Non-24-Hour Sleep-Wake Rhythm Disorder

Neurological Disorder MONDO:0019137 Pathograph 6 Show in embeddings browser Sleep Disorder Neurological Disease

Non-24-hour sleep-wake rhythm disorder (free-running disorder, hypernycthemeral syndrome) is the circadian disorder in which the pacemaker is not locked to the 24-hour day at all. The human circadian clock has an intrinsic period slightly longer than 24 hours and is reset each morning by retinal light exposure. Where that light signal cannot reach the suprachiasmatic nucleus - as in total blindness without light perception - the clock runs at its own period, so sleep onset and wake time drift progressively later day after day. The clinical consequence follows directly from the arithmetic: symptoms are cyclical rather than constant, because the drifting endogenous phase passes in and out of alignment with the imposed schedule over weeks. Patients therefore have alternating periods of entirely normal sleep and severe insomnia with daytime sleepiness, which is what makes the diagnosis so often missed - a patient assessed during an aligned stretch looks well. Diagnosis requires demonstrating a circadian period outside the normal range, which needs repeated measurement of a phase marker over time rather than a single assessment. It is rare in the general population and common in the totally blind, where it may affect up to half of those without light perception.

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4
Pathophys.
3
Phenotypes
1
Gaps
6
Pathograph
2
Medical Actions
🏷

Classifications

Harrison's Part
NEUROLOGIC
?

Discussions and Knowledge Gaps

1
What causes non-24-hour sleep-wake rhythm disorder in sighted people, whose photic input is intact?
KNOWLEDGE GAP gap_sighted_non24_mechanism
Attached to
pathophysiology#Absence of Photic Input to the Suprachiasmatic Nucleus
This entry's trigger node is the absence of photic input, which cannot be the mechanism in sighted patients - yet the disorder occurs in them, typically in young men and typically evolving out of a delayed sleep-wake phase disorder. The candidate explanations are mechanistically different and predict different treatments: an unusually long intrinsic period exceeding what daily light can correct; reduced sensitivity of the entrainment pathway; or a behavioural loop in which an already-delayed phase leads to light exposure timed to reinforce the delay rather than correct it, which would make the disorder partly self-inflicted and reversible by schedule management. Distinguishing them requires measuring the phase-response curve, which is rarely done clinically, and the entry deliberately does not extend its trigger claim to this group until they are separated.
Proposed experiments
Phase-response characterisation in sighted free-running patients
exp_sighted_non24_phase_response
Measure intrinsic circadian period under forced desynchrony and construct individual light phase-response curves in sighted patients with non-24-hour sleep-wake rhythm disorder, comparing them against patients with delayed sleep-wake phase disorder and against controls, with concurrent light dosimetry to establish whether the received light signal is adequate but ineffective or simply mistimed.
⚙

