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Volume 11 No 1 - Issue 35 2018

N eur o l ogy N ewsl etter

Genetics• HowwecanuseDNAtestinginneurology• HuntingtonDiseaseinSouthAfrica:Ageneticsperspective• Ethicalimplicationsofgenetictestingfordreaddiseases

Choose Control. Choose Life.

Valproate derivatives should never be prescribed to female children, female adolescents, pregnant women and women of childbearing potential for any indication other than epilepsy which is not effectively controlled by other available medicines with less risk of toxicity to an unborn child, or if these other medicines with less risk of toxicity to an unborn child are not tolerated. Such patients and/or their relatives should be fully informed of the risks to unborn children. Summary:• Children exposed in utero to valproate are at a high risk of serious developmental disorders (in up to 30 - 40 %) and/or congenital malformations (in approximately 10 % of cases).

• Valproate should not be prescribed to female children, female adolescents and pregnant women or women of childbearing potential with epilepsy unless other treatments with a lower risk of causing congenital abnormalities or developmental defects are ineffective or not tolerated.

• Valproate treatment must be started and supervised by a doctor experienced in managing epilepsy or bipolar disorder.

Sodium valproateValproic acid

Reference: 1. Lösher W. and Schmidt D. Modern antiepileptic drug development has failed to deliver: Ways out of the current dilemma. Epilepsia 2011;52(4):657-678For full prescribing information refer to the package insert(s) approved by the medicines regulatory authority.S3 Epilizine® CR 200/300/500 (Tablets). COMPOSITION: Each CR tablet contains 133,2/199,8/333,0 mg sodium valproate and 58,0/87,0/145,0 mg valproic acid equivalent to 200/300/500 mg sodium valproate respectively. REGISTRATION NUMBERS: A39/2.5/0038; A39/2.5/0039; A39/2.5/0040. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION: Zentiva South Africa (Pty) Ltd, a Sanofi company. Reg. no.: 1931/002901/07. Sanofi House, 2 Bond Street, Grand Central Ext. 1 Midrand 1685. Tel: (011) 256 3700. Fax: (011) 256 3707. www.zentiva.com.SAZA.GVAVA.17.03.0183

Recommendations

• Carefully balance the benefits of valproate treatment against the risks of congenital malformations and developmental abnormalities. This assessment should be made when prescribing valproate for the first time, at routine treatment reviews, when a female child reaches puberty and when a woman plans a pregnancy or becomes pregnant.

• You must ensure that all female patients are fully informed of and understand:

- the risks associated with valproate during pregnancy;

- the need to use effective contraception;

- the need for regular review of treatment;

- the need to rapidly consult her prescribing physician if she is planning a pregnancy or becomes pregnant.

In Epilepsy a wide unsurpassed spectrum1

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NEURON SA Volume 11 No 1 Issue 35 2018This newsletter is proudly sponsored by

Editorial - Neurogenetics

Editor: Dr Shaheed GoraNeurologist, Health Systems ConsultantNetcare Milpark Hospital, Johannesburg

Choose Control. Choose Life.

Valproate derivatives should never be prescribed to female children, female adolescents, pregnant women and women of childbearing potential for any indication other than epilepsy which is not effectively controlled by other available medicines with less risk of toxicity to an unborn child, or if these other medicines with less risk of toxicity to an unborn child are not tolerated. Such patients and/or their relatives should be fully informed of the risks to unborn children. Summary:• Children exposed in utero to valproate are at a high risk of serious developmental disorders (in up to 30 - 40 %) and/or congenital malformations (in approximately 10 % of cases).

• Valproate should not be prescribed to female children, female adolescents and pregnant women or women of childbearing potential with epilepsy unless other treatments with a lower risk of causing congenital abnormalities or developmental defects are ineffective or not tolerated.

• Valproate treatment must be started and supervised by a doctor experienced in managing epilepsy or bipolar disorder.

Sodium valproateValproic acid

Reference: 1. Lösher W. and Schmidt D. Modern antiepileptic drug development has failed to deliver: Ways out of the current dilemma. Epilepsia 2011;52(4):657-678For full prescribing information refer to the package insert(s) approved by the medicines regulatory authority.S3 Epilizine® CR 200/300/500 (Tablets). COMPOSITION: Each CR tablet contains 133,2/199,8/333,0 mg sodium valproate and 58,0/87,0/145,0 mg valproic acid equivalent to 200/300/500 mg sodium valproate respectively. REGISTRATION NUMBERS: A39/2.5/0038; A39/2.5/0039; A39/2.5/0040. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION: Zentiva South Africa (Pty) Ltd, a Sanofi company. Reg. no.: 1931/002901/07. Sanofi House, 2 Bond Street, Grand Central Ext. 1 Midrand 1685. Tel: (011) 256 3700. Fax: (011) 256 3707. www.zentiva.com.SAZA.GVAVA.17.03.0183

Recommendations

• Carefully balance the benefits of valproate treatment against the risks of congenital malformations and developmental abnormalities. This assessment should be made when prescribing valproate for the first time, at routine treatment reviews, when a female child reaches puberty and when a woman plans a pregnancy or becomes pregnant.

