phase and models a clearance consequence rather than a timing lesion.
Not an Xogenesis module - a timing relationship fails, nothing pathological is formed.
Is a single dim-light melatonin onset an adequate measurement of the misalignment this module makes rate-limiting?
KNOWLEDGE GAP
gap_phase_marker_vs_schedule_measurement
Attached to:
Misalignment Between Endogenous Circadian Phase and the Imposed Sleep-Wake Schedule
The central node is a relation between an internal phase and an imposed schedule, but in practice almost all clinical and research characterisation measures only the internal half, usually as a single dim-light melatonin onset. That leaves the relation inferred rather than measured, and it makes two clinically different situations - a pacemaker that cannot be shifted, and one that could be shifted but is being held in place by the patient's own light exposure and schedule - indistinguishable on the standard workup. It matters therapeutically, because only the second is expected to respond to behavioural light and schedule management.
Proposed experiments:
Paired circadian phase and imposed-schedule assessment
Intrinsic Core Clock Period or Phase Lesion
trigger
First of two entry arms. The circadian pacemaker is a cell-autonomous transcription-translation negative feedback loop: CLOCK-BMAL1 drives expression of PER and CRY, whose protein products feed back to inhibit their own activators, with the loop's period set largely by the rate at which PER is phosphorylated and degraded. A variant that changes either the phosphorylation substrate (PER2 S662G, which is hypophosphorylated by casein kinase I), the kinase (CSNK1D T44A), or the repressor's affinity for its activators (a gain-of-function CRY1 variant) alters the endogenous period and therefore the phase at which the oscillator stabilises under a 24-hour light-dark cycle. A shortened period advances phase; a lengthened period delays it. Conforming disorder nodes substitute the disorder-specific clock gene and the direction of the period change.
Downstream
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Shifted or Free-Running Endogenous Circadian Phase
An altered endogenous period causes the pacemaker to stabilise at an abnormally early or late phase relative to the 24-hour day.
Show evidence (5 references)
"The circadian clock is an endogenous oscillator that generates daily rhythms in metabolism and physiology in almost all cells via a conserved transcriptional-translational negative feedback loop."
Establishes the molecular substrate this node is a lesion in, and its cell-autonomous nature, which is why a single coding variant can reset whole-organism timing.
"Affected individuals have a serine to glycine mutation within the casein kinase Iepsilon (CKIepsilon) binding region of hPER2, which causes hypophosphorylation by CKIepsilon in vitro."
The canonical advance-direction substitution at this node: a phosphorylation-site lesion in a core clock protein, with the biochemical consequence shown directly.
"a variant in human sleep behavior can be attributed to a missense mutation in a clock component, hPER2, which alters the circadian period"
States the causal step this node encodes - variant to altered period - which is what a conforming disorder must evidence to enter through this arm rather than the entrainment arm.
+ 2 more references
Shifted or Free-Running Endogenous Circadian Phase
amplifier
Both arms converge here. The suprachiasmatic pacemaker holds a phase - as read out by the dim-light melatonin onset, the core body temperature minimum, and the timing of the endogenous sleep propensity window - that is abnormally advanced, abnormally delayed, or not stably locked to 24 hours at all. The distinction between a shifted and a free-running phase matters for prognosis and for treatment timing: a shifted phase is stable and can be treated at a fixed clock hour, whereas a free-running phase drifts through all clock times and produces cyclically recurring symptoms.
Downstream
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Misalignment Between Endogenous Circadian Phase and the Imposed Sleep-Wake Schedule
An abnormal or drifting endogenous phase can no longer coincide with the sleep-wake schedule the person is required to keep.
Show evidence (2 references)
"affected individuals are "morning larks" with a 4-hour advance of the sleep, temperature, and melatonin rhythms"
Shows that the shift is a property of the pacemaker rather than of sleep behaviour: temperature and melatonin rhythms move together with sleep, which is what this node asserts.