Pathophysiology

4
Absence of Photic Input to the Suprachiasmatic Nucleus
The trigger. Photoentrainment does not use the image-forming visual pathway: melanopsin-expressing intrinsically photosensitive retinal ganglion cells project directly to the suprachiasmatic nucleus, and rods and cones are not required. The clinically important consequence is that visual and circadian blindness dissociate - a person with no useful vision but a surviving ipRGC pathway can still entrain normally, while loss of the eyes or of the retinohypothalamic projection removes entrainment entirely. This is why the disorder tracks light perception rather than visual acuity, and why the at-risk group is specifically those without light perception rather than the blind generally.
melanopsin-expressing intrinsically photosensitive retinal ganglion cell CL:0020014 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves decreased melanopsin-expressing intrinsically photosensitive retinal ganglion cell, annotated with intrinsically photosensitive retinal ganglion cell (CL:0020014). CL:0020014 is a cell type from the Cell Ontology. ↓ DECREASED
entrainment of the circadian clock by photoperiod GO:0043153 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased entrainment of the circadian clock by photoperiod, annotated with entrainment of circadian clock by photoperiod (GO:0043153). GO:0043153 is a biological process from the Gene Ontology. ↓ DECREASED
retina UBERON:0000966 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in retina (UBERON:0000966). UBERON:0000966 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Free-Running Circadian Period Without a daily resetting signal the pacemaker reverts to its own intrinsic period, which in most people is slightly longer than 24 hours.
Show evidence (3 references)
PMID:29326647 SUPPORT Other
"Daily retinal light exposure is necessary for the synchronization of the circadian rhythms with the external 24-h solar environment."
States the input this node loses, and that it is a requirement rather than a contributor to entrainment.
PMID:11834834 SUPPORT Model Organism
"The primary circadian pacemaker, in the suprachiasmatic nucleus (SCN) of the mammalian brain, is photoentrained by light signals from the eyes through the retinohypothalamic tract. Retinal rod and cone cells are not required for photoentrainment."
Establishes that the entrainment pathway is separable from image-forming vision, which is the basis for the dissociation between visual and circadian blindness this node turns on.
PMID:26466871 SUPPORT Human Clinical
"Most totally blind people have non-24-hour sleep-wake disorder (non-24), a rare circadian rhythm disorder caused by an inability of light to reset their circadian pacemaker."
States the causal claim of this node directly - the disorder is caused by light being unable to reset the pacemaker, not by any abnormality of the pacemaker itself.
Free-Running Circadian Period
The pacemaker runs at its intrinsic period rather than at 24 hours. Under stringent measurement the human circadian period lies roughly between 23.8 and 25.1 hours; in an entrained person daily light resets it to exactly 24, and without that correction the residual difference accumulates. The arithmetic is what generates the clinical picture: a person whose non-entrained period is 24.5 hours goes to sleep and wakes half an hour later each day, so their phase completes a full circuit relative to the clock roughly every seven weeks. Crucially the oscillator itself is normal - this is a failure of correction, not of the clock, which distinguishes the disorder from the familial advanced and delayed phase syndromes.
circadian rhythm GO:0007623 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal circadian rhythm (GO:0007623). GO:0007623 is a biological process from the Gene Ontology. ⚠ ABNORMAL
suprachiasmatic nucleus UBERON:0002034 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in suprachiasmatic nucleus (UBERON:0002034). UBERON:0002034 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cyclical Misalignment with the 24-Hour Schedule A phase that drifts continuously passes in and out of alignment with the fixed social schedule, rather than sitting at a stable wrong offset.
Show evidence (2 references)
PMID:29326647 SUPPORT Other
"This master clock has, for most humans, an intrinsic rhythm slightly longer than 24 h."
Gives the intrinsic period that this node reverts to, and its direction - longer than 24 hours - which is why the drift is almost always later rather than earlier.
PMID:30083814 SUPPORT Other
"In most humans, the circadian period is slightly longer than 24 h and without regular resetting it tends to drift, leading to progressively later bedtimes and wake times and a tendency to cycle though periods of normal and abnormal sleep."
States the whole mechanism of this node and the next in one sentence, including the cyclical alternation of normal and abnormal sleep that follows from a drifting phase.
Cyclical Misalignment with the 24-Hour Schedule
The rate-limiting step, and it differs from the fixed-phase circadian disorders in a way that matters clinically. In advanced or delayed sleep phase disorder the misalignment is constant, so symptoms are constant. Here the endogenous phase migrates through all clock times, so the patient cycles between stretches of entirely normal sleep, when phase happens to coincide with the schedule, and stretches of severe insomnia and daytime sleepiness, when it is opposed. That cyclicity is the disorder's signature and its main diagnostic obstacle: a single clinical assessment, a single sleep study, or a single phase marker taken during an aligned stretch will all look normal, and the complaint can be dismissed as inconsistent or behavioural.
entrainment of circadian clock GO:0009649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased entrainment of circadian clock (GO:0009649). GO:0009649 is a biological process from the Gene Ontology. ↓ DECREASED regulation of the circadian sleep/wake cycle GO:0042749 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of the circadian sleep/wake cycle, annotated with regulation of circadian sleep/wake cycle (GO:0042749). GO:0042749 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Cyclical Insomnia and Daytime Dysfunction When the drifting phase opposes the required schedule, sleep is attempted against an active circadian wake signal and wake is required at the circadian trough.
Show evidence (2 references)
PMID:29326647 SUPPORT Other
"Affected patients experience cyclical or periodic episodes of poor sleep and daytime dysfunction, severely interfering with social, academic, and professional life."
Establishes the cyclical rather than constant symptom pattern that this node encodes, and its functional impact.
PMID:29326647 SUPPORT Other
"remains challenging from a clinical point of view due to the cyclical symptoms and should be confirmed by measurements of circadian biomarkers such as urinary melatonin to demonstrate a circadian period outside the normal range"
Supports the diagnostic obstacle named in the description - that cyclicity itself is what makes the disorder hard to recognise, and why repeated biomarker measurement rather than a single assessment is required.
Cyclical Insomnia and Daytime Dysfunction
The clinical endpoint: alternating weeks of normal sleep and of severe sleep-onset insomnia with daytime sleepiness, cycling with a period set by the difference between the patient's intrinsic period and 24 hours. The resulting disability is social and occupational as much as symptomatic, because the unpredictability makes fixed commitments - school, employment, childcare - difficult to sustain even though the total amount of disturbed sleep is modest.
circadian sleep/wake cycle, sleep GO:0050802 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal circadian sleep/wake cycle, sleep (GO:0050802). GO:0050802 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (1 reference)
PMID:29326647 SUPPORT Other
"This circadian drift leads to cyclical sleep disturbances and daytime sleepiness which pose a major handicap."
States the endpoint and its severity, linking it explicitly to the drift rather than to sleep loss as such.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Non-24-Hour Sleep-Wake Rhythm Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Cyclical Sleep-Onset Insomnia OBLIGATE Neurological HP:0031354 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep onset insomnia (HP:0031354), qualified as temporality recurrent. HP:0031354 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:29326647 SUPPORT Other
"Affected patients experience cyclical or periodic episodes of poor sleep and daytime dysfunction"
OBLIGATE by definition: cyclical poor sleep is the defining presentation of the disorder.
Cyclical Excessive Daytime Sleepiness OBLIGATE Neurological HP:0001262 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Excessive daytime somnolence (HP:0001262), qualified as temporality recurrent. HP:0001262 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:29326647 SUPPORT Other
"This circadian drift leads to cyclical sleep disturbances and daytime sleepiness which pose a major handicap."
OBLIGATE by definition: cyclical daytime sleepiness is part of the defining presentation.
Sleep-Wake Cycle Disturbance OBLIGATE Neurological HP:0006979 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep-wake cycle disturbance (HP:0006979), qualified as temporality chronic. HP:0006979 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:30083814 SUPPORT Other
"without regular resetting it tends to drift, leading to progressively later bedtimes and wake times"
OBLIGATE by definition: progressive drift of sleep timing is what the diagnosis consists of.
💊

Medical Actions

2
Tasimelteon
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tasimelteon CHEBI:79042 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tasimelteon (CHEBI:79042). CHEBI:79042 is a therapeutic agent from Chemical Entities of Biological Interest.
A dual MT1/MT2 melatonin receptor agonist taken at a fixed clock time each evening, and the only agent approved for this indication by both the FDA and the European Medicines Agency. It substitutes a pharmacological phase-setting signal for the missing photic one, entraining the free-running pacemaker to 24 hours. Two properties should be preserved by any entry citing it. It is substitutive, not curative: withdrawal loses entrainment again, which is itself the cleanest evidence that it acts on the phase node rather than on sleep. And the response rate is modest - entrainment was achieved in 20% of treated patients at one month against 3% on placebo - so it should not be curated as reliably effective.
Mechanism Target:
ACTIVATES Free-Running Circadian Period — Timed MT1/MT2 agonism at the suprachiasmatic nucleus supplies the phase-setting signal that light cannot, entraining the free-running pacemaker to a 24-hour period.
Show evidence (3 references)
PMID:26466871 SUPPORT Human Clinical
"Once-daily tasimelteon can entrain totally blind people with non-24; however, continued tasimelteon treatment is necessary to maintain these improvements."
Randomised evidence for both halves of the claim: the agent entrains the pacemaker, and the effect is substitutive rather than curative.
PMID:26466871 SUPPORT Human Clinical
"Circadian entrainment occurred in eight (20%) of 40 patients in the tasimelteon group compared with one (3%) of 38 patients in the placebo group at month 1"
Cited as PARTIAL because it bounds the effect: entrainment at one month was achieved in a minority, so the node is druggable but far from reliably correctable.
PMID:26466871 SUPPORT Human Clinical
"Two (20%) of ten patients who were withdrawn to placebo remained entrained compared with nine (90%) of ten who continued to receive tasimelteon"
The randomised-withdrawal arm, and the strongest evidence that the drug maintains entrainment rather than the patient having re-entrained spontaneously.
Timed Melatonin
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: melatonin CHEBI:16796 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses melatonin (CHEBI:16796). CHEBI:16796 is a therapeutic agent from Chemical Entities of Biological Interest.
Low-dose melatonin at a fixed evening time is the long-standing alternative, acting on the same receptors and the same node. It is used alongside behavioural measures - fixed sleep and wake times, structured daily routine, consistent meal and activity timing - which supply non-photic timing cues in the absence of light. Curated without an efficacy claim from a randomised trial, since the evidence cited here supports its use in management rather than quantifying its effect.
Mechanism Target:
ACTIVATES Free-Running Circadian Period — Timed exogenous melatonin acts on the same MT1/MT2 receptors as tasimelteon to supply a daily phase-setting cue.
Show evidence (1 reference)
PMID:29326647 SUPPORT Other
"Management includes behavioral modification and melatonin."
Establishes melatonin plus behavioural measures as standard management; the source states the approach rather than quantifying efficacy, which is why no effect size is asserted here.
🔬

Diagnosis

1
Serial circadian phase marker measurement
The diagnosis cannot be made from a single assessment, which is the practical point that distinguishes it from every other sleep disorder here. Repeated measurement of a phase marker - urinary 6-sulphatoxymelatonin or plasma melatonin profiles over 24 hours, sampled on multiple occasions weeks apart - is required to demonstrate a circadian period outside the normal range. Actigraphy with a sleep diary over an extended period shows the characteristic progressive drift. A patient assessed during an aligned stretch will look entirely normal on any single measurement.
actigraphy NCIT:C180883 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:29326647 SUPPORT Other
"should be confirmed by measurements of circadian biomarkers such as urinary melatonin to demonstrate a circadian period outside the normal range"
Establishes the diagnostic standard: a measured period outside the normal range, which requires serial rather than single measurement.
PMID:30083814 SUPPORT Other
"New screening tools have been developed but actigraphy and repeated melatonin profiles over 24 h remain essential."
Confirms that repeated profiling remains essential despite newer screening instruments, which is why this entry does not list a screening tool as sufficient.
📊

Prevalence

2
Totally blind adults without light perception
Point Prevalence 50000.0 per 100,000 >1 in 1,000
Reported as affecting up to 50% of blind patients without light perception - an upper bound in a highly selected population, not a general-population rate. Recorded at that upper bound with the caveat attached, since the source gives no lower estimate. Contrast the general-population figure below.
Show evidence (1 reference)
PMID:30083814 SUPPORT Other
"the most common abnormality in totally blind patients without light perception is non-24-hour sleep-wake disorder (N24SWD). This is rare in the general population but may affect up to 50% of blind patients without light perception."
Gives both the at-risk-population figure curated here and the general-population rarity recorded in the second record.
General population
Point Prevalence Ultra Rare
Described as an orphan disease in the general population; no numeric rate is given in the sources curated here, so the class is recorded qualitatively rather than a rate being inferred.
Show evidence (1 reference)
PMID:29326647 SUPPORT Other
"Non-24-h sleep–wake rhythm disorder is an orphan disease in the general population but common in the totally blind."
States the general-population rarity and the contrast with the blind population directly.
{ }

Source YAML

click to show 
name: Non-24-Hour Sleep-Wake Rhythm Disorder
creation_date: "2026-08-24T00:00:00Z"
category: Neurological Disorder
parents:
- Sleep Disorder
- Neurological Disease
disease_term:
  preferred_term: non-24-hour sleep-wake rhythm disorder
  term:
    id: MONDO:0019137
    label: non-24-hour sleep-wake syndrome
description: >-
  Non-24-hour sleep-wake rhythm disorder (free-running disorder,
  hypernycthemeral syndrome) is the circadian disorder in which the pacemaker is
  not locked to the 24-hour day at all. The human circadian clock has an
  intrinsic period slightly longer than 24 hours and is reset each morning by
  retinal light exposure. Where that light signal cannot reach the
  suprachiasmatic nucleus - as in total blindness without light perception - the
  clock runs at its own period, so sleep onset and wake time drift progressively
  later day after day. The clinical consequence follows directly from the
  arithmetic: symptoms are cyclical rather than constant, because the drifting
  endogenous phase passes in and out of alignment with the imposed schedule over
  weeks. Patients therefore have alternating periods of entirely normal sleep
  and severe insomnia with daytime sleepiness, which is what makes the diagnosis
  so often missed - a patient assessed during an aligned stretch looks well.
  Diagnosis requires demonstrating a circadian period outside the normal range,
  which needs repeated measurement of a phase marker over time rather than a
  single assessment. It is rare in the general population and common in the
  totally blind, where it may affect up to half of those without light
  perception.
notes: >-
  THE WORKED CONFORMER FOR THE ENTRAINMENT ARM. This entry is the cleanest
  available case of circadian_phase_misalignment's second entry arm, and is
  curated partly for that reason: the oscillator is entirely normal, and the
  disorder consists of losing the input that should reset it. That separation is
  hard to demonstrate in jet lag or shift work, where the light signal is present
  but mistimed, and impossible in the familial clock-variant disorders, where the
  oscillator itself is altered. It is also the setting in which the module's
  drug-target pattern is cleanest, since a timed melatonin-receptor signal
  entrains the pacemaker with no competing photic input.

