Research Relating to Diagnosis, Evaluation, and Treatment

The Rare Diseases Intramural Research Program is a collaborative effort between the ORD and the NHGRI at the NIH Clinical Center. The program includes evaluating and treating gynecological aspects of rare diseases, investigating undiagnosed inborn errors of metabolism, and managing select clinical research protocols.

In the past year, researchers at the Intramural Research Program of the Office of Rare Diseases diagnosed, cared for, and treated a number of patients with rare diseases, including Chediak-Higashi disease (CHD), Hermansky-Pudlak syndrome (HPS), Gray platelet syndrome (GPS), Griscelli syndrome, oculocutaneous albinism associated with other systemic disorders such as increased pulmonary mucus production, a progeroid syndrome (HGPS), alkaptonuria, autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF), autosomal dominant polycystic kidney disease, Joubert syndrome, renal tubular Fanconi syndrome, cystinosis, glutathione synthase deficiency, homocystinuria, and idiopathic nephrocalcinosis.

Intramural staff evaluated gynecologic issues of patients with HPS, cystinosis, alkaptonuria, xeroderma pigmentosum, Smith-Magenis syndrome, and Smith-Lemli-Opitz syndrome. A member of the intramural program of the ORD provided gynecology consultations for rare disease patients throughout the NIH Clinical Center as she continued her fellowship in the field of clinical biochemical genetics.

Currently, the program also supports the conduct of clinical therapeutic trials of pirfenidone for the pulmonary fibrosis of HPS, nitisinone for the ochronotic joint disease of alkaptonuria, cysteamine for the renal and systemic disease of cystinosis, and intravenous immune globulin for the muscle wasting of HIBM. Staff also collaborated on an NEI-sponsored treatment protocol for the use of cysteamine eye drops for the corneal crystals of cystinosis and on an NIAID-sponsored diagnostic protocol for the colitis associated with HPS.

In the past year, intramural ORD staff has:

• Obtained additional Gray Platelet syndrome patients for linkage mapping of the gene for GPS, brining us closer to identifying the gene responsible for this disease.
• Continued to enroll patients in a protocol entitled, “Clinical Investigations into Autosomal Recessive Polycystic Kidney Disease (ARPKD) and Congenital Hepatic Fibrosis”. Under this protocol, 90 patients have been examined and evaluated for the possibility of future treatment.
• Submitted for publication a comprehensive report on 15 patients with Hutchinson-Gilford Progeria Syndrome, a disorder of premature aging that is fatal in adolescence, under a new clinical protocol.
• Investigated new patients with the rare disease Chediak-Higashi syndrome on clinical, molecular, and cell biological grounds
• Performed an interim analysis of the effects of nitisinone on hip joint range of motion in 40 patients with alkaptonuria
• Recruited 25 Hermansky-Pudlak syndrome patients to a therapeutic protocol testing pirfenidone for its efficacy and safety in treating the pulmonary fibrosis associated with this rare disorder
• Obtained approval for a clinical protocol involving aggressive, multi-drug treatment for end-stage pulmonary fibrosis in Hermansky-Pudlak syndrome.

Conduct of Clinical Protocols

Intramural ORD-supported caregivers are Principal or Associate Investigators on the following clinical protocols approved by the NHGRI Institutional Review Board:

Rare Diseases Research Initiative
The Office of the Clinical Director of NHGRI continues to admit patients with rare, undiagnosed disorders under a protocol entitled Diagnosis and Treatment of Patients with Inborn Errors of Metabolism. Examples of patients include a family with albinism and increased mucus production, a boy with hypopigmentation and lax joints, a young man with autosomal dominant Fanconi syndrome, and a boy with a progeroid disorder. Plans are underway to expand this service to become a regular program examining patients with rare undiagnosed disorders and triaging them to existing specialty clinical at the NIH Clinical Center.

