We report 9 new cases of osteoporosis-pseudoglioma (OPPG) syndrome in three related nuclear families. All OPPG patients had a severe ocular phenotype, characterized by congenital blindness, regardless of genotype. By contrast, the bone phenotype was more severe in those with a homozygous W425X genotype than in W425X/ T409A compound heterozygotes. The two novel mutations in LRP5
described here were both in the second beta-propeller structure. Four of the six adult obligate heterozygotes studied (parents of affected individuals) had mild osteopenia or osteoporosis, as has been shown in other families [4
], and another one was normal. Improvement was seen in bone mineral density Z
-score from treatment with bisphosphonates in the four treated OPPG patients (from baseline to most recent: A1 −6.4 to −2.4, A2 −4.7 to −0.4, A3 −2.9 to −0.5, C2 −4.2 to −0.3).
The clinical features described in our OPPG patients A1–3 and C1–2 were similar to those described previously, with congenital blindness, severe osteoporosis, short stature (in 2/9) and fractures occurring in early childhood [2
]. Our patient A1 had the most severe bone disease with multiple fractures and bone deformity leading to wheelchair confinement since age 7. Although he also had propionic academia, this condition has not been associated with bony fragility [27
]. As found in previous reports [2
], most of our obligate heterozygotes had reduced bone mineral density, but none had eye pathology.
The homozygous W425X mutation predicts a stop codon and a severely truncated form of the LRP5 protein containing 425 instead of the normal 1615 amino acids, likely resulting in complete absence of functional protein. The clinical result was classic OPPG syndrome in the 4 affected children homozygous for this genotype, with mean spine Z
-scores of −4.6, similar to the reported mean in OPPG of −4.7 ± 0.9 [4
]. The homozygous W425X phenotype was similar to a previously reported case of OPPG caused by a homozygous R428X mutation [4
]. It is noteworthy that we found a milder bone phenotype in compound heterozygotes (cases B1–4, W425X/T409A) consisting of normal stature and a mean Z
-score of −1.9 vs −4.6 for W425X homozygotes (p
= 0.02). These compound heterozygotes, however, had similarly severe blindness to W425X homozygotes.
We are unaware of any previous reports of a mild bone phenotype with a compound heterozygous genotype that combines a stop codon and a missense mutation. We speculate that the missense T409A mutation might result in partially functional LRP5, adequate to stimulate slightly reduced bone production through the Wnt pathway, yet inadequate for normal eye development. LRP5 expression constructs studies [2
] designed to assess Wnt signal transduction have demonstrated variable β-catenin-mediated signal transduction. Interestingly, mutant constructs G404R and D434N that flank T409A and R425X had <50% of wild type activity, while the majority of other constructs were unable to transduce Wnt1 or Wnt10b signal. Despite this in vitro
result demonstrating some Wnt signal transduction capability, the clinical result of the construct mutations in patients was OPPG. The function of LRP5 in eye development is complex and involves varied mechanisms, including direct stabilization of b-catenin (through Axin binding) [42
] and transduction of Norrin signaling [2
]. We speculate that our T409A mutation, as found in other OPPG missense mutations [2
], resulted in reduced Norrin transduction, disrupting eye development but resulted in enough Wnt signaling to disrupt bone formation less severely. However, the mechanism of mutational effect in the compound heterozygotes must await functional studies of the mutant proteins.
Bone turnover markers, urine N-telopeptide (NTX) and alkaline phosphatase were normal for age in our OPPG patients. In the two previous reports of treatment in OPPG, one did not report markers of bone resorption [14
]; in the other, one of three patients had minimally elevated urinary deoxypyridinoline [13
]. We also found that vitamin D deficiency [25(OH)D<20] and insufficiency [25(OH)D<30 ng/ml] were common in our OPPG patients. Because of the importance of vitamin D to bone health [29
], we recommend following 25(OH)D levels in OPPG patients.
The most robust treatment responses were seen in the youngest patients treated with alendronate (1 mg/kg/day). Possible explanations include a reduced response with age or more likely a better response with alendronate because it is a more potent antiresorptive agent than pamidonate and risedronate used previously. In our patient with the most severe osteoporosis and the oldest of those treated, OPPG A1, bisphosphonates appeared to lose efficacy over time. Because of ongoing fractures, he was given a trial of teriparatide, synthetic parathyroid hormone (PTH), the only anabolic bone agent available for treatment of osteoporosis [30
]. PTH treatment is known to stimulate the Wnt signaling pathway, by decreasing DKK-1 [33
] and sclerostin [34
], both of which bind to LRP5 and decrease Wnt signaling. In studies on Lrp5 knock out mice, PTH treatment increased bone formation similarly to that seen in wild type mice [28
], with the predominant increase seen in cortical bone [30
]. Therefore, studies in mice have predicted a beneficial response to PTH in human OPPG. However, the human response to PTH is somewhat different from that in mice in that the BMD increase is seen in trabecular bone in humans [31
] and in cortical bone in mice [28
]. This raises the possibility that the mouse response to PTH might not be a perfect predictor of the human response.
Our OPPG patient treated with PTH (teriparatide) did not appear to have a definitive response to it in that his Z
-score did not improve after 15 months of treatment. This could be explained by his prior longterm treatment with bisphosphonates, which are known to blunt the effect of teriparatide [36
]. The 6 month gap between bisphosphonate and teriparatide treatment may have been inadequate to reduce the bisphosphonate effect of suppressing bone turnover. In this patient, we observed what appeared to be a paradoxical decrease in urine NTX (bone resorption marker) while on teriparatide, opposite to the increase in NTX expected [24
]. We do not have an explanation for this. After discontinuing teriparatide, this patient was started on alendronate, with subsequent improvement in Z
-score and further reduction in NTX. A controlled trial of teriparatide as the first line treatment in humans with OPPG could help to determine whether this drug is effective in this condition.
OPPG is a rare genetic syndrome. However, LRP5 has been shown to be important in the attainment of peak bone mass and skeletal response to loading [37
] and to be a determinant for normal bone density [38
mutations have been reported in several cases of idiopathic juvenile osteoporosis [40
]. In addition, common polymorphisms of LRP5
have been associated with variations in BMD, fracture risk and height in youth and old age ([41
] for review). Therefore, learning more about OPPG could potentially help our understanding of the pathophysiology of common osteoporosis.
In summary, we report 9 new cases of OPPG and describe a milder bone phenotype in individuals who were W425X/T409A compound heterozygotes than in W425X homozygotes. We report a beneficial response to bisphosphonates in four patients and a lack of definitive response to teriparatide in one. We recommend starting treatment with bisphosphonates in OPPG patients within the first few years of life.