Genetics

Will Australia’s current regulatory framework protect consumers?

Dianne Nicol PhD(Biology), LLM · Meredith Hagger LLB(Hons)

Tailoring interventions for the variable behaviours in individuals with autism ultimately depends on determining the neurobiological causes of these behaviours.

Andrew J O Whitehouse PhD · Fiona J Stanley MB BS, MSc, MD

Objectives: To evaluate the outcomes of preconception screening of Jewish Australians for Tay Sachs disease (TSD) carrier status on Jewish TSD-affected births.Design, participants and setting: Epidemiological observational study involving a complete retrospective audit of infantile and intermediate TSD cases diagnosed in Sydney and Melbourne between 1 January 1995 and 31 December 2011 (Royal Children’s Hospital Melbourne; Pacific Laboratory Medicine Services, Pathology North, NSW Health Pathology, Sydney; ...

Raelia M Lew MB BS(Hons) MMed · Anne L Proos MSc, FFSc(RCPA) · Leslie Burnett MB BS, PhD, FRCPA · Martin Delatycki MB BS, FRACP, PhD · Agnes Bankier MB BS, FRACP · Michael J Fietz PhD

Marfan syndrome is a multisystem disorder of connective tissue that is inherited in an autosomal dominant fashion, and results from mutation of the FBN1 gene on human chromosome 15. There are a number of conditions of the connective tissue with a similar phenotype that can be confused with Marfan syndrome. Modifications of the diagnostic criteria have recently been published, facilitating the differentiation of Marfan ...

Kim M Summers BSc(Hons) PhD · Jennifer A West RN · Annette Hattam BSc, FHGSA · Denis Stark MB BS, FRCS(Edin), FRANZCO · James J McGill MB BS, FRACP · Malcolm J West MBBS, FRACP, PhD

To the Editor: Kowal’s article resonates with our experience.1 However, the National Health and Medical Research Council has supported genetic testing in Indigenous Australians for longer than she cites. Through a 1995–1997 project grant, a 1998 PhD scholarship,2,3 a 2006 program grant and an Australia Research Fellowship (2008–), the NHMRC has supported work on kidney and related chronic diseases, in protocols endorsed by two remote communities and approved ...

Wendy E Hoy

To the Editor: We read with interest the article by Kowal about genetic research in Indigenous health.1 As stated, this topic is extremely sensitive, but it is one that we must now tackle. The article raises a related issue that has not received any attention: the provision of genetic health services to Aboriginal and Torres Strait Islander people. We should not presume that Aboriginal and Torres ...

Gail Garvey · Christina M Bernardes

In reply: I thank Hoy, and Garvey and Bernardes, for their responses. Hoy highlights the difficulties her group has experienced in conducting genetic research in an Aboriginal community over two decades. Indeed, this was the project I referred to as losing its ethics approval as a direct result of the Human Genome Diversity Project. She attributes the difficulties she has faced to conflicting views between ...

Emma E Kowal

About 80% of congenital heart disease (CHD) is multifactorial and arises through various combinations of genetic and environmental contributors. About 20% of cases can be attributed to chromosomal anomalies, Mendelian syndromes, non-syndromal single gene disorders or teratogens. Down syndrome and velocardiofacial syndrome are the most commonly seen syndromes in patients with CHD. To date, more than 30 genes have been linked to non-syndromal forms ...

Gillian M Blue MSc, GradDipGenCouns · Edwin P Kirk MB BS, PhD, FRACP · Gary F Sholler MB BS, FRACP · Richard P Harvey PhD · David S Winlaw MB BS, MD, FRACS

Objective: To compare three cystic fibrosis (CF) newborn screening strategies used in Victoria since 1989.Design, setting and participants: Retrospective review of newborn screening and clinical records for people with CF born in Victoria between 1989 and 2008 to compare screening strategies: repeat immunoreactive trypsinogen (IRT) testing (IRT/IRT, 1989–1990), IRT and p.F508del mutation analysis (IRT/p.F508del, 1991–2006) and IRT with analysis of 12 CFTR mutations (IRT/12 mutations, 2007–2008).Main outcome measures: Total number of infants screened, people identified with CF (by screening or clinical diagnosis), number of CF-affected terminations of pregnancy, and number of carriers detected.Results: There were 420 people born with CF (live-birth prevalence, 1/3139; 95% CI, 1/2853–1/3462) and 78 CF-affected pregnancy terminations (overall prevalence, 1/2647; 95% CI, 1/2425–1/2896). Of the babies born with CF, 283 (67.4%) were detected by newborn screening alone, 61 (14.5%) had meconium ileus, 33 (7.9%) had a family history of CF, nine (2.1%) were diagnosed antenatally, and 34 (8.1%) were missed by screening (17 missed because IRT level was < 99th percentile, two with repeat IRT level not elevated, 14 without a screened CFTR mutation, and one with missing data). The sensitivities of the protocols were 86.6% for IRT/IRT, 89.9% for IRT/p.F508del, and 95.8% for IRT/12 mutations. Including 12 mutations in the analysis detected one patient who would otherwise have been missed and, had this protocol been implemented from 1989, it would have detected four others.Conclusion: Most babies with CF without meconium ileus, a family history or antenatal diagnosis are detected by newborn screening. Despite improved sensitivity with the 12-mutation analysis, most infants detected would have been diagnosed using the IRT/p.F508del protocol.

R John H Massie MB BS, PhD, FRACP · Lisette Curnow BSc · Judith Glazner RN · David S Armstrong MB ChB, FRACP, MD · Ivan Francis BSc, GradDipCompSc

To the Editor: MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) syndrome has not been reported previously in the Aboriginal Australian population. Here, we describe a patient with MELAS syndrome in this population. A 29-year-old Aboriginal Australian woman presented with a 3-day history of seizures and confusion and a background of cognitive impairment, sensorineural deafness, epilepsy and short stature. On admission, she weighed 29.9 kg and was 1.46 m tall (body mass index, 14 kg/m2). She had myopathic facies, generalised mild motor weakness (4/5) and brisk reflexes (3+). These neurological findings represented a stepwise deterioration from previous assessments. On admission, the patient’s blood count, liver function tests, and serum urea, electrolytes and creatinine levels were normal. Her plasma bicarbonate level, anion gap and thyroid function were also normal. The patient had elevated resting arterial lactate (2.7 mmol/L; reference interval [RI], 0.7–2.5 mmol/L) and pyruvate (98 μmol/L; RI, 30–90 μmol/L) levels. The cerebrospinal fluid (CSF) protein concentration was 820 mg/L (RI, 150–500 mg/L) and the CSF lactate level was 5.4 mmol/L (RI, 0.7–2.5 mmol/L). Magnetic resonance imaging of the patient’s brain demonstrated increased T2 signal involving grey and white matter throughout both cerebral hemispheres, most confluent in the right temporal and parietal lobes (Box 1, A). An electroencephalogram displayed a slow rhythm with epileptic activity in the temporal and centroparietal regions. Histological examination of a biopsy of the gastrocnemius muscle was consistent with MELAS syndrome (Box 1, B). Electron microscopy of a muscle biopsy sample revealed mitochondria with abnormally arranged cristae and abnormal electron densities. Mitochondrial respiratory chain enzyme studies on muscle samples were within normal limits, but the common m.3243A>G mutation in the MTTL1 gene was detected in about 70% of the mitochondrial DNA (mtDNA) in muscle tissue and in 10% of the mtDNA of the peripheral blood. MELAS syndrome is a maternally inherited multisystem disorder resulting from mutations in mtDNA.1 Mitochondrial dysfunction leads to the clinical phenotype and lactic acidosis. Cerebral ischaemia unrelated to vascular territories is suggestive of the diagnosis,2 which is confirmed by genetic studies, enzyme assays and histological examination of affected tissue.3 The patient’s family was of Aboriginal Australian descent and she was not aware of any European ancestry. Further inquiry revealed a family history of deafness, diabetes and epilepsy (Box 2). Consequently, the family were offered genetic counselling. A literature review prompted initiation of arginine and coenzyme Q10 therapy.3 Twelve months later, she had good seizure control and had not been re-hospitalised. The disproportionate differences in health between Indigenous and non-Indigenous Australians are often appropriately ascribed to environmental factors. However, potentially treatable causes should always be considered. 1 Magnetic resonance imaging (MRI) and muscle histological studies A. T1-weighted MRI of the brain showing atrophy and enhancing low attenuation lesions. B. Gomori trichrome stain showing a ragged red fibre (black arrow) and two severely atrophic denervated fibres (white arrow). 2 Pedigree of the family of the patient (arrow)

Luke J Conway · Thomas E Robertson · James J McGill · Josh P Hanson

Registries have an important role in monitoring outcomes of complex diseases In the 1950s, a diagnosis of cystic fibrosis (CF) brought with it a high likelihood of dying from lung disease and a low expectation of surviving beyond 10 years of age.1 By 2011, expectations of survival for people living with CF have been transformed; mean age at death now approaches 27 years,2 and over 90% of patients survive beyond 17 years of age.3 Two studies reported in this issue of the Journal provide a broad overview of recent outcomes achieved in the management of Australian patients with CF.2,3 Both of these Australian studies recognised improved survival among people with CF, but reasons for this improvement remain unclear. Many factors probably contribute, including improvements in medical care, such as anti-pseudomonas antibiotics and better chest therapy in general, and the proven benefit of a high-fat diet for maintaining normal growth and nutritional status.4 Improved socioeconomic status may be a factor: a recent analysis of mortality rates among people with CF in the United Kingdom emphasised that lower socioeconomic status (based on two UK government classifications) contributes to higher mortality rates.5 In addition, a fall in the number of early deaths from CF with the advent of newborn screening has been clearly demonstrated.6 Newborn screening was commenced in New South Wales in 1981 and is of particular significance in the Australian setting. Recent data demonstrate a significant survival advantage for a cohort of babies who were diagnosed with CF during the first 3 years of screening compared with a non-screened cohort. Mortality among the non-screened population after 25 years was nearly twice that among the screened population (66% v 32%).7 Unfortunately, the data for the studies reported in this issue2,3 did not allow calculation of the median survival age, which has been the accepted measure for assessing survival of patients with CF.8 However, to give a perspective on the Australian outcome, in a comparable German study that reported a median age of death of 23.7 years, the median age of survival in 2005 was 37.4 years.8 Considering the higher median age of death in the Australian study, the median age of survival could well approach 40 years. This would also compare favourably with data from France and the United States showing median ages of survival of 36.4 years in 2003 and 37.4 years in 2007, respectively.8 Nevertheless, it is likely that we are behind the Canadian achievement of a median age of survival in 2009 of 46.7 years.9 The Australian studies suggest that further research needs to answer two specific questions: Why does the greatest decline in lung function occur during adolescence? Why is there a “gender gap” of significant survival disadvantage among female patients (with the rate of mortality events among girls more than twice the rate among boys2)? Certainly, it would be important to assess adolescent behavioural issues, including compliance; and the described increase in energy expenditure of over 10% in females during adolescence similarly warrants further investigation.10 A 2009 Canadian Cystic Fibrosis Patient Data Registry report9 confirms that a higher proportion of female adolescents with CF are underweight, and the cause remains enigmatic. The databases used by the Australian investigators — the Australian Cystic Fibrosis Data Registry (ACFDR)3 and the General Record of Incidence of Mortality (GRIM)2 — have provided invaluable outcome data for comparison of Australian clinics and thus have a benchmark function. CF centres can measure their performance and, at least in part, justify the estimated annual government expenditure on care for patients with CF of A$67 million.3 The investigators emphasise the importance of known factors that influence the effectiveness of databases, including clinic compliance and the painstaking entry of confirmed and accurate data that conforms with standards for international databases. They also have concerns about the longevity of the ACFDR, given that it depends on ad-hoc private funding. Shortfalls in funding will necessitate shortcuts in data entry that will inevitably compromise the completeness and value of the project. It is essential that governments and the community ensure the sustainability of clinical registries that can identify and report on the cost-effectiveness of treatment plans in complex diseases such as CF.

Kevin J Gaskin MD, FRACP · Bridget Wilcken MB ChB, MD, FRACP

To the Editor: A daunting idea for health care providers is the statistic that, for many medications, only about half of the patients given standard doses will receive the desired therapeutic benefit.1 In the past decade or so, it has been argued that some of this variation in response may be attributed to genetic differences between individuals in mechanisms responsible for the pharmacokinetics and pharmaco-dynamics of many drugs.2 The disparity in health standards among Aboriginal and Torres Strait Islander people compared with non-Indigenous groups is a cause for concern, and requires a concerted political effort to instigate adequate solutions.3,4 Some of the problems include a higher rate of diseases such as hypertension, diabetes, obesity, cardiac disease and depression.3,4 The range of medicines prescribed for these conditions is broad, and some people may not receive the full therapeutic benefit, or may have more severe side effects compared with others. Genetically determined variables contribute to the pharmacokinetics and pharmaco-dynamics of these drugs. Many medications used to treat such diseases are metabolised by the cytochrome P450 (CYP) hepatic enzyme systems, and/or their pharmacokinetics are altered by drug influx and efflux systems. Many of these mechanisms are under genetic control and their efficiency may vary between individuals. Despite this, there are few data on the pharmacogenetics of Indigenous populations generally, and the data on Aboriginal and Torres Strait Islander populations are particularly scant.5 Of the few genetic studies of Indigenous Australians, one found that CYP2C19 and CYP2D6 allele frequencies in a group from remote north-western Australia differed significantly from those for Australians of European ancestry, but were similar to those for East Asian populations.5 An altered CYP2C19 allele could mean alterations in levels of drugs such as phenytoin and clopidogrel, and an altered CYP2D6 allele could mean alterations in levels of drugs such as tricyclic antidepressants, selective serotonin reuptake inhibitors, codeine and tamoxifen. We urgently need to identify clinically relevant issues relating to the capacity of people from these groups to metabolise certain medicines. Screening for genetic variations in drug metabolism and transport mechanisms may highlight significant variations in capacity. This may influence whether people benefit from or are harmed by commonly prescribed medications for hypertension, type 2 diabetes, cardiac disease and depression. The high and increasing prevalence of these diseases among Aboriginal and Torres Strait Islander populations supports a detailed, methodical assessment of the genetics of their drug-metabolising capacity.

Joseph D Tucci

Objective: To investigate how Australian print news media portray psychiatric genetics.Design and setting: Content and framing analysis of a structured sample of print news items about psychiatric genetics published in Australian newspapers between 1996 and 2009.Main outcome measures: Identify dominant discourses about aetiology of mental illness, and perceived clinical outcomes and implications of psychiatric genetics research.Results: We analysed 406 eligible items about the genetics of psychiatric disorders. News coverage of psychiatric genetics has steadily increased since 1996. Items attributing the aetiology of psychiatric disorders to gene–environment interactions (51%) outnumbered items attributing only genetic (30%) or only environmental factors (20%). Of items that referred to heritability of mental illness, frames of genetic determinism (78%) occurred more frequently than probabilistic frames (22%). Of frames related to genetic prophesy, genetic optimism frames (78%) were used more frequently than frames of genetic pessimism (22%). Psychosocial and ethical implications of psychiatric genetics received comparatively relatively little coverage (23%). The analysis identified 22 predictions about psychiatric genetic discoveries and the availability of molecular-based interventions in psychiatry, most of which (20/22, 91%) failed to manifest by the predicted year.Conclusions: Excessive optimism about the power of genetic technology in psychiatric health care, perceived clinical benefits, and largely unfulfilled predictions about availability of these benefits could encourage unrealistic expectations about future molecular-based treatment options for mental health.

Alex Wilde BSc(Hons),PhD · Catriona Bonfiglioli BA(Hons), PhD · Bettina Meiser PhD · Philip B Mitchell AM, MD · Peter R Schofield PhD, DSc