REPATRIATION MEDICAL AUTHORITY
STATEMENT OF REASONS
REGARDING THE OUTCOME OF THE INVESTIGATION INTO ALKAPTONURIA
Part I
INTRODUCTION ............................................................................................................3
Part II
Background to the Investigation .....................................................................................3
Part III
Submissions received by the Authority pursuant to section 196F ..................................3
Part IV
Evidence/Information Available to the Repatriation Medical Authority ...........................3
Part V
Disease and injury ..........................................................................................................4
Part VI
Reasons for the decision ................................................................................................5
Existing Factors .......................................................................................................................... 5
Factors 6(a) and (b) ............................................................................................................ 5
Factor 6(c) - Inability ........................................................................................................... 5
No other Factors ........................................................................................................................ 6
Conclusion.................................................................................................................................. 6
Part VII
Decision ..........................................................................................................................6
Part VIII
Bibliography ....................................................................................................................7
Statement of Reasons – Re: Investigation into Alkaptonuria
Page 2 of 8
PART I
INTRODUCTION
1.
The Repatriation Medical Authority (the Authority) has decided to revoke the
Statements of Principles Instrument Nos. 47 and 48 of 2007 concerning
alkaptonuria, in accordance with subsection 196B(9) of the Veterans’ Entitlements
Act 1986 (the Act), following notice of an investigation gazetted on 31 October 2012
in the Commonwealth of Australia Gazette.
2.
On consideration of the sound medical-scientific evidence available to the Authority
concerning alkaptonuria, the Authority formed the view that this condition does not
have any factors which can be related to service as defined in subsection 196B(14)
of the Act.
PART II
3.
BACKGROUND TO THE INVESTIGATION
Alkaptonuria is defined in Statements of Principles Instrument Nos 47 and 48 of
2007 as:
a genetic metabolic disorder heritable as an autosomal recessive trait, characterised by
deficiency of the hepatic enzyme homogentisic acid oxidase. This leads to the accumulation
of homogentisic acid, a metabolite of tyrosine in connective tissues of various organs.
4.
The Repatriation Medical Authority, under section 196G of the Act, decided to
review the contents of the Statements of Principles, to find out if there is new
information available about how alkaptonuria may be contracted, or death from
alkaptonuria may occur, or the extent to which alkaptonuria or death from
alkaptonuria may be due to eligible service.
5.
The notice of investigation was signed by the Chairperson of the Authority on
22 October 2012 and was gazetted in accordance with section 196G of the Act in
the Commonwealth of Australia Gazette on 31 October 2012. Submissions were
invited from persons and organisations wishing to make a submission by 4 April
2014.
PART III
SUBMISSIONS RECEIVED BY THE AUTHORITY PURSUANT TO SECTION 196F
6.
PART IV
7.
Following notification of its investigation, the Authority did not receive any
information from persons or organisations eligible to make submissions pursuant to
section 196F of the Act.
EVIDENCE/INFORMATION AVAILABLE TO THE REPATRIATION MEDICAL
AUTHORITY
The following information was available to the Authority.
Statement of Reasons – Re: Investigation into Alkaptonuria
Page 3 of 8
7.1. A literature search conducted using Pubmed for any relevant articles
concerning alkaptonuria. Recent review articles were obtained.
7.2. Medical or scientific publications as set out in the bibliography attached
hereto.
7.3. Briefing papers prepared for presentation to the Authority by a research officer
of the Secretariat.
8.
PART V
9.
On 10 December 2014 the Authority considered the draft Declaration and
Statements of Reasons concerning alkaptonuria. A decision was made to consult
with the major national Ex-Service Organisations (ESOs) regarding the revocation
of the alkaptonuria Statements of Principles and review any submissions received
at the April 2015 meeting before proceeding with the revocation. No submissions
were received.
