The Natural History Study of Patients with GNE Myopathy collects genetic and medical information from people with GNE myopathy. Patients are followed over time to understand the symptoms and clinical course of GNE myopathy. This information is essential to prepare clinical treatment trials.

What is GNE Myopathy?

GNE Myopathy is a rare genetic (autosomal recessive) disorder that causes progressive skeletal muscle atrophy and weakness. Previous names include hereditary inclusion body myopathy (HIBM), inclusion body myopathy type 2 (IBM2) or Nonaka myopathy.

Symptoms of the disease usually appear between 20 and 40 years of age and include foot drop and difficulty walking. The disease slowly affects other muscles of the arms and legs. Patients typically start using a wheelchair one or two decades later and eventually some patients may need assistance with activities of daily living.

GNE myopathy results from mutations in a gene called GNE, which is responsible for a step in the production of a sugar called sialic acid. GNE myopathy is diagnosed in patients presenting at the age of 20-40 with foot drop and progressive muscle weakness. Red-rimmed vacuoles (inclusions) are found on muscle biopsy. The diagnosis is confirmed by sequencing of the GNE gene.

GNE myopathy patients may go undiagnosed for many years. There are ~2,000 patients known worldwide and ~200 in the United States. However, we estimate (based on examining DNA sequencing databases) that there are at least 40,000 GNE myopathy patients worldwide, including ~13,000 in Asia (~750 in Japan), ~4,000 in Europe and ~3,000 in North America, meaning that many patients are undiagnosed.

No therapies are currently approved for GNE myopathy. Studies on mouse models of GNE myopathy have provided promising data and several therapeutic trials are currently underway. NIH investigators are developing ManNAc as a therapy for GNE myopathy.

What is Involved?

This study collects genetic and medical information from people with GNE myopathy. Patients are followed over time to understand the symptoms and clinical course of GNE myopathy. This information is essential to prepare clinical treatment trials.

To be eligible to participate, individuals must be between 18 and 80 years of age, have GNE myopathy confirmed by genetic testing, and be able to travel.

During their first visit, participants will have the following tests:

  • Muscle strength and endurance tests, including walking
  • Medical history, physical exam and a neurological exam.
  • Questionnaires about the impact of the disease on daily activities and quality of life
  • Blood and urine samples
  • Heart and lung function tests
  • Imaging study of the leg muscles

Participants will return for follow-up visits every 6-12 months. Not all tests will be performed at each visit. Treatment will not be provided as part of this protocol.

For more information, view our Frequently Asked Questions about the study.

What is ManNAc?

ManNAc is an abbreviation for N-acetyl-D-mannosamine. ManNAc is an uncharged sugar and an intermediate molecule in the production of sialic acid within cells (See Figure). Patients with GNE myopathy have decreased GNE enzyme activity, and do not produce enough ManNAc or sialic acid. This deficiency results in a decreased attachment of sialic acid groups to skeletal muscle cells, which is thought to be the cause of the muscle wasting in GNE myopathy.

sialic acid pathway

Studies have shown that supplementation of ManNAc to cell cultures or to mice with a dysfunctional GNE protein (as in GNE myopathy) bypasses the need for GNE function and enables the production of sialic acid. Studies in mouse models of GNE myopathy have shown efficacy of oral ManNAc in mice with GNE Myopathy.

ManNAc is currently under investigation by NIH researchers in collaboration with Escala Therapeutics in an Open-Label Phase 2 study.

The FDA has provided an orphan designation for ManNAc to treat GNE Myopathy.

GNE Myopathy Team

If you are interested in joining our research group, we have opportunities for recent college graduates to spend a year engaged in biomedical investigation in our NHGRI laboratory through the Post-Baccalaureate Intramural Research Training Award (Post-Bac IRTA) program. We also have opportunities for an intramural postdoctoral fellowship or a medical fellowship.

Principle Investigators

Nuria Carrillo, M.D.
Principal Investigator of GNE Myopathy Clinical Studies at NIH
carrilln@mail.nih.gov

Dr. Carrillo follows one of the largest cohorts of national and international patients with GNE myopathy at the NIH Clinical Center. She is interested in understanding the natural history of the disease and advancing promising therapies for GNE myopathy. She has led multidisciplinary collaborations to develop endpoints, biomarkers and novel trial designs for GNE myopathy.

Marjan Huizing. Ph.D.
Staff Scientist, Clinical Project Manager
mhuizing@mail.nih.gov

Dr. Huizing studies disease mechanisms of GNE myopathy since 2001. Her team's studies on a mouse model of GNE myopathy identified that oral ManNAc therapy could increase tissue sialylation in a mouse model of GNE myopathy. She has been involved in all stages of clinical development of ManNAc for GNE myopathy at NIH.