• You must ensure that all female patients are fully informed of and understand:

- the risks associated with valproate during pregnancy;

- the need to use effective contraception;

- the need for regular review of treatment;

- the need to rapidly consult her prescribing physician if she is planning a pregnancy or becomes pregnant.

In Epilepsy a wide unsurpassed spectrum1

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hinking about genetics in neurology almost immediately transported me to the exam hall at the CMSA sitting for part one of the neurology exam. The genetics question was clearly designed to push a rookie registrar to the brink of despair (read: Mentally curling up in the foetal

position wondering why I had spent two weeks on a neurogenetics textbook and have NEVER seen this word?!). The question responsible for the momentary lapse in sanity was: Define the LOD score. (10 marks)

Beyond this, my neurology training and early career would be punctuated by more wonderfully mind numbing neurogenetic terms and phrases. Linkage analysis, polymorphisms, the locus for Huntingtin and dystrophin, and the genetic forms of ALS were gems that could easily tip an already tense teaching round into career questioning crisis.

And then there was the ever-increasing list of spinocerebellar ataxias and limb girdle dystrophies. These two were truly the gifts that kept giving.

But it wasn’t all Mordor and Sauron. One of my favourite neurogenetic anecdotes is about how a single mutation on chromosome 3 could potentially be responsible the infamous Hatfield – McCoy feud. The feud between 2 families on the Kentucky/ West Virginia border of the US lasted generations and killed dozens of family members on each side. Many McCoy descendants were subsequently found to have Von Hippel Lindau syndrome which manifested with phaeochromocytomas (other manifestations included orbital and cerebellar haemangioblastomas). These phaeos were associated with episodes of rage thought to contribute to the McCoy outbursts that kept the feud going for 30 odd years in the 1800s.

Back in the 21st century, neurogenetics has established itself as a cornerstone for diagnosis and even management in many neurological disorders.

Professor Amanda Krause reviews that paragon of neurogenetics, Huntington Disease, which has recently captured much public attention. Researchers at University College London have started human trials into a potential silencer for the Huntingtin protein. If this intrathecal therapy works to slow down or prevent disease onset in genetically susceptible individuals, it could be the biggest breakthrough in neurodegenerative disease in 50 years.

Utilising DNA testing in practice can be vexing when trying to be both comprehensive and pragmatic. In addition, the ethical issues surrounding the diagnosis of potentially life-threatening conditions in individuals that are currently asymptomatic can be challenging. The fact that this testing is often carried out on children adds an additional layer of complexity.

Dr Daniel Meyersfeld elegantly introduces the concept of personalised medicine and the increasingly important role of genotype knowledge in neurological disorders. The concept of using genetic testing as the initial investigation to establish a diagnosis has the potential for positive disruption in our current clinical routine. This truly requires a shift in mindset and expertise that may well be the catalyst for unmasking the undiagnosed and obscure neurologic syndromes that we are often faced with in clinical practice.

The ethical and legal issues in genetic testing expand beyond informed consent and confidentiality. The legal provisions are unpacked and simplified for us by Elsabe Klinck. It is also clear that the role of the genetic counsellor will become more established in neurology.

My nostalgic anxiety surrounding neurogenetics is firmly replaced with excitement about a rapidly expanding field of neurology that we should all embrace to remain relevant.

Finally, the answer you’ve undoubtedly been waiting for: The LOD score, or logarithm of odds, is a statistical test used in linkage analysis. It compares the likelihood of obtaining test data if two loci are indeed linked. Truly the gift that keeps on giving!

Till next time Shaheed

Utilising DNA testing in practice can be vexing when trying to be both

comprehensive and pragmatic. In addition, the ethical issues surrounding the diagnosis of potentially life-threatening conditions in

individuals that are currently asymptomatic can be challenging.

AckNowlEDgEmENtANDtHANkSOn behalf of Sanofi, Ann Lake Publications and myself, I would like to take the opportunity of this first issue of my editorship to thank outgoing editor, Dr Jody Pearl for launching Neuron SA and steering it over the past 10 years. Thanks, too, to the esteemed outgoing editorial board whose input and dedication have set a high standard for us to maintain and the challenge for us to grow. We wish you all well in your future endeavours!