DISEASE AND INJURY
Section 196B(14) of the Act, states as follows:
(14) A factor causing, or contributing to, an injury, disease or death is related to service
rendered by a person if:
(a) it resulted from an occurrence that happened while the person was rendering that
service; or
(b) it arose out of, or was attributable to, that service; or
(c) it resulted from an accident that occurred while the person was travelling, while
rendering that service but otherwise than in the course of duty, on a journey:
(i) to a place for the purpose of performing duty; or
(ii) away from a place of duty upon having ceased to perform duty; or
(d) it was contributed to in a material degree by, or was aggravated by, that service; or
(e) in the case of a factor causing, or contributing to, an injury—it resulted from an accident
that would not have occurred:
(i) but for the rendering of that service by the person; or
(ii) but for changes in the person’s environment consequent upon his or her having
rendered that service; or
(f) in the case of a factor causing, or contributing to, a disease—it would not have occurred:
(i) but for the rendering of that service by the person; or
(ii) but for changes in the person’s environment consequent upon his or her having
rendered that service; or
(g) in the case of a factor causing, or contributing to, the death of a person—it was due to
an accident that would not have occurred, or to a disease that would not have been
contracted:
(i) but for the rendering of that service by the person; or
Statement of Reasons – Re: Investigation into Alkaptonuria
Page 4 of 8
(ii) but for changes in the person’s environment consequent upon his or her having
rendered that service.
10.
Section 196B(14) above, outlines how a factor may cause or contribute to a
disease, injury or death, in relation to service rendered by a person.
11.
The Authority relied upon its expert medical knowledge when considering whether
any risk factors were associated with alkaptonuria and if these factors could be
related to the service rendered by a person.
PART VI
REASONS FOR THE DECISION
12.
The Authority previously determined that alkaptonuria (Instruments Nos. 47 and 48
of 2007) could be related to relevant service.
13.
Having further considered and evaluated the sound medical-scientific evidence
available to it as part of the review, the Authority is now of the view that the
evidence is insufficient to justify the making of Statements of Principles or the
amendment of the existing Statements of Principles as alkaptonuria does not have
any factors which can be related to service, in accordance with subsection 196B(14)
of the Act.
Existing Factors
14.
The current factors in Statements of Principles Instrument Nos. 47 & 48 of 2007
concerning alkaptonuria, determined under subsections 196B(2) and (3), are as
follows:
6(a)
having cirrhosis of the liver at the time of the clinical worsening of alkaptonuria; or
6(b)
having moderate to severe renal failure at the time of the clinical worsening of
alkaptonuria; or
6(c)
inability to obtain appropriate clinical management for alkaptonuria.
Factors 6(a) and (b)
15.
The sound medical-scientific evidence in relation to these factors is limited to a few
case reports only, and having evaluated and considered that evidence the Authority
concluded that the direction of effect was unclear and that in these cases it is likely
that alkaptonuria worsened the pre-existing liver or renal failure, rather than the liver
or renal failure worsening the alkaptonuria.
Factor 6(c) - Inability
16.
The treatments generally prescribed for this condition include dietary restriction and
enzyme inhibitors. Having considered and evaluated the sound medical-scientific
evidence the Authority concluded that the clinical benefits of these interventions are
uncertain and, as there is no effective clinical management available for
Statement of Reasons – Re: Investigation into Alkaptonuria
Page 5 of 8
alkaptonuria, there is no basis to include a factor relating to an inability to obtain
appropriate clinical management for this condition.
No other Factors
17.
Having regard to the sound medical-scientific evidence only and having considered
and evaluated it, the Authority is of the view that there is no other factor by which
alkaptonuria can be related to service.
Conclusion
18.
The Authority concluded that the sound medical-scientific evidence available to it is
insufficient to justify the making of Statements of Principles and that the existing
Statements of Principles, Instrument Nos. 47 and 48 of 2007 concerning
alkaptonuria, should be revoked.
PART VII
19.
DECISION
At its meeting on 1 October 2014 the Authority decided not to make a Statement of
Principles in respect of alkaptonuria for the purposes of subsection (9) of section
196B of the Act as the Authority concluded, for the reasons set out above, that there
are no applicable factors which can be related to service.
Statement of Reasons – Re: Investigation into Alkaptonuria
Page 6 of 8
PART VIII
BIBLIOGRAPHY
RMA ID
Number
39307
39313
39316
39312
39310
39315
43782
39314
39435
39437
39308
39425
39434
15968
33794
39436
41470
71738
Reference List
Al-Essa M, Al-Shamsan L, Rashed MS, Ozand PT (1998). Alkaptonuria:
case report and review of the literature. Obtained from
http://www.kfshrc.edu.sa/annals/185/98-055.html
Alkaptonuria (Ochronosis). Obtained from
http://www.medicinenet.com/script/main/art.asp?articlekey=7804&pf=3&pa
ge=1
Alkaptonuria and Ochronosis. Obtained from
http://healthlink.mcw.edu/content/printer_friendly/article_printer_friendly?9
21733488
Alkaptonuria. Genetics Home Reference. Obtained from
http://ghr.nlm.nih.gov/condition=alkaptonuria
Alkaptonuria. Harrison's Internal Medicine, Part 14 Section 3 Chapter 343.
Obtained from
http://www.accessmedicine.com/popup.aspx?aID=103567&print=yes
Alkaptonuria. Obtained from http://en.wikipedia.org/wiki/alkaptonuria
Alkaptonuria. Obtained from
http://www.mercksource.com/pp/us/cns/cns_hl_dorlands.jspzQzpgzEzzSz
ppdocszSzuszSzcommonzSzdorlandszSzdorlandzSzdmd_a_24zPzhtm
Alkaptonuria. Obtained from
http://www.nlm.nih.gov/medlineplus/ency/article/001200.htm
Balint G, Szebenyi B (2000). Hereditary disorders mimicking and/or
causing premature osteoarthritis. Balliere's Clinical Rheumatology, 14(2)
pp 219-250.
Borman P, Bodur H, Ciliz D (2002). Ochronotic arthropathy. Rheumatol Int,
Vol 21 pp 205-209.
Causes of secondary osteoarthritis. Metabolic and endocrine disorders.
Ochronosis. Obtained from
http://www.acpmedicine.com/acpmedicine/highlight/highlighter.asp
Cetinus E, Cever I, Kural C, Erturk H, Akyildiz M (2005). Ochronotic
arthritis: case reports and review of the literature. Rheumatol Int, Vol 25 pp
465-468.
Collins EJ, Hand R (2005). Alkaptonuric ochronosis: a case report. AANA
Journal, 73(1) pp 41-46.
Corrigan FM, Murray L, Wyatt CL et al (1998). Diorthosubstituted
polychlorinated biphenyls in caudate nucleus in Parkinson's disease.
Experimental Neurology, 150: 339-42.
Deng Y, Newman B, Dunne MP et al (2004). [Comment] Further evidence
that interactions between CYP2D6 and pesticide exposure increase risk
for Parkinson's Disease. Annals of Neurology, 55(6): 897.
Fisher AA, Davis MW (2004). Alkaptonuric ochronosis with aortic valve
and joint replacements and femoral fracture. Clinical Medicine & Research,
2(4) pp 209-215.
Glomerular Filtration Rate (GFR) (2006). National Kidney Foundation.
Obtained from http://www.kidney.org/kidneydisease/ckd/knowGFR.cfm
Grompe M (2012). Disorders of tyrosine metabolism. . Retrieved 10 June
2014, from http://www.uptodate.com/contents/disorders-of-tyrosinemetabolism?
Statement of Reasons – Re: Investigation into Alkaptonuria
Page 7 of 8
39430
39428
39424
39652
39433
39431
39427
39432
39612
39429
23219
41023
39317
71740
71739
39426
39311
39683
39309
Introne WJ, Phornphutkul C, Bernardini I, McLaughlin K, Fitzpatrick D,
Gahl WA (2002). Exacerbation of the ochronosis of alkaptonuria due to
renal insufficiency and improvement after renal transplantation. Molecular
Genetics and Metabolism, Vol 77 pp 136-142.
Keller JM, Macaulay W, Nercessian OA, Jaffe IA (2005). New
developments in ochronosis: review of the literature. Rheumatol Int, Vol 25
pp 81-85.
Kobak AC, Oder G, Kobak S, Argin M, Inal V (2005). Ochronotic
arthropathy. Disappearance of alkaptonuria after liver transplantation for
hepatitis B-related cirrhosis. Journal of Clinical Rheumatology, 11(6) pp
323-325.
La Du BN Jr (1991). Alcaptonuria and Ochronotic Arthritis. Molecular
Biology & Medicine, Vol 8 pp 31-38.
La Du BN Jr (1998). Are we ready to cure alkaptonuria? Invited editorial.
Am J Hum Genet, Vol 62 pp 765-767.
Lubics A, Schneider I, Sebok B, Havass Z (2000). Extensive bluish gray
skin pigmentation and sever arthropathy. Arch Dermatol, 136(4) pp 547552.
Mannoni A, Selvi E, Lorenzini S, Giorgi M, Airo P, Cammelli D, et al
(2004). Alkaptonuria, ochronosis, and ochronotic arthropathy. Seminars in
Arthritis and Rheumatism, 33(4) pp 239-248.
Mayatepek E, Kallas K, Anninos A, Muller E (1998). [Letter] Effects of
ascorbic acid and low-protein diet in alkaptonuria. European Journal of
Pediatrics, 157(10) pp 867-868.
Moghtaderi S, Rokito AS, Zuckerman JD (2005). Ochronotic Arthropathy: a
report of 3 cases. Am J Orthopedics, 34(3) pp 136-139.
Morava E, Kosztolanyi G, Engelke UFH, Wevers RA (2003). Reversal of
clinical symptoms and radiographic abnormalities with protein restriction
and ascorbic acid in alkaptonuria. Case report. Ann Clin Biochem, Vol 40
pp 108-111.
Reddy DR, Prasad VSSV (1998). Alkaptonuria presenting as lumbar disc
prolapse: case report and review of literature. Spinal Cord, Vol 36 pp 523524.
Renal failure (2006). Obtained from http://www.answers.com/topic/renalfailure-1
Roth KS (2005). Alkaptonuria. Obtained from http://www.emedicine.com/
Roth KS (2013). Alkaptonuria Treatment & Management. . Retrieved 10
June 2014, from http://emedicine.medscape.com/article/941530-treatment
Roth KS (2013). Alkaptonuria. . Retrieved 10 June 2014, from
http://emedicine.medscape.com/article/941530-overview
Suwannarat P, Phornphutkul C, Bernardini I, Turner M, Gahl WA (2004).
Minocycline-induced hyperpigmentation masquerading as alkaptonuria in
individuals with joint pain. Arthritis & Rheumatism, 50(11) pp 3698-3701.
Suwannarat P, Phornphutkul C, Introne W, Gahl WA (2005). Alkaptonuria.
Obtained from
http://www.genetests.org/servlet/access?id=8888890&key=aQ7HpRZEjbX
Pa&gry=I
Venkataseshan VS, Chandra B, Graziano V, Steinlauf P, Marquet E,
Irmiere V, Needle MA (1992). Alkaptonuria and renal failure: a case report
and review of the literature. Distinctive Case. Modern Pathology, 5(4) pp
464-471.
Wise C (2006). Osteoarthritis. Obtained from
http://www.acpmedicine.com/acpmedicine/highlight/highlighter.asp, : .
Statement of Reasons – Re: Investigation into Alkaptonuria
Page 8 of 8