Molecular Diagnostics of Rare Diseases
In collaboration with the NHGRI, the intramural program of the ORD previously conducted a program to contract with Clinical Laboratory Improvement Act (CLIA)-certified laboratories to establish molecular diagnostic tests for specific rare diseases. Thereafter, these tests are made available on a fee-for-service, insurance-reimbursable basis to the general public. This intramural initiative was transferred to extramural ORD under the title of CETT, but members of the intramural ORD continue to serve as consultants in the metabolic diseases. They will also assist in the future development of CLIA-certified biochemical testing for rare disorders.

Research Training
In FY07, one pediatrician and one obstetrician/gynecologist in the ORD Intramural Research Program completed training in clinical biochemical genetics. A third ORD-supported fellow entered the clinical biochemical genetics training program.

Bench-to Bedside Program
The Director of the intramural ORD sits on the NIH Clinical Center Committee to evaluate bench-to-bedside proposals for funding.

Publications

The following papers involving intramural ORD-supported staff were published in FY07:

1. Savelkoul PJM, Manoli I, Sparks SE, Ciccone C, Gahl WA, Krasnewich DM, Huizing M. Normal sialylation of serum N-linked and O-GalNAc-linked glycans in hereditary inclusion-body myopathy. Mol Genet Metab 88:389-390, 2006.
2. Sparks S, Rakocevic G, Joe G, Manoli I, Shrader J, Love MH, Sonies B, Ciccone C, Dorward H, Krasnewich D, Huizing M, Dalakas MC, Gahl WA. Intravenous immune globulin in hereditary inclusion body myopathy: A pilot study. BMC-Neurology 7:3, 2007.
3. Galeano B, Klootwijk R, Manoli I, Sun M-S, Ciccone C, Darvish D, Starost MF, Zerfas PM, Hoffmann VJ, Hoogstraten-Miller S, Krasnewich DM, Gahl WA, Huizing M. Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. J Clin Invest 117:1585-1594, 2007.
4. Gahl WA, Balog JZ, Kleta R. Nephropathic cystinosis in adults: Natural history and effects of oral cysteamine therapy. Annals Intern Med 147:242-250, 2007.
5. Westbroek W, Adams D, Huizing M, Koshoffer A, Dorward H, Tinloy B, Parkes J, Helip-Wooley A, Kleta R, Tsilou E, Duvernay P, Digre K, Creel D, White JG, Boissy R, Gahl WA. Cellular defects in Chediak-Higashi syndrome correlate with the molecular genotype and clinical phenotype. J Invest Dermatol. In press, 2007.
6. Helip-Wooley A, Kleta R, Gahl WA. Lysosomal free sialic acid storage disorders: Salla disease and ISSD. In Lysosomal Storage Diseases (Barranger JA, Cabrera M, eds). Springer, 2007.
7. Kleta R, Helip-Wooley A, Gahl WA. Cystinosis. In Lysosomal Storage Diseases (Barranger JA, Cabrera M, eds). Springer, 2007.
8. Kleta R, Gahl WA. Collecting evidence: the case of collectrin (TMEM27) and amino acid transport. Am J Physiol 292:F531-2, 2007.

Abstracts published by intramural ORD-funded staff in FY07 included:

1. Westbroek W, Adams D, Helip-Wooley A, Dorward H, Kleta R, Boissy R, Parks J, Huizing M, Gahl WA. Chediak-Higashi syndrome: A genotype-phenotype correlation. Pigment Cell Res 19:356-377, 2006.
2. Ciccone C, Krasnewich D, Klootwijk R, Manoli I, Sparks S, Gahl WA, Huizing M. Understanding diseases associated with mutation in the GNE gene, coding for UDP-GlcNAc 2-epimerse/ManNAc kinase. Am Soc Hum Genet Abstract Issue 259/1366C, 2006.
3. Manoli I, Sparks S. Rakocevic G, Joe G, Shrader J, Sonies B, Ciccone C, Krasnewich D, Huizing M, Dalakas M, Gahl WA. Intravenous immune globulin treatment for Hereditary Inclusion Body Myopathy: A pilot study. Am Soc Hum Genet Abstract Issue 432/2385B, 2006.
4. Huizing M, Klootwijk E, Manoli I, Galeano B, Sun MS, Ciccone C, Darvish D, Krasnewich D, Gahl WA. N-Acetylmannosamine treatment rescues a mouse model of Hereditary Inclusion Body Myopathy. Am Soc Hum Genet Abstract Issue 29/62, 2006.
5. Gunay-Aygun M, Font-Montgomery E, Choyke P, Guay-Woodford L, Heller T, Kleta R, Mohan P, Quezado Z, Gahl WA. Natural history of Autosomal Recessive Polycystic Kidney Disease/Congenital Hepatic Fibrosis (ARPKD/CHF). Am Soc Hum Genet Abstract Issue 33/80, 2006.
6. Introne WJ, Merideth MA, Gordon LB, Perry MB, Turner M, Clauss S. Sachdev V, Graf J, Smith ACM, Gerber LH, Reynolds JC, Yanovski JA, Cannon R, Gahl WA. Hutchinson-Gilford Progeria Syndrome (HGPS): Consistency of phenotype in 15 children. Am Soc Hum Genet Abstract Issue 116/529C, 2006.
7. Font-Montgomery E, Ocak I, Choyke P, Guay-Woodford L, Heller T, Kleta R, Mohan P, Quezado Z, Gunay-Aygun M, Gahl WA. Portal hypertension associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Am Soc Hum Genet Abstract Issue 125/579B, 2006.
8. Bernardini I, Balog J, Golas G, O’Brien K, Kleta R, Gahl WA. Long-term benefits of early oral cysteamine therapy in cystinosis. Am Soc Hum Genet Abstract Issue 430/2372A, 2006.
9. Kayser MA, Suwannarat P, Tuchman M, Tinloy B, Klein C, O’Brien K, Bernardini I, Gahl WA, Kleta R. Is disease severity in alkaptonuria modified by a common SNP in the organic anion transporter MRP4/ABCC4? Am Soc Hum Genet Abstract Issue 256/1351C, 2006.
10. Kleta R, Coskun T, Tinloy B, Aydin HI, Gunay-Aygun M, Stanescu H, Bernardini, I Gahl WA. Iminoglycinuria: Molecular findings. Am Soc Hum Genet Abstract Issue 269/1427A, 2006.
11. Tinloy B, Topaloglu R, Coskun T, Gunay-Aygun M, Anikster Y, Jeong A, Bakkaloglu A, Besbas N, Kalkanoglu S, Gahl WA, Kleta R. New molecular findings in Turkish cystinosis patients. Am Soc Hum Genet Abstract Issue 356/1945C, 2006.
12. Golas G, Hess R, Helip-Wooley A, Huizing M, Gahl WA. Hermansky-Pudlak Syndrome in non-Puerto Rican Hispanic children. Am Soc Hum Genet Abstract Issue 262/1385A, 2006.
13. O’Brien K, Tsilou E, Lynch M, Stuart C, Jeong A, Kleta R, Gahl WA. Gitelman syndrome and sclerochoroidal calcifications: The critical importance of renal regulation in calcium homeostasis. Am Soc Hum Genet Abstract Issue 250/1311B, 2006.
14. Tuchman M, Kleta R, Gunay-Aygun M, Huizing M, Westbroek W, Helip-Wooley A, Hetz JM, Gahl WA. A novel mutation in the RAB27A gene causing Griscelli Syndrome. Am Soc Hum Genet Abstract Issue 216/1116B, 2006.
15. Stanescu H, Unwin R, Heikkila TJ, Willoughby C, Kashgarian M, O’Brien K, Siegel N, van’t Hoff W, Bockenhauer D, Gahl WA, Povey S, Kleta R. Redefining a locus for autosomal dominant Fanconi syndrome with kidney failure. Am Soc Hum Genet Abstract Issue 288/1543C, 2006.