May Christine Malicdan, M.D., Ph.D.
Staff Scientist
maychristine.malicdan@nih.gov

Dr. Malicdan joined the NIH research team in 2011. She studies disease mechanism and biomarker development of GNE myopathy. In 2009, Dr. Malicdan was the lead author of a landmark paper describing sialylation-increasing therapies in a mouse model of GNE myopathy, which completed as a graduate student in Dr. Nishino's laboratory (Tokyo, Japan).

William A. Gahl, M.D., Ph.D.
Clinical Director NHGRI
Director, NIH Undiagnosed Diseases Program

gahlw@helix.nih.gov

NIH Co-Investigators

Kennan Bradley, M.Sc.
Clinical Research Coordinator
kennan.bradley@nih.gov

Petcharat Leoyklang, Ph.D.
Postdoctoral Research Fellow
petcharat.leoyklang@nih.gov

Ashleigh Glowacki, B.Sc.
Postbaccalaureate intramural research trainee
ashleigh.glowacki@nih.gov

Carla Ciccone, M.Sc.
Biologist, Laboratory Manager
cciccone@mail.nih.gov

Related Clinical Studies

Ongoing, Not Recruiting:

An Open-Label Phase 2 Study ManNAc in Subjects with GNE Myopathy 

Upcoming Studies

Multicenter Trial of ManNAc for GNE Myopathy
Coming in 2018

Completed Studies

Phase 1 Study of ManNAc in Patients with GNE Myopathy

Intravenous Immune Globulin to Treat Hereditary Inclusion Body Myopathy

Contact Information

For Patients or Trial Enrollment

Kennan Bradley, M.Sc.
Clinical Research Coordinator
kennan.bradley@nih.gov

For Providers and Clinical Trials

Nuria Carrillo, M.D.
carrilln@mail.nih.gov
(301) 402-2324

For Basic Research

Marjan Huizing, Ph.D.
mhuizing@mail.nih.gov
(240) 893-4742

To Submit Medical Records

Fax: 301-402-0006

Address

NIH Clinical Center
10 Center Drive
Building 10, Room 10C103
Bethesda, MD 20895
USA

Additional Resources

News Releases

NIH Launches Trial to Evaluate Drug for Rare Degenerative Muscle Disease Treatment (2012)

New Zealand Pharmaceuticals Ltd Announces a phase I clinical trial using DEX-M74 to treat a rare degenerative muscle disease (2012)

Mouse Model Points to Possible New Strategy for Treating Rare Muscle Disease, Kidney Disorders (2007)

Lectures by NIH Investigators

Disorders of Sialic Acid Synthesis: Pathway and Prospects for Therapy
Presented February 2016: SBP Rare Disease Day Symposium 2016
Presenter: Marjan Huizing, Ph.D., NHGRI, NIH.

Advancing ManNAs as a Therapy for GNE Myopathy
Presented February 2015: SBP Rare Disease Day Symposium 2015
Presenter: Nuria Carrillo, M.D., NIH.

N-acetylmannosamine (ManNAc) or Sialic Acid as Therapy for Disorders of Hyposialylation
Presented February, 2012: SBP Rare Disease Day Symposium 2012
Presenter: Marjan Huizing, Ph.D., NHGRI, NIH.

Scientific Publications

2017

Garland, J., J. Stephen, B. Class, A. Gruber, C. Ciccone, A. Poliak, C. P. Hayes, V. Singhal, C. Slota, J. Perreault, R. Gavrilova, J. A. Shrader, P. Chittiboina, G. Joe, J. Heiss, W. A. Gahl, M. Huizing, N. Carrillo and M. C. V. Malicdan. Identification of an Alu element-mediated deletion in the promoter region of GNE in siblings with GNE myopathy. Mol Genet Genomic Med, 5(4):410-417. 2017. [PubMed]

Xu, X., A. Q. Wang, L. L. Latham, F. Celeste, C. Ciccone, M. C. Malicdan, B. Goldspiel, P. Terse, J. Cradock, N. Yang, S. Yorke, J. C. McKew, W. A. Gahl, M. Huizing and N. Carrillo. Safety, pharmacokinetics and sialic acid production after oral administration of N-acetylmannosamine (ManNAc) to subjects with GNE myopathy. Mol Genet Metab, April 26, 2017. [PubMed]

Slota C, Bevans M, Yang L, Shrader J, Joe G, Carrillo N. Patient reported outcomes in GNE myopathy: incorporating a valid assessment of physical function in a rare disease. Disabil Rehabil, Feb. 7:1-8. 2017. [PubMed]

2015

Shi Y, Xu X, Fang M, Zhang M, Li Y, Gillespie B, Yorke S, Yang N, McKew JC, Gahl WA, Huizing M, Carrillo-Carrasco N, Wang AQ. Quantitative hydrophilic interaction chromatography-mass spectrometry analysis of N-acetylneuraminic acid and N-acetylmannosamine in human plasma. Journal of Chromatography BAnalytical Technologies in the Biomedical Life Sciences, 000: 105-111. 2015. [PubMed]

Nishino I, Carrillo-Carrasco N, Argov Z. GNE myopathy: current update and future therapy. J Neurol Neurosurg Psychiatry, 86:385-392. 2015. [PubMed]

Hinderlich S, Weidemann W, Yardeni T, Horstkorte R, Huizing M. UDP-GlcNAc 2-epimerase/ ManNAc kinase (GNE): A master regulator of sialic acid synthesis. Topics in Current Chemistry, 366:97-137. 2015. [PubMed]

2014

Huizing M, Malicdan MC, Krasnewich DM, Manoli I, Carrillo-Carrasco N. GNE Myopathy. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. eds. OMMBID - The Online Metabolic and Molecular Bases of Inherited Diseases. New York: McGraw-Hill; 2014.

de Dios JK, Shrader JA, Joe GO, McClean JC, Williams K, Evers R, Malicdan MC, Ciccone C, Mankodi A, Huizing M, McKew JC, Bluemke DA, Gahl WA, Carrillo-Carrasco N. Atypical presentation of GNE myopathy with asymmetric hand weakness. Neuromuscular Disorders, 24: 1063-1067. 2014. [PubMed]

Celeste F, Vilboux T, Ciccone C, de Dios JK, Malicdan MC, Leoyklang P, McKew JC, Gahl WA, Carrillo-Carrasco N, Huizing M. Mutation Update for GNE Gene Variants Associated with GNE Myopathy. Human Mutation, 35: 915-926. 2014. [PubMed]

Leoyklang P, Malicdan MC, Yardeni T, Celeste F, Ciccone C, Li X, Jiang R, Gahl WA, Carrillo-Carrasco N, He M, Huizing M. Sialylation of Thomsen-Friedenreich antigen is a noninvasive blood-based biomarker for GNE myopathy. Biomarkers in Medicine, 8:641-652. 2014. [PubMed]

Huizing M, Carrillo-Carrasco N, Malicdan MC, Noguchi S, Gahl WA, Mitrani-Rosenbaum S, Argov Z, Nishino I. GNE myopathy: new name and new mutation nomenclature. Neuromuscular Disorders, 24: 387-389. 2014. [PubMed]

Patzel KA, Yardeni T, Le Poëc-Celic E, Leoyklang P, Dorward H, Alonzi DS, Kukushkin NV, Xu B, Zhang Y, Sollogoub M, Blériot Y, Gahl WA, Huizing M, Butters TD. Non-specific accumulation of glycosphingolipids in GNE myopathy. Journal of Inherited Metabolic Disease, 37:297-308. 2014. [PubMed]

2013

Yardeni T, Jacobs K, Niethamer TK, Ciccone C, Anikster Y, Kurochkina N, Gahl WA, Huizing M. Murine isoforms of UDP-GlcNAc 2-epimerase/ManNAc kinase: Secondary structures, expression profiles, and response to ManNAc therapy. Glycoconjugate Journal, 30:609-618. 2013. [PubMed]

2012

Niethamer TK, Yardeni T, Leoyklang P, Ciccone C, Astiz-Martinez A, Jacobs K, Dorward HM, Zerfas PM, Gahl WA, Huizing M. Oral monosaccharide therapies to reverse renal and muscle hyposialylation in a mouse model of GNE myopathy. Molecular Genetics and Metabolism, 107:748-755. 2012. [PubMed]

Kakani S, Yardeni T, Poling J, Ciccone C, Niethamer T, Klootwijk RD, Manoli I, Darvish D, Hoogstraten-Miller S, Zerfas P, Tian E, Ten Hagen KG, Kopp JB, Gahl WA, Huizing M. The Gne M712T mouse as a model for human glomerulopathy. The American Journal of Pathology , 180:1431-1440. 2012. [PubMed]

