title: Alkaptonuria: An example of a "fundamental disease"--A rare disease with important lessons for more common disorders.
abstract: "Fundamental diseases" is a term introduced by the charity Findacure to describe rare genetic disorders that are gateways to understanding common conditions and human physiology. The concept that rare diseases have important lessons for biomedical science has been recognised by some of the great figures in the history of medical research, including Harvey, Bateson and Garrod. Here we describe some of the recently discovered lessons from the study of the iconic genetic disease alkaptonuria (AKU), which have shed new light on understanding the pathogenesis of osteoarthritis. In AKU, ochronotic pigment is deposited in cartilage when collagen fibrils become susceptible to attack by homogentisic acid (HGA). When HGA binds to collagen, cartilage matrix becomes stiffened, resulting in the aberrant transmission of loading to underlying subchondral bone. Aberrant loading leads to the formation of pathophysiological structures including trabecular excrescences and high density mineralised protrusions (HDMPs). These structures initially identified in AKU have subsequently been found in more common osteoarthritis and appear to play a role in joint destruction in both diseases.
authors.affiliation: Musculoskeletal Biology, University of Liverpool, Apex Building, Liverpool L7 8TX, UK. Electronic address: jag1@liv.ac.uk.
authors.forename: James A
authors.initials: JA
authors.lastname: Gallagher
authors.affiliation: Musculoskeletal Biology, University of Liverpool, Apex Building, Liverpool L7 8TX, UK. Electronic address: dillon@liv.ac.uk.
authors.forename: Jane P
authors.initials: JP
authors.lastname: Dillon
authors.affiliation: Findacure, 66 Devonshire Road, Cambridge CB1 2BL, UK. Electronic address: nick@findacure.org.uk.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sireau
authors.affiliation: AKU Society, 66 Devonshire Road, Cambridge CB1 2BL, UK. Electronic address: oliver@akusociety.org.
authors.forename: Oliver
authors.initials: O
authors.lastname: Timmis
authors.affiliation: Musculoskeletal Biology, University of Liverpool, Apex Building, Liverpool L7 8TX, UK; Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Prescot Street,Liverpool L7 8XP, UK. Electronic address: lrang@liv.ac.uk.
authors.forename: Lakshminarayan R
authors.initials: LR
authors.lastname: Ranganath
mesh_terms: D000474:Alkaptonuria / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D006801:Humans; D051379:Mice; D009794:Ochronosis / Q000209:etiology / Q000503:physiopathology; D010003:Osteoarthritis / Q000209:etiology / Q000503:physiopathology; D035583:Rare Diseases / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology
keywords: Alkaptonuria; Exposed collagen hypothesis; Fundamental disease; High density mineralised protrusions (HDMPs); Osteoarthritis; Rare disease; Trabecular excrescences