"The SCN receives photic information from the environment and conveys this to other parts of the brain and body to synchronize all circadian clocks."
Establishes the SCN as the phase-setting hub whose output timing this node describes, and why a single pacemaker shift moves peripheral rhythms too.
Misalignment Between Endogenous Circadian Phase and the Imposed Sleep-Wake Schedule
central effector
The rate-limiting, disorder-agnostic node and the key conformance target. Misalignment is a relation, not a state of the clock alone: it requires both an endogenous phase and an externally imposed schedule that disagree. This is what makes the circadian disorders unusual - the same pacemaker phase is pathological or benign depending only on what the person is required to do, which is why an extreme evening chronotype with a permissive schedule is not a patient and the same physiology with a 07:00 start is. A conforming disorder node should name both halves of the relation.
Used by disorders
Jet Lag
as Circadian Desynchronization
Downstream
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Sleep Attempted at an Adverse Circadian Phase
When the required sleep opportunity falls outside the endogenous sleep propensity window, sleep is attempted against an active circadian wake signal.
Show evidence (2 references)
"This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm."
States the relation this node models explicitly - sleep episodes shifted relative to an external norm - rather than an abnormality of sleep itself.
"CRSDs result from a misalignment between the timing of the circadian rhythm and the external environment (eg, jet lag and shift work) or a dysfunction of the circadian clock or its afferent and efferent pathways (eg, delayed sleep-phase, advanced sleep-phase, non-24-hour, and irregular..."
States the module's central claim in the clinical literature's own terms, and names both entry arms as the two routes to the same misalignment, which is the arm-selection rule recorded in the module notes.
Sleep Attempted at an Adverse Circadian Phase
effector
The physiological expression of misalignment. Sleep initiated during the circadian wake-maintenance zone is delayed in onset and shortened; wake required near the core body temperature minimum is accompanied by maximal sleepiness and impaired performance. The resulting sleep is curtailed rather than structurally abnormal, which is the diagnostic hallmark distinguishing this module from primary insomnia: released from the schedule, the same person sleeps normally at their own phase.
Downstream
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Circadian Sleep-Wake Disorder Syndrome
Chronically sleeping at an adverse phase produces the presenting clinical syndrome.
Show evidence (1 reference)
"reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers"
Documents the sleep-level consequence - late and fragmented sleep - in carriers of a defined clock lesion, connecting the molecular arm to this node.
Circadian Sleep-Wake Disorder Syndrome
consequence
The clinical endpoint: insomnia at the scheduled bed time, excessive sleepiness at the scheduled wake time, and impaired daytime function, with the specific complaint determined by the direction of the misalignment. Advanced phase presents as early-morning awakening and evening sleepiness; delayed phase as sleep-onset insomnia and severe morning sleep inertia; a free-running phase as symptoms that cycle in and out over weeks as the endogenous phase drifts through the imposed schedule. Conforming entries should preserve that the pattern of symptoms, not their severity, identifies the underlying misalignment.
Used by disorders
Jet Lag
as Sleep-Wake Symptom Cluster
Show evidence (2 references)
"The planned step-down primary endpoint assessed the proportion of patients who had a clinical response (entrainment at month 1 or month 7 plus clinical improvement, measured by the Non-24 Clinical Response Scale)."
Shows the clinical syndrome is treated as a distinct outcome from entrainment itself, which is why the module keeps them as separate nodes.
"Circadian misalignment, when subjects ate and slept approximately 12 h out of phase from their habitual times, systematically decreased leptin (-17%, P < 0.001), increased glucose (+6%, P < 0.001) despite increased insulin (+22%, P = 0.006), completely reversed the daily cortisol rhythm (P <..."
Forced-desynchrony evidence that misalignment itself, imposed experimentally with sleep loss controlled, produces cardiometabolic derangement - which is why this consequence node extends beyond the sleep complaint and why the module treats misalignment rather than sleep loss as the causal quantity.