NEURON SA Volume 11 No 1 Issue 35 2018

NeurosurgeryDrchristosProfyrisBBiomedSciHon(monash),mA(cantab),Bm,Bch(oxon),mRcS,FcNeurosurg(SA),mmedNeurosurg(wItS)Head of Department, Neurosurgery, Helen Joseph Hospital, Netcare Milpark HospitalDr Profyris has a special interest in skull base surgery and neuro- oncology. He is aiming toward establishing Helen Joseph Hospital as a centre of excellence for skull base and brain tumour surgery.

NeurologyDrShaheedgoramBBch(wits)FcNeurol(SA)ENlS(NeurocriticalcareSociety)Neurologist, Health Systems ConsultantNetcare Milpark Hospital, JohannesburgDr Gora is a member of the American Academy of Neurology and his special interests include epilepsy, Health tech and health systems consulting

Neurology and SleepDrRakshaSitharammBchB,FcNeurol(SA)Neurologist Netcare Waterfall City Hospital, MidrandDr Sitharam is a member of the American Academy of sleep medicine (AASM) and the European Sleep Research Society and holds the ESRS qualification of Somnologist, Expert in Sleep Medicine. Her special interests also include epilepsy.

Public Health NeurologyDrStaceyRossouwmBchB(SU),Fc(Neurol)SAAHmP(YAlE)Specialist Neurologist, Frere Hospital, East LondonDr Rossouw’s focus is in the field of stroke medicine, more specifically implementing integrated stroke care pathways in an under-resourced setting. She was involved in establishing a neurology department at both Frere and Cecelia Makiwane Hospitals and in 2015/2016 she launched the “Frere Stroke Readiness Programme” in response to the identified high burden of disease.

eHealth ExpertmsAmeeraHamidBHScHonsFS,PDm,mBAeHealth Strategist and InnovatorOperations Manager, African Centre for eHealth Excellence (Acfee)Systems analyst, Health Information Systems Program South Africa (HISP-SA)Ms Hamid is an editor and frequent contributor to the blog site eHealth Network for Africa (eHNA) and is currently pursuing a qualification in Applied Mathematics and Computer Science.

Neurology, vascular neurology and medical innovation DrNaeemBreymBchB(Uct),FcNeurol(SA),DipHIVman.(SA)Neurologist, Neurology Division, Tygerberg Hospital Lecturer, Faculty of Medicine and Health Sciences Stellenbosch UniversityDr Brey has an interest in cerebrovascular disease and neuro-im-munology, as well as in medical training, and applications for ac-cessible technology within medicine. He is a member of the South African Stroke Society (SASS) and on the organising committee for the Stroke and Hypertension Congress 2018 in Stellenbosch.

Neuro PsychiatryDrFranskorbBSc(Hons)(UFS),mAclinicalPsychology(wits),mBchB(Uct),mmedPsychiatry(wits)Psychiatrist and psychologist in private practice, Blairgowrie, JohannesburgDr Korb is currently editor of Mental Health Matters (Journal for General Practitioners in Mental Health). Past executive appoint-ments include the University Science Students’ Association of South-ern Africa (USSASA), Associated Scientific and Technical Societies of South Africa (AS&TS), Southern African Association for the Advance-ment of Science (S2A3), University of the Witwatersrand Psychiatry Registrars’ Association, SA Association for Child and Adolescent Psychiatry and Allied Professions (ACAPAP), SA Society of Psychia-trists (SASOP), Southern African Society of Biological Psychiatry, the Rotary Club of Sandown, SA Sexual Health Association (SASHA), SA Medical Association (SAMA) and the South African Depression and Anxiety Group (SADAG).


How we can use DNA tests in Neurology

Dr Daniel MeyersfeldMolecular biologist, Founder of DNAlysis

hat is food to one person may be bitter poison to others.' These words were first written by The Roman author Lucretius in 1576 and reflect a very early recognition of the concept of individuality. Despite

this, it took a few hundred years for the sentiment to gain widespread acknowledgement and acceptance, and even longer for the application of precision medicine to begin to permeate into routine medical practice.

Personalized medicine, which is also called precision or individualised medicine, is an evolving field of practice in which physicians are given the tools determine which medical treatments will work best for each individual patient.

Much of the individuality on which these clinical decisions are made can be attributed to genetics; specifically, small genetic variations in our DNA that have a profound effect on the manner in which genes are expressed and controlled.

Small genetic variations, known as Single Nucleotide Polymorphisms (SNPs), are the most frequent type of variation in the human genome, occurring once every several hundred

base pairs. For any given SNP, the location at which it occurs will have a bearing on the significance or relevance of the SNP. For example, the SNP can occur in a coding region but not cause a change in amino acid. It can occur in a coding region and cause an amino acid change, it can occur in a regulatory region where the result is a change in gene expression, or it can occur in a region between genes.1

The vast majority of SNPs have no known functional significance. However, some can have a significant effect on the manner in which a particular gene is expressed or regulated, which in turn affects the biochemical pathway in which this gene/protein plays a role. The “effect” of any given SNP is often also called “penetