Biological Clock Dysfunction Clinical Trial
Official title:
Identification and Treatment of Biological Clock Dysfunction in Optic Nerve Hypoplasia
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.
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.
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