  A NOTE ON THE SIGHTED FORM. Non-24 also occurs in sighted people, usually young
  men, typically evolving out of a delayed sleep-wake phase disorder, and there
  the mechanism cannot be simple absence of light input - it is more plausibly a
  combination of a long intrinsic period with behaviourally mistimed light
  exposure. This entry curates the blind form, where the mechanism is
  established, and does not extend the trigger node's claim to the sighted form.
pathophysiology:
- name: Absence of Photic Input to the Suprachiasmatic Nucleus
  description: >-
    The trigger. Photoentrainment does not use the image-forming visual pathway:
    melanopsin-expressing intrinsically photosensitive retinal ganglion cells
    project directly to the suprachiasmatic nucleus, and rods and cones are not
    required. The clinically important consequence is that visual and circadian
    blindness dissociate - a person with no useful vision but a surviving ipRGC
    pathway can still entrain normally, while loss of the eyes or of the
    retinohypothalamic projection removes entrainment entirely. This is why the
    disorder tracks light perception rather than visual acuity, and why the
    at-risk group is specifically those without light perception rather than the
    blind generally.
  role: trigger
  biological_scale: CELLULAR
  conforms_to: "circadian_phase_misalignment#Loss or Mistiming of Photic Entrainment Input"
  cell_types:
  - preferred_term: melanopsin-expressing intrinsically photosensitive retinal ganglion cell
    term:
      id: CL:0020014
      label: intrinsically photosensitive retinal ganglion cell
    modifier: DECREASED
  biological_processes:
  - preferred_term: entrainment of the circadian clock by photoperiod
    term:
      id: GO:0043153
      label: entrainment of circadian clock by photoperiod
    modifier: DECREASED
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  evidence:
  - reference: PMID:29326647
    reference_title: "Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Daily retinal light exposure is necessary for the synchronization of the
      circadian rhythms with the external 24-h solar environment.
    explanation: >-
      States the input this node loses, and that it is a requirement rather than
      a contributor to entrainment.
  - reference: PMID:11834834
    reference_title: "Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The primary circadian pacemaker, in the suprachiasmatic nucleus (SCN) of
      the mammalian brain, is photoentrained by light signals from the eyes
      through the retinohypothalamic tract. Retinal rod and cone cells are not
      required for photoentrainment.
    explanation: >-
      Establishes that the entrainment pathway is separable from image-forming
      vision, which is the basis for the dissociation between visual and
      circadian blindness this node turns on.
  - reference: PMID:26466871
    reference_title: "Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most totally blind people have non-24-hour sleep-wake disorder (non-24), a
      rare circadian rhythm disorder caused by an inability of light to reset
      their circadian pacemaker.
    explanation: >-
      States the causal claim of this node directly - the disorder is caused by
      light being unable to reset the pacemaker, not by any abnormality of the
      pacemaker itself.
  downstream:
  - target: Free-Running Circadian Period
    description: >-
      Without a daily resetting signal the pacemaker reverts to its own intrinsic
      period, which in most people is slightly longer than 24 hours.
    causal_link_type: DIRECT

- name: Free-Running Circadian Period
  description: >-
    The pacemaker runs at its intrinsic period rather than at 24 hours. Under
    stringent measurement the human circadian period lies roughly between 23.8
    and 25.1 hours; in an entrained person daily light resets it to exactly 24,
    and without that correction the residual difference accumulates. The
    arithmetic is what generates the clinical picture: a person whose
    non-entrained period is 24.5 hours goes to sleep and wakes half an hour later
    each day, so their phase completes a full circuit relative to the clock
    roughly every seven weeks. Crucially the oscillator itself is normal - this
    is a failure of correction, not of the clock, which distinguishes the
    disorder from the familial advanced and delayed phase syndromes.
  role: amplifier
  biological_scale: ORGANISM
  conforms_to: "circadian_phase_misalignment#Shifted or Free-Running Endogenous Circadian Phase"
  biological_processes:
  - preferred_term: circadian rhythm
    term:
      id: GO:0007623
      label: circadian rhythm
    modifier: ABNORMAL
  locations:
  - preferred_term: suprachiasmatic nucleus
    term:
      id: UBERON:0002034
      label: suprachiasmatic nucleus
  evidence:
  - reference: PMID:29326647
    reference_title: "Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This master clock has, for most humans, an intrinsic rhythm slightly longer
      than 24 h.
    explanation: >-
      Gives the intrinsic period that this node reverts to, and its direction -
      longer than 24 hours - which is why the drift is almost always later rather
      than earlier.
  - reference: PMID:30083814
    reference_title: Circadian Rhythm Disturbances in the Blind.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In most humans, the circadian period is slightly longer than 24 h and
      without regular resetting it tends to drift, leading to progressively later
      bedtimes and wake times and a tendency to cycle though periods of normal
      and abnormal sleep.
    explanation: >-
      States the whole mechanism of this node and the next in one sentence,
      including the cyclical alternation of normal and abnormal sleep that
      follows from a drifting phase.
  downstream:
  - target: Cyclical Misalignment with the 24-Hour Schedule
    description: >-
      A phase that drifts continuously passes in and out of alignment with the
      fixed social schedule, rather than sitting at a stable wrong offset.
    causal_link_type: DIRECT

