Patients with Hypophosphatasia disease or high-grade suspicion for Hypophosphatasia disease

For the development of the new biomarkers using the technique of Mass-spectrometry 7, 5 ml EDTA blood and a dry blood spot filter card are taken. To proof the correct di- agnosis of Hypophosphatasia in those patients where up to the enrollment in the study no genetic testing has been done, sequencing of Hypophosphatasia disease will be done. The analyses will be done at the: Centogene AG Am Strande 7 18055 Rostock Germany

Defective Mineralization

Centogene is one of the leading laboratories focusing on genetic testing for rare hereditary disorders. We now offer more than 2200 routine genetic and biochemical tests.

Centogene AG

NIRMAN Navi Mumbai Institute of Research In Mental And Neurological Handicap/Pediatric Geneticist

Lady Ridgeway Hospital for Children

Biomarker for Hypophosphatasia Disease (BioHypophos)

Biomarker for Hypophosphatasia Disease AN INTERNATIONAL, MULTICENTER, EPIDEMIOLOGICAL PROTOCOL

Next-Generation Sequencing (NGS) of the ALPL gene will be performed. The mutation will be confirmed by Sanger sequencing.

The quantitative determination of small molecules (molecular weight 150-700 kD, given as ng/μl) within a dried blood spot sample will be validated via liquid chromatography multiple reaction-monitoring mass spectrometry (LC/MRM-MS) and compared with a merged control cohort. The statistically best validated molecule will be considered as a disease specific biomarker.

Centogene AG Rostock

Focal laser photocoagulation (modified Early Treatment Diabetic Retinopathy Study (ETDRS) technique)

Posterior peribulbar injection of 40 mg triamcinolone (Kenalog)

Anterior peribulbar injection of 20 mg triamcinolone

Posterior peribulbar injection of 40 mg triamcinolone followed after one month by laser

Anterior peribulbar injection of 20 mg triamcinolone followed after one month by laser

Modified Early Treatment diabetic retinopathy Study technique (m-ETDRS, Laser burns-50 microns, gray intensity Multiple settings (all completed in single setting).

Focal Laser Photocoagulation

Posterior Peribulbar Injection of 40 mg Triamcinolone

Anterior Peribulbar Injection of 20 mg Triamcinolone

Posterior peribulbar injection of 40 mg triamcinolone followed by focal photocoagulation after one month

Posterior Peribulbar Injection of 40 mg Triamcinolone + Laser

Anterior peribulbar injection of 20 mg triamcinolone followed by focal photocoagulation after one month

Anterior Peribulbar Injection of 20 mg Triamcinolone + Laser

Total

Sex: Female, Male

Race/Ethnicity, Customized

Cystoid Abnormality on Ocular Coherence Tomography (OCT)

Diabetes Type

Best corrected visual acuity letter score as measured by a certified tester using an electronic early treatment diabetic retinopathy study (e-ETDRS) method and approximate Snellen equivalent. Best value on the scale is 97, worst value 0.

Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity

Received Prior Focal Photocoagulation

Received Prior Scatter (Panretinal) Photocoagulation

Ocular Coherence Tomography (OCT) images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology.

Subretinal Fluid on Ocular Coherence Tomography (OCT)

Measured by Ocular Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology.

Central Subfield Thickness

Duration of Diabetes

Hemoglobin A1c

Intraocular Pressure (mm Hg)

Baseline Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) Visual Acuity Letter Score: best value = 97; letter score worst value = 0

Mean visual acuity letter score

Total Retinal Volume (mm^3)

Change in Central Subfield Thickening from Baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology. Negative changes represent a decrease in retinal thickening.

Change in Central Subfield Thickening From Baseline Through 34 Weeks

Number of eyes that were retreated at 17 weeks. According to the protocol, primary criterion for retreatment was central subfield thickness >=250 microns or macular edema was still present according to the investigator's judgment.

Persistence/Recurrence of Diabetic Macular Edema (DME) Either Retreated or Meeting Criteria for Retreatment at 17 Weeks

Change in visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the electronic Early Treatment for Diabetic Retinopathy Study(E-ETDRS) technique. Letter score best value = 97 and worst value = 0; an increase in a letter score by 10 is considered clinically significant. Negative changes represent a worsening in visual acuity.

Change in Visual Acuity Letter Score From Baseline Through 34 Weeks

Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) mean visual acuity letter score: best value = 97; letter score worst value = 0

Mean Visual Acuity Letter Score at Each Follow-up Visit

Number of eyes that had a reduction in central subfield retinal thickness by ≥ 50% at each follow-up. Change in Central Subfield Thickening from Baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology.

Reduction of ≥ 50% in Retinal Thickening in the Central Subfield From Baseline Through 34 Weeks

Primary criterion for retreatment is central subfield thickness >=250 microns. Central subfield thickness of <250 microns indicates no need for retreatment. Change in Central Subfield Thickening from Baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology.

Central Subfield Thickness <250 Microns From Baseline Through 34 Weeks

4-Week Visit

8-Week Visit

17-Week Visit

34-Week Visit

Adam R. Glassman, M.S., Director

Diabetic Macular Edema

Focal laser photocoagulation (modified Early Treatment Diabetic Retinopathy Study technique)

papilledema/phosphatase

Biomarker for Hypophosphatasia Disease (BioHypophos)

A Pilot Study of Peribulbar Triamcinolone Acetonide for Diabetic Macular Edema

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