Biological Clock Dysfunction in Optic Nerve Hypoplasia
Condition: Biological Clock Dysfunction; Optic Nerve Hypoplasia
MeSH terms: Optic Nerve Hypoplasia
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Background: Optic Nerve Hypoplasia (ONH) is a leading cause of blindness in children. For
      unclear reasons, the incidence of ONH is increasing, with ONH affecting about 1 in 10,000
      live-born infants. In addition to visual deficits, ONH is associated with varying degrees of
      hypopituitarism, developmental delay, brain malformations and obesity. Although genetic
      mutations have been rarely observed to result in ONH, the causes of ONH are largely not
      known. In limited anatomical observations, the suprachiasmatic nuclei (SCN) located in the
      anterior hypothalamus, which generate circadian rhythms, have been observed to be abnormal in
      children with ONH. Thus, children with ONH may have biological clock dysfunction.

      In collaborative studies with Dr. Mark Borchert of Childrens Hospital Los Angeles (CHLA), we
      have recently discovered that one-half of children with ONH have grossly abnormal sleep-wake
      patterns, as assessed by actigraphy. Although not known for children with ONH, abnormal
      sleep-wake patterns have been observed to be associated with neurocognitive impairment and
      obesity. We also observe that nocturnal melatonin administration can improve abnormal
      sleep-wake cycles in these children, raising the possibility that it will be possible to
      treat abnormal rhythmicity in children with ONH.
    

Detailed description: 
      Objectives and Hypotheses. Our objectives are to define the scope and problems related to
      biological clock disorders in children with ONH and to develop effective treatments for this
      condition. Based on our observations, we hypothesize: (1) Daily rest-activity patterns and
      sleep will be abnormal in up to 50% of children with ONH. (2) It is possible to identify risk
      factors for abnormal circadian system function and sleep problems in ONH. (3) Nocturnal
      melatonin administration will improve abnormal sleep and activity patterns in children with
      ONH.

      Design: These studies will involve collaborative efforts between Yale University and Dr. Mark
      Borchert of Childrens Hospital Los Angeles, who follows the largest population of children
      with ONH in the world. We will study children ages 2-10 years with documented ONH using
      standard criteria. Based on these criteria, we have more than 100 eligible patients.

      To test our hypotheses, we will: (1) examine expressed rhythmicity in children with ONH.
      These studies will use actigraphy, sleep questionnaires, and assessment of melatonin
      secretory profiles. (2) We will correlate hypothalamic anatomical abnormalities and the
      degree endocrine dysfunction with sleep and expressed rhythmicity. (3) We will test if
      short-term administration of melatonin improves sleep-wake patterns in children with
      abnormally-expressed rhythmicity.

      Potential Impact: Our preliminary data raise the possibility that children with ONH will have
      circadian system dysfunction resulting in abnormal rhythmicity and sleep. However, to date
      there have been no formal attempts to identify children with ONH who are at risk for such
      problems, nor have there been efforts aimed at developing potential treatments. The proposed
      prospective clinical study will represent an important attempt to identify a group of
      children with circadian system dysfunction.

      At the completion of this study, we anticipate having determined risk factors for circadian
      system dysfunction in children with ONH. Insights gained from these studies should lead to
      the development of new approaches for treating circadian clock lesions in ONH, with the hope
      of improving the well-being of circadian system function in the boys and girls with this
      condition.
    

Intervention name(s): Melatonin; Placebo Comparator
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Oral administration before bed. We will test two doses (0.5 or 3.0 mg/m2. 6 week duration.); Oral administration before bed. 6 week duration.
Intervention MeSH terms: Melatonin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Diagnostic
Keywords: optic nerve hypoplasia; septo-optic dysplasia; melatonin; circadian rhythm