- name: Cyclical Misalignment with the 24-Hour Schedule
  description: >-
    The rate-limiting step, and it differs from the fixed-phase circadian
    disorders in a way that matters clinically. In advanced or delayed sleep
    phase disorder the misalignment is constant, so symptoms are constant. Here
    the endogenous phase migrates through all clock times, so the patient cycles
    between stretches of entirely normal sleep, when phase happens to coincide
    with the schedule, and stretches of severe insomnia and daytime sleepiness,
    when it is opposed. That cyclicity is the disorder's signature and its main
    diagnostic obstacle: a single clinical assessment, a single sleep study, or a
    single phase marker taken during an aligned stretch will all look normal, and
    the complaint can be dismissed as inconsistent or behavioural.
  role: central_effector
  biological_scale: ORGANISM
  conforms_to: "circadian_phase_misalignment#Misalignment Between Endogenous Circadian Phase and the Imposed Sleep-Wake Schedule"
  biological_processes:
  - preferred_term: entrainment of circadian clock
    term:
      id: GO:0009649
      label: entrainment of circadian clock
    modifier: DECREASED
  - preferred_term: regulation of the circadian sleep/wake cycle
    term:
      id: GO:0042749
      label: regulation of circadian sleep/wake cycle
    modifier: ABNORMAL
  evidence:
  - reference: PMID:29326647
    reference_title: "Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Affected patients experience cyclical or periodic episodes of poor sleep
      and daytime dysfunction, severely interfering with social, academic, and
      professional life.
    explanation: >-
      Establishes the cyclical rather than constant symptom pattern that this
      node encodes, and its functional impact.
  - reference: PMID:29326647
    reference_title: "Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      remains challenging from a clinical point of view due to the cyclical
      symptoms and should be confirmed by measurements of circadian biomarkers
      such as urinary melatonin to demonstrate a circadian period outside the
      normal range
    explanation: >-
      Supports the diagnostic obstacle named in the description - that cyclicity
      itself is what makes the disorder hard to recognise, and why repeated
      biomarker measurement rather than a single assessment is required.
  downstream:
  - target: Cyclical Insomnia and Daytime Dysfunction
    description: >-
      When the drifting phase opposes the required schedule, sleep is attempted
      against an active circadian wake signal and wake is required at the
      circadian trough.
    causal_link_type: DIRECT