2011

Nemunaitis G, Jay CM, Maples PB, Gahl WA, Huizing M, Yardeni T, Tong AW, Phadke AP, Pappen BO, Bedell C, Allen H, Hernandez C, Templeton NS, Kuhn J, Senzer N, Nemunaitis J. Hereditary Inclusion Body Myopathy: Single Patient Response to Intravenous Dosing of GNE Gene Lipoplex. Human Gene Therapy, 22:1331-1341. 2011. [PubMed]

Yardeni T, Choekyi T, Jacobs K, Ciccone C, Patzel K, Anikster Y, Gahl WA, Kurochkina N, Huizing M. Identification, Tissue Distribution and Molecular Modeling of Novel Human Isoforms of the Key Enzyme in Sialic Acid Synthesis, UDP-GlcNAc 2-epimerase/ManNAc Kinase. Biochemistry, 50:8914-8925. 2011. [PubMed]

2010

Nemunaitis G, Maples PB, Jay C, Gahl WA, Huizing M, Poling J, Tong AW, Phadke AP, Pappen BO, Bedell C, Templeton NS, Kuhn J, Senzer N, Nemunaitis J. Hereditary Inclusion Body Myopathy: Single Patient Response to GNE Gene Lipoplex Therapy. The Journal of Gene Medicine, 12:403-412. 2010. [PubMed]

Voermans NC, Guillard M, Doedée R, Lammens M, Huizing M, Padberg GW, Wevers RA, van Engelen BG, Lefeber DJ. Clinical features, lectin staining, and a novel GNE frameshift mutation Hereditary Inclusion Body Myopathy. Clinical Neuropathology, 29:71-77. 2010. [PubMed]

Kurochkina N, Yardeni T, Huizing M. Molecular modeling of the bifunctional enzyme uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase and predictions of structural effects of mutations associated with HIBM and sialuria. Gycobiology, 20:322-337. 2010. [PubMed]

2009

Huizing M, Krasnewich DM. Hereditary Inclusion Body myopathy: A decade of progress. Biochimica et Biophysica Acta, Molecular Basis of Disease, 1792:881-887. 2009. [PubMed]

2007

Galeano B, Klootwijk R, Manoli I, Sun MS, Ciccone C, Darvish D, Starost MF, Zerfas PM, Hoffmann VJ, Hoogstraten-Miller S, Krasnewich DM, Gahl WA, Huizing M. N-Acetylmannosamine treatment rescues UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase knock-in mice from severe neonatal glomerular hematuria and podocytopathy. Journal of Clinical Investigation, 17:1585-1594. 2007. [PubMed]

Sparks S, Rakocevic G, Joe G, Manoli I, Shrader J, Sonies B, Ciccone C, Dorward H, Krasnewich D, Huizing M, Dalakas M, Gahl W. Pilot Study of the Use of Intravenous Immune Globulin in Hereditary Inclusion Body Myopathy. BMC Neurology, 7:3. [PubMed]

2006

Savelkoul PJM, Manoli I, Sparks S, Ciccone C, Gahl WA, Krasnewich DM, Huizing M. Normal sialylation status of N-linked and O-GalNAc linked glycans in Hereditary Inclusion Body Myopathy. Molecular Genetics and Metabolism, 88:389-390. 2006. [PubMed]

2005

Sparks SE, Ciccone C, Lalor M, Orvisky E, Klootwijk R, Savelkoul PJ, Dalakas MC, Krasnewich DM, Gahl WA, Huizing M. Use of a cell-free system to determine UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities in human Hereditary Inclusion Body Myopathy. Glycobiology, 15:1102-1110. 2005. [PubMed]

Gottlieb E, Ciccone C, Darvish D, Naiem S, Dalakas MC, Savelkoul PJ, Krasnewich DM, Gahl WA, Huizing M. Single nucleotide polymorphisms within the dystroglycan gene in hereditary inclusion body myopathy. Molecular Genetics and Metabolism, 86: 244-249. 2005. [PubMed]

2004

Huizing M, Rakocevic G, Sparks SE, Mamali I, Shatunov A, Goldfarb L, Krasnewich D, Gahl WA, Dalakas M. Hypoglycosylation of α-dystroglycan in patients with hereditary IBM due to GNE mutations. Molecular Genetics and Metabolism, 81:196-202. 2004. [PubMed]

Contacts

Nuria Carrillo
Nuria Carrillo, Ph.D.
  • Principal Investigator, NIH GNE Myopathy Team
  • Human Biochemical Genetics Section
Marjan Huizing, Ph.D.
Marjan Huizing, Ph.D.
  • Staff Scientist
  • Medical Genetics Branch

Last updated: January 2, 2018