Heritability of frontotemporal dementia

One of my side projects over the past 2 years has been research in the cognitive neurosciences under the supervision of Dr James Burrell at Neuroscience Research Australia (NeuRA). Specifically, we were looking at the heritability of frontotemporal dementia.

Preliminary results from our study were published as a poster at the Australian and New Zealand Association of Neurologists (ANZAN) Annual Scientific Meeting 2014 in Adelaide. I doubt that anyone else at a neurology conference would typeset a poster in Helvetica Neue Light!

Our poster at ANZAN ASM 2014

This culminated in a paper which was accepted in the Journal of Neurology and published in November 2014 (vol 261 no 11). The abstract is reproduced below, along with the correct author affiliations (an error was introduced by the journal subeditors – Professors Kwok, Halliday and Hodges are not affiliated with Concord Repatriation General Hospital).

Po et al. J Neurol 2014

Author Affiliations

Concord Repatriation General Hospital, Sydney, Australia – KP, JB
Sydney Medical School, The University of Sydney, Australia – KP
Neurosciences Research Australia, Sydney, Australia – FL, NG, LB, JK, GH, JH, JB
The University of New South Wales, Sydney, Australia – JK, GH, JH, JB

Abstract

Frontotemporal dementia (FTD) is reportedly highly heritable, even though a recognized genetic cause is often absent. To explain this contradiction, we explored the “strength” of family history in FTD, Alzheimer’s disease (AD), and controls. Clinical syndromes associated with heritability of FTD and AD were also examined. FTD and AD patients were recruited from an FTD-specific research clinic, and patients were further sub-classified into FTD or AD phenotypes. The strength of family history was graded using the Goldman score (GS), and GS of 1-3 was regarded as a “strong” family history. A subset of FTD patients underwent screening for the main genetic causes of FTD. In total, 307 participants were included (122 FTD, 98 AD, and 87 controls). Although reported positive family history did not differ between groups, a strong family history was more common in FTD (FTD 17.2 %, AD 5.1 %, controls 2.3 %, P < 0.001). The bvFTD and FTD-ALS groups drove heritability, but 12.2 % of atypical AD patients also had a strong family history. A pathogenic mutation was identified in 16 FTD patients (10 C9ORF72 repeat expansion, 5 GRN, 1 MAPT), but more than half of FTD patients with a strong family history had no mutation detected. FTD is a highly heritable disease, even more than AD, and patients with bvFTD and FTD-ALS drive this heritability. Atypical AD also appears to be more heritable than typical AD. These results suggest that further genetic influences await discovery in FTD.

Citation

Po K, Leslie FVC, Gracia N, Bartley L, Kwok JBJ, Halliday GM, Hodges JR, Burrell JR. Heritability in frontotemporal dementia: more missing pieces? J Neurol. 2014;261(11):2170–7.

doi: 10.1007/s00415-014-7474-9
PMID: 25156163 (PubMed)

HbA1c now funded for diagnosis

From 1 November 2014, glycated haemoglobin (HbA1c) testing is now funded on the Medicare Benefits Schedule for the diagnosis of diabetes mellitus – MBS item 66841 (up to once every 12 months).

MBS item 66841

The Australian Diabetes Society and other international organisations have recommended since 2011 that an HbA1c ≥48 mmol/mol (≥6.5%) can be used to establish a diagnosis of diabetes.1 Until now this has been impracticable in Australia as it was only Medicare-funded for patients with established diabetes, however this new listing on the MBS provides clinicians with a more practical and efficient way to make the diagnosis.

Reference:
1. d’Emden M, et al. The role of HbA1c in the diagnosis of diabetes mellitus in Australia. Med J Aust 2012;197:220–1. (full text)

RACP exams

“Congratulations. You have been successful in the 2014 Clinical Examination.”

Getting through the Royal Australasian College of Physicians (RACP) examinations this year has been a long, difficult, but ultimately rewarding journey. More than a year of near-constant study, the evening lectures at work and online, the Deltamed course in Melbourne, the written exam at Wentworth Park (with the plastic picnic chairs!), a brief period of respite after passing the written, the many evenings and Saturday mornings spent at the hospital practising cases, and finally the clinical exam held interstate (in my case Greenslopes Private Hospital, Brisbane)…

Greenslopes Private Hospital

My colleagues and I are immensely grateful to everyone who taught and supported us over the past 18 months – we couldn’t have done it without you. Thank you!

Photo credits: Dr Kieren Po (photos 1 & 3), Dr Priyanka Sagar (photo 2)

eGFR vs CrCl

Estimated glomerular filtration rate (eGFR) and creatinine clearance (CrCl) are often, incorrectly, used interchangeably when discussing renal function and drug dose adjustment.

Creatinine clearance, usually estimated using the 1976 Cockcroft-Gault formula rather than actually measured by (notoriously unreliable) 24-hour urine collection, has traditionally been used for drug dosing as it is relatively standardised despite overestimating renal function due to tubular secretion of creatinine. In addition to the usual caveats associated with basing renal function estimates on serum creatinine (acute illness, muscle mass, diet, etc), accuracy of the formula is limited by changes to serum creatinine assays and the rise in obesity since 1976.

Renal function is assessed nowadays using formula-derived eGFR (actual GFR is impracticable to measure routintely). Until recently this was usually calculated using the MDRD formula (1999), which has been well validated but has limited accuracy above 60 mL/min. Laboratories in Australia now report eGFR calculated using the superior CKD-EPI formula (2009). Although both of these formulae give better estimates of true renal function (GFR) than CrCl, they are both still based on serum creatinine with its associated caveats above.

Some studies have shown a reasonable concordance between CrCl (Cockcroft-Gault) and eGFR (MDRD) with respect to drug dosing,1 whereas others have noted significant differences.2–3 At the end of the day, CrCl and eGFR are not the same thing and prescribers should remain vigilant as to which measurement has been used to formulate dosage adjustment recommendations.

References:
1. Stevens LA, et al. Am J Kidney Dis 2009;54:3342
2. Wargo KA, et al. Ann Pharmacother 2006;40:124853
3. Park EJ, et al. Ann Pharmacother 2012;46:117487

Biotechnology descriptors

Whilst giving a presentation at grand rounds recently, I noted that approved names for biological medications in Australia are suffixed with a three-letter abbreviation – the “biotechnology descriptor” – to indicate the biotechnology production system used, e.g. insulin lispro (rbe).

The most common biotechnology descriptors are:

  • ghu – gene-activated human cell line
  • rbe – recombinant bacteria Escherichia coli
  • rch – recombinant Chinese Hamster ovary cell line
  • rmc – recombinant mouse cell line
  • rys – recombinant yeast Saccharomyces cerevisiae

Incidentally, I cringe whenever someone refers to this group of medications as “biologics” – an Americanism that has crept into the Australian medical lexicon. Australian English still retains the “-ical” ending (rather than shortening to “-ic” in American English), therefore we should continue to refer to these medications as “biologicals”.

A day in the life of a medical registrar

14 new patients post-take (1 DOA)
7am consultant rounds
Interviewed by the police
Discussion with an Assistant Coroner
Rescued from a difficult dilemma by one of the geriatricians (again)
Spoke with the hospital Director of Medical Services
AWOL patient urinating on the hospital front lawn
Challenging discussions with families about end-of-life issues
Asked for two consults at 4pm (because my consultant specifically wanted me to ask)
Somehow didn’t get shouted at for the late consults
Finished my ward round after-hours
Left the hospital at 7.30pm

… and very grateful for my fantastic intern Angela!