16. Landoure G, Stanescu H, Knight MA, Arcos-Burgos M, Pineda D, Gahl WA, Fischbeck KH, Kleta R. Pitfalls in homozygosity mapping – revisited. Am Soc Hum Genet Abstract Issue 294/1579C, 2006.
17. Merideth M, Introne WJ, Gordon LB, Smith ACM, Gahl WA. Clinical presentation and diagnosis of patients with Hutchinson-Gilford Progeria Syndrome. Am Soc Hum Genet Abstract Issue 119/545A, 2006.
18. Hess R, Helip-Wooley A, Kleta R, Huizing M, Gahl WA. The genetics of Hermansky-Pudlak Syndrome. Am Soc Hum Genet Abstract Issue 255/1343A, 2006.
19. Westbroek W, Adams D, Koshoffer A, Dorward H, Helip-Wooley A, Huizing M, Parks J, Kleta R, Boissy R, Gahl WA. Chediak-Higashi syndrome: A genotype-phenotype correlation. Am Soc Hum Genet Abstract Issue 59/211, 2006.
20. Perry MB, Introne WJ, Merideth M, Gordon LB, Gahl WA, Gerber LH. Impairments and function limitations in Hutchinson-Gilford Progeria. Arch Phys Med Rehab 87:E23, 2006.
21. Klootwijk E, Manoli I, Galeano B, Sun MS, Ciccone C, Bond W, Darvish D, Krasnewich D, Gahl WA, Huizing M. N-Acetylmannosamine treatment rescues GNE knock-in mice from severe neonatal glomerular hematuria and podocytopathy: Insights for hereditary inclusion body myopathy. Mol Genet Metab 90:241-2/7, 2007.
22. Font-Montgomery EE, Ocak I, Choyke P, Heller T, Kleta R, Edwards H, Mohan P, Guay-Woodford L, Daryanani K, Quezado Z, Gahl WA, Gunay-Aygun M. Autosomal dominant polycystic kidney disease (ADPKD) mimicking autosomal recessive polycystic kidney disease (ARPKD) with congenital hepatic fibrosis (CHF) and portal hypertension (PH). Mol Genet Metab 90:251/20, 2007.
23. Kayser MA, Suwannarat P, Introne W, Austin HA, Tuchman M, Tinloy B, Klein C, O’Brien K, Bernardini I, Gahl WA, Kleta R. Can a common SNP in the organic anion transporter MRP4/ABCC4 influence homogentisic acid secretion and the severity of ochronosis in alkaptonuria? Mol Genet Metab 90:255/34, 2007.
24. Merideth MA, Introne WJ, Zalewski C, Brewer C, Gordon LB, Smith ACM, Kim HJ, Gahl WA. Hearing loss in children with Hutchinson-Gilford Progeria Syndrome. ACMG Annual Meeting Abstract Issue 121/127, 2007.
25. Gunay-Aygun M, Font-Montgomery E, Choyke P, Guay-Woodford L, Heller T, Kleta R, Mohan P, Daryanani K, Quezado Z, Gahl WA. Autosomal Recessive Polycystic Kidney Disease/Congenital Hepatic Fibrosis (ARPKD/CHF): Differential diagnosis and natural history. ACMG Annual Meeting Abstract Issue 94/28, 2007.
26. Huizing M, Klootwijk R, Manoli I, Sun MS, Ciccone C, Darvish D, Starost MF, Zerfas PM, Hoffmann VJ, Hoogstraten-Miller S, Krasnewich DM, Gahl WA. Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. J Inherit Metab Dis 30 (Suppl 1): 249-O, 2007.
27. Domingo DL,Trujillo MI, Guadagnini JP, Gordon L, Merideth MA, Introne WJ, Gahl WA, Hart TC. Hutchinson-Gilford Progeria Syndrome: Oral-craniofacial phenotypes. Am Assoc Dental Research Annual Meeting, 2007.
28. Klootwijk E, Manoli I, Galeano B, Hickey D, Bond W. Ciccone C, Darvish D, Krasnewich D, Gahl WA, Huizing M. Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. Glycobiology Society Annual Meeting, San Diego, 2007.

For more information, please contact:
William Gahl, M.D., Ph.D.
Director, Intramural Research Program
Office of Rare Diseases
National Institutes of Health
10 Center Drive
Building 10, Room 10C101, MSC 1851
Bethesda, MD 20892-1851
Telephone: 301-402-8255
Fax: 301-496-7157
E-mail: bgahl@helix.nih.gov