Genetic Newborn Screening for Cystinosis and Primary Hyperoxaluria

NCT05843851 | Recruiting

• 1 other identifier: 1801-GEN-9852
• Study Type: interventional
• Target: 200,000
• Locations: 1 country
• Sites: 1

Brief Summary

In Germany parents of newborns are offered newborn screening (NBS) for 17 congenital diseases as a standard benefit of statutory health insurance. NBS in Germany is voluntary. Cystinosis and hyperoxaluria are very rare diseases. They are inherited autosomal-recessively. Neither disease can be detected by the methods established in routine NBS. However, common genetic mutations are known for both diseases. The aim of the study is to provide a scientific basis for molecular genetic NBS for cystinosis and primary hyperoxaluria (PH). Specifically, the study will investigate whether the inclusion of these diseases into general NBS should be recommended. By observing the identified infants in comparison to patients symptomatically diagnosed outside of the pilot project, it will be determined whether and to what extent early diagnosis and therapy lead to a more favorable prognosis. The screening laboratory Hannover, Germany is involved in the project. Hospitals that send their dry blood spot cards for routine NBS to Hannover are offered participation in the project. Parents who want to participate receive an additional information sheet. A parent and the attending physician sign the information sheet as documentation of informed consent, which allows data transfer and patient referral to a specialist in case of a positive result. Molecular genetic screening in the pilot project is performed from the same dry blood spot card used for routine NBS. In both diseases, testing is performed for 2 known mutations: In cystinosis for the 2 mutations most common in Germany, and in PH for the most common mutation in infantile hyperoxaluria (PH1) and in Europe (PH3). Normal findings are not communicated to the parents, which may contact the laboratory to ask for them. Parents of newborns with two mutations in the cystinosis gene are immediately informed about the disease by a physician. Further diagnostics to confirm the disease are organized close to home. In contrast, parents of newborns with only one mutation in one of the two hyperoxaluria genes are informed. They are asked to send spot urines of the newborn to the hyperoxaluria center. Only if these are abnormal, further evaluation will be performed. The study started on 15.03.2022. The aim is to screen 200,000 newborns until 2025. If the benefit of early diagnosis and therapy can be shown, an application for inclusion of a NBS for these two diseases in the routine NBS program will be submitted to the German government.

Conditions

Cystinosis; Primary Hyperoxaluria

Keywords

Molecular based newborn screening; Cystinosis; Primary Hyperoxaluria

Outcome Measures

Primary Outcomes (3)

• Newborns with confirmed diagnosis of Cystinosis

  Newborns identified with 57-kb CTNS mutation homozygous, compound heterozygous, with c.18\_21delGACT p.T7Ffs\*7 homozygous or compound heterozygous and elevated white blood cell cystine level.

  12 months

• Number of newborns with heterozygous mutations

  Newborns identified with heterozygous CTNS mutations of 57-kb CTNS and heterozygous c.18\_21delGACT p.T7Ffs\*7 mutations

  12 months

• Patients with PH1 and PH3

  Newborns identified with heterozygous PH1 c.508G\>A and PH3, C700+5G\>T and further positive evaluation of urine and genetic analysis.

  12 months

Secondary Outcomes (1)

• Newborns identified with heterozygous PH1 c.508G>A and PH3, C700+5G>T

  12 months

Other Outcomes (1)

• Both diseases

  time interval until start of treatment

Study Arms (1)

Tested newborns

EXPERIMENTAL

Tested for two mutations in the CTNS gene and one mutation in the PH1 gene and PH 3.

Diagnostic Test: Diagnostic test

Interventions

Diagnostic test DIAGNOSTIC_TEST

Test for two mutations in the CTNS gene and one mutation in the PH1 gene and PH 3.

Tested newborns

Eligibility Criteria

• Age: 32 Hours - 72 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Newborns participating at the NGS with parent's consent to participate in this screening project

You may not qualify if:

• Newborns without parent's consent to participate in this screening project.

Sponsors & Collaborators

• Cystinose Stiftung: lead
• Screening Laboratory Hannover: collaborator
• Pediatry Kastanienhof Koeln: collaborator
• Medical Genetics Mainz: collaborator
• University Hospital Cologne: collaborator

Study Sites (1)

Screening Laboratory Hanover

Hanover, Lower Saxony, 30430, Germany

RECRUITING

Related Publications (10)

• Hohenfellner K, Bergmann C, Fleige T, Janzen N, Burggraf S, Olgemoller B, Gahl WA, Czibere L, Froschauer S, Roschinger W, Vill K, Harms E, Nennstiel U. Molecular based newborn screening in Germany: Follow-up for cystinosis. Mol Genet Metab Rep. 2019 Sep 18;21:100514. doi: 10.1016/j.ymgmr.2019.100514. eCollection 2019 Dec.

  PMID: 31641587 BACKGROUND

• Fleige T, Burggraf S, Czibere L, Haring J, Gluck B, Keitel LM, Landt O, Harms E, Hohenfellner K, Durner J, Roschinger W, Becker M. Next generation sequencing as second-tier test in high-throughput newborn screening for nephropathic cystinosis. Eur J Hum Genet. 2020 Feb;28(2):193-201. doi: 10.1038/s41431-019-0521-3. Epub 2019 Sep 30.