- name: Cyclical Insomnia and Daytime Dysfunction
  description: >-
    The clinical endpoint: alternating weeks of normal sleep and of severe
    sleep-onset insomnia with daytime sleepiness, cycling with a period set by
    the difference between the patient's intrinsic period and 24 hours. The
    resulting disability is social and occupational as much as symptomatic,
    because the unpredictability makes fixed commitments - school, employment,
    childcare - difficult to sustain even though the total amount of disturbed
    sleep is modest.
  role: consequence
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: circadian sleep/wake cycle, sleep
    term:
      id: GO:0050802
      label: circadian sleep/wake cycle, sleep
    modifier: ABNORMAL
  evidence:
  - reference: PMID:29326647
    reference_title: "Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This circadian drift leads to cyclical sleep disturbances and daytime
      sleepiness which pose a major handicap.
    explanation: >-
      States the endpoint and its severity, linking it explicitly to the drift
      rather than to sleep loss as such.
phenotypes:
- category: Neurological
  name: Cyclical Sleep-Onset Insomnia
  description: >-
    Sleep-onset insomnia that recurs in stretches lasting days to weeks, with
    intervening periods of normal sleep, as the endogenous phase drifts through
    the imposed schedule.
  phenotype_term:
    preferred_term: Sleep onset insomnia
    term:
      id: HP:0031354
      label: Sleep onset insomnia
    temporality: RECURRENT
  frequency: OBLIGATE
  evidence:
  - reference: PMID:29326647
    reference_title: "Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Affected patients experience cyclical or periodic episodes of poor sleep
      and daytime dysfunction
    explanation: >-
      OBLIGATE by definition: cyclical poor sleep is the defining presentation of
      the disorder.
- category: Neurological
  name: Cyclical Excessive Daytime Sleepiness
  description: >-
    Daytime sleepiness alternating with normal alertness on the same cycle as the
    insomnia, reflecting wake required at the circadian trough.
  phenotype_term:
    preferred_term: Excessive daytime somnolence
    term:
      id: HP:0001262
      label: Excessive daytime somnolence
    temporality: RECURRENT
  frequency: OBLIGATE
  evidence:
  - reference: PMID:29326647
    reference_title: "Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This circadian drift leads to cyclical sleep disturbances and daytime
      sleepiness which pose a major handicap.
    explanation: >-
      OBLIGATE by definition: cyclical daytime sleepiness is part of the defining
      presentation.
- category: Neurological
  name: Sleep-Wake Cycle Disturbance
  description: >-
    Progressive daily delay of sleep onset and wake time, the direct behavioural
    readout of a free-running pacemaker.
  phenotype_term:
    preferred_term: Sleep-wake cycle disturbance
    term:
      id: HP:0006979
      label: Sleep-wake cycle disturbance
    temporality: CHRONIC
  frequency: OBLIGATE
  evidence:
  - reference: PMID:30083814
    reference_title: Circadian Rhythm Disturbances in the Blind.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      without regular resetting it tends to drift, leading to progressively later
      bedtimes and wake times
    explanation: >-
      OBLIGATE by definition: progressive drift of sleep timing is what the
      diagnosis consists of.
diagnosis:
- name: Serial circadian phase marker measurement
  description: >-
    The diagnosis cannot be made from a single assessment, which is the practical
    point that distinguishes it from every other sleep disorder here. Repeated
    measurement of a phase marker - urinary 6-sulphatoxymelatonin or plasma
    melatonin profiles over 24 hours, sampled on multiple occasions weeks apart -
    is required to demonstrate a circadian period outside the normal range.
    Actigraphy with a sleep diary over an extended period shows the characteristic
    progressive drift. A patient assessed during an aligned stretch will look
    entirely normal on any single measurement.
  diagnosis_term:
    preferred_term: actigraphy
    term:
      id: NCIT:C180883
      label: Actigraphy
  evidence:
  - reference: PMID:29326647
    reference_title: "Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      should be confirmed by measurements of circadian biomarkers such as urinary
      melatonin to demonstrate a circadian period outside the normal range
    explanation: >-
      Establishes the diagnostic standard: a measured period outside the normal
      range, which requires serial rather than single measurement.
  - reference: PMID:30083814
    reference_title: Circadian Rhythm Disturbances in the Blind.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      New screening tools have been developed but actigraphy and repeated
      melatonin profiles over 24 h remain essential.
    explanation: >-
      Confirms that repeated profiling remains essential despite newer screening
      instruments, which is why this entry does not list a screening tool as
      sufficient.
treatments:
- name: Tasimelteon
  description: >-
    A dual MT1/MT2 melatonin receptor agonist taken at a fixed clock time each
    evening, and the only agent approved for this indication by both the FDA and
    the European Medicines Agency. It substitutes a pharmacological
    phase-setting signal for the missing photic one, entraining the free-running
    pacemaker to 24 hours. Two properties should be preserved by any entry citing
    it. It is substitutive, not curative: withdrawal loses entrainment again,
    which is itself the cleanest evidence that it acts on the phase node rather
    than on sleep. And the response rate is modest - entrainment was achieved in
    20% of treated patients at one month against 3% on placebo - so it should not
    be curated as reliably effective.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tasimelteon
      term:
        id: CHEBI:79042
        label: tasimelteon
  target_mechanisms:
  - target: Free-Running Circadian Period
    treatment_effect: ACTIVATES
    description: >-
      Timed MT1/MT2 agonism at the suprachiasmatic nucleus supplies the
      phase-setting signal that light cannot, entraining the free-running
      pacemaker to a 24-hour period.
  evidence:
  - reference: PMID:26466871
    reference_title: "Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once-daily tasimelteon can entrain totally blind people with non-24;
      however, continued tasimelteon treatment is necessary to maintain these
      improvements.
    explanation: >-
      Randomised evidence for both halves of the claim: the agent entrains the
      pacemaker, and the effect is substitutive rather than curative.
  - reference: PMID:26466871
    reference_title: "Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Circadian entrainment occurred in eight (20%) of 40 patients in the
      tasimelteon group compared with one (3%) of 38 patients in the placebo
      group at month 1
    explanation: >-
      Cited as PARTIAL because it bounds the effect: entrainment at one month was
      achieved in a minority, so the node is druggable but far from reliably
      correctable.
  - reference: PMID:26466871
    reference_title: "Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two (20%) of ten patients who were withdrawn to placebo remained entrained
      compared with nine (90%) of ten who continued to receive tasimelteon
    explanation: >-
      The randomised-withdrawal arm, and the strongest evidence that the drug
      maintains entrainment rather than the patient having re-entrained
      spontaneously.
- name: Timed Melatonin
  description: >-
    Low-dose melatonin at a fixed evening time is the long-standing alternative,
    acting on the same receptors and the same node. It is used alongside
    behavioural measures - fixed sleep and wake times, structured daily routine,
    consistent meal and activity timing - which supply non-photic timing cues in
    the absence of light. Curated without an efficacy claim from a randomised
    trial, since the evidence cited here supports its use in management rather
    than quantifying its effect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: melatonin
      term:
        id: CHEBI:16796
        label: melatonin
  target_mechanisms:
  - target: Free-Running Circadian Period
    treatment_effect: ACTIVATES
    description: >-
      Timed exogenous melatonin acts on the same MT1/MT2 receptors as
      tasimelteon to supply a daily phase-setting cue.
  evidence:
  - reference: PMID:29326647
    reference_title: "Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Management includes behavioral modification and melatonin.
    explanation: >-
      Establishes melatonin plus behavioural measures as standard management; the
      source states the approach rather than quantifying efficacy, which is why
      no effect size is asserted here.
prevalence:
- population: Totally blind adults without light perception
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 50000.0
  notes: >-
    Reported as affecting up to 50% of blind patients without light perception -
    an upper bound in a highly selected population, not a general-population
    rate. Recorded at that upper bound with the caveat attached, since the source
    gives no lower estimate. Contrast the general-population figure below.
  evidence:
  - reference: PMID:30083814
    reference_title: Circadian Rhythm Disturbances in the Blind.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the most common abnormality in totally blind patients without light
      perception is non-24-hour sleep-wake disorder (N24SWD). This is rare in the
      general population but may affect up to 50% of blind patients without light
      perception.
    explanation: >-
      Gives both the at-risk-population figure curated here and the
      general-population rarity recorded in the second record.
- population: General population
  measure_type: POINT_PREVALENCE
  prevalence_class: ULTRA_RARE
  notes: >-
    Described as an orphan disease in the general population; no numeric rate is
    given in the sources curated here, so the class is recorded qualitatively
    rather than a rate being inferred.
  evidence:
  - reference: PMID:29326647
    reference_title: "Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Non-24-h sleep–wake rhythm disorder is an orphan disease in the general
      population but common in the totally blind.
    explanation: >-
      States the general-population rarity and the contrast with the blind
      population directly.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:29326647
      reference_title: "Non-24-Hour Sleep-Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The rhythms are generated spontaneously by an internal "pacemaker," the
        suprachiasmatic nuclei within the anterior hypothalamus.
      explanation: >-
        A disorder of a hypothalamic pacemaker's entrainment; classified under
        the nervous-system chapter, the schema having no dedicated sleep chapter.
discussions:
- discussion_id: gap_sighted_non24_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    What causes non-24-hour sleep-wake rhythm disorder in sighted people, whose
    photic input is intact?
  attaches_to:
  - pathophysiology#Absence of Photic Input to the Suprachiasmatic Nucleus
  rationale: >-
    This entry's trigger node is the absence of photic input, which cannot be the
    mechanism in sighted patients - yet the disorder occurs in them, typically in
    young men and typically evolving out of a delayed sleep-wake phase disorder.
    The candidate explanations are mechanistically different and predict different
    treatments: an unusually long intrinsic period exceeding what daily light can
    correct; reduced sensitivity of the entrainment pathway; or a behavioural
    loop in which an already-delayed phase leads to light exposure timed to
    reinforce the delay rather than correct it, which would make the disorder
    partly self-inflicted and reversible by schedule management. Distinguishing
    them requires measuring the phase-response curve, which is rarely done
    clinically, and the entry deliberately does not extend its trigger claim to
    this group until they are separated.
  proposed_experiments:
  - experiment_id: exp_sighted_non24_phase_response
    name: Phase-response characterisation in sighted free-running patients
    description: >-
      Measure intrinsic circadian period under forced desynchrony and construct
      individual light phase-response curves in sighted patients with
      non-24-hour sleep-wake rhythm disorder, comparing them against patients
      with delayed sleep-wake phase disorder and against controls, with
      concurrent light dosimetry to establish whether the received light signal
      is adequate but ineffective or simply mistimed.