Trial of Lithium Carbonate for Treatment of Osteoporosis-pseudoglioma Syndrome

Osteoporosis-pseudoglioma (OPPG) syndrome is a very rare genetic disorder (approximately 50
cases have been reported worldwide) due to mutations in the LRP5 gene, causing blindness from
birth and fragile bones (osteoporosis)in early childhood. The bony fragility can lead to
recurrent fractures of major bones such as the hip (femur) and spine, leaving some children
in wheelchairs.

Treatment to strengthen the bones in OPPG has primarily been with osteoporosis medications
used in other fragile bone disorders of childhood and in adults, namely the bisphosphonates
(eg. pamidronate, alendronate). These drugs have helped the bone strength in OPPG somewhat
but have not prevented all fractures. We have observed fractures of the hip in 3 children
with OPPG who we have treated, in spite of their attaining normal bone density (determined by
DXA, dual xray absorptiometry) with bisphosphonates. Therefore, new treatments for OPPG are
greatly needed and new methods besides DXA are needed to monitor bone strength on treatment.

A mouse model of OPPG has been created. In the mouse model of OPPG, lithium dramatically
improved their bones, returning them to normal strength and preventing fractures. Lithium,
which is used for people with psychiatric disease, is known to lead to higher bone strength
and reduced fractures in people who are on it for psychiatric disease. Lithium has been used
safely and is approved for children 12 and above. The theory is that lithium will improve
bone strength in OPPG in humans, as it has in the mouse, by stimulating bone production
bypassing the genetic defect in OPPG.

In this study, we recruited 10 patients with OPPG and treated those who agreed (n=5) with
lithium for 6 months, monitoring the response of the bones by both DXA and pQCT (peripheral
quantitative computed tomography), the latter which gives information about bone quality. An
IND was obtained to use lithium in this study.

Eligibility Criteria

Inclusion Criteria

- Age 4 years or greater

- Diagnosed with osteoporosis pseudoglioma syndrome (OPPG) or a first degree relative of
someone with OPPG. For diagnosis of OPPG, one of the following is required: (1)
congenital blindness in a child born into a family with known OPPG where at least one
affected family member has had an LRP5 mutation demonstrated or (2) a child with no
known family members with OPPG who has congenital blindness, DXA Z-score < -2.0 and
mutation in LRP5 documented

- No contraindications to lithium carbonate

- For women of child bearing age, willing to undergo urine pregnancy test

Exclusion Criteria

- Age under 4 years

- Not diagnosed with osteoporosis pseudoglioma (OPPG) syndrome or a first degree
relative of someone with OPPG, or a member of the Old Order Mennonite community

- Pregnant

- For women of childbearing age, not willing to undergo urine pregnancy test

- Contraindication to Lithium (serum creatinine > 1.3, known cardiovascular disease
[history of myocardial infarction, heart failure], currently on diuretic or ACE
inhibitor)

- Glomerular filtration rate below 80 cc/min