  PMID: 31570786 BACKGROUND

• Niessl C, Boulesteix AL, Oh J, Palm K, Schlingmann P, Wygoda S, Haffner D, Wuhl E, Tonshoff B, Buescher A, Billing H, Hoppe B, Zirngibl M, Kettwig M, Moeller K, Acham-Roschitz B, Arbeiter K, Bald M, Benz M, Galiano M, John-Kroegel U, Klaus G, Marx-Berger D, Moser K, Mueller D, Patzer L, Pohl M, Seitz B, Treikauskas U, von Vigier RO, Gahl WA, Hohenfellner K. Relationship between age at initiation of cysteamine treatment, adherence with therapy, and glomerular kidney function in infantile nephropathic cystinosis. Mol Genet Metab. 2022 Aug;136(4):268-273. doi: 10.1016/j.ymgme.2022.06.010. Epub 2022 Jul 2.

  PMID: 35835062 BACKGROUND

• Hohenfellner K, Niessl C, Haffner D, Oh J, Okorn C, Palm K, Schlingmann KP, Wygoda S, Gahl WA. Beneficial effects of starting oral cysteamine treatment in the first 2 months of life on glomerular and tubular kidney function in infantile nephropathic cystinosis. Mol Genet Metab. 2022 Aug;136(4):282-288. doi: 10.1016/j.ymgme.2022.06.009. Epub 2022 Jul 1.

  PMID: 35843134 BACKGROUND

• Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, Lieske JC, Milliner DS, Harris PC; Rare Kidney Stone Consortium. Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria. J Am Soc Nephrol. 2015 Oct;26(10):2559-70. doi: 10.1681/ASN.2014070698. Epub 2015 Feb 2.

  PMID: 25644115 BACKGROUND

• Garrelfs SF, Rumsby G, Peters-Sengers H, Erger F, Groothoff JW, Beck BB, Oosterveld MJS, Pelle A, Neuhaus T, Adams B, Cochat P, Salido E, Lipkin GW, Hoppe B, Hulton SA; OxalEurope Consortium. Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up. Kidney Int. 2019 Dec;96(6):1389-1399. doi: 10.1016/j.kint.2019.08.018. Epub 2019 Sep 3.

  PMID: 31685312 BACKGROUND

• Hoyer-Kuhn H, Kohbrok S, Volland R, Franklin J, Hero B, Beck BB, Hoppe B. Vitamin B6 in primary hyperoxaluria I: first prospective trial after 40 years of practice. Clin J Am Soc Nephrol. 2014 Mar;9(3):468-77. doi: 10.2215/CJN.06820613. Epub 2014 Jan 2.

  PMID: 24385516 BACKGROUND

• Hoppe B, Koch A, Cochat P, Garrelfs SF, Baum MA, Groothoff JW, Lipkin G, Coenen M, Schalk G, Amrite A, McDougall D, Barrios K, Langman CB. Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria. Kidney Int. 2022 Mar;101(3):626-634. doi: 10.1016/j.kint.2021.08.015. Epub 2021 Sep 2.

  PMID: 34481803 BACKGROUND

• Hoppe B, Martin-Higueras C. Improving Treatment Options for Primary Hyperoxaluria. Drugs. 2022 Jul;82(10):1077-1094. doi: 10.1007/s40265-022-01735-x. Epub 2022 Jul 2.

  PMID: 35779234 BACKGROUND

• Elmonem MA, Veys KR, Soliman NA, van Dyck M, van den Heuvel LP, Levtchenko E. Cystinosis: a review. Orphanet J Rare Dis. 2016 Apr 22;11:47. doi: 10.1186/s13023-016-0426-y.

  PMID: 27102039 BACKGROUND

MeSH Terms

Conditions

Cystinosis; Hyperoxaluria, Primary

Interventions

Diagnostic Tests, Routine

Condition Hierarchy (Ancestors)

Lysosomal Storage Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperoxaluria; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carbohydrate Metabolism, Inborn Errors

Intervention Hierarchy (Ancestors)

Diagnostic Techniques and Procedures; Diagnosis

Study Officials

• Sonja Froschauer

  Cystinosis Foundation (Cystinose Stiftung)

  STUDY DIRECTOR

• Katharina Hohenfellner

  Ro Med Clinics Rosenheim

  STUDY CHAIR

Central Study Contacts

Katharina Hohenfellner, PD Dr.

CONTACT

+4986170532262; Katharina.Hohenfellner@ro-med.de

Sonja Froschauer, Dipl. Phys.

CONTACT

+491771760755; sonja.froschauer@cystinose-stiftung.de

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: SCREENING
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Pediatric Nephrology

Model Details: All newborns whose parents have agreed to participate in the pilot project will be tested for two mutations in the CTNS gene and one mutation in the PH1 gene and PH 3.

Study Record Dates

• First Submitted: April 11, 2023
• First Posted: May 6, 2023
• Study Start: March 15, 2022
• Primary Completion: December 31, 2025
• Study Completion (Estimated): June 30, 2026
• Last Updated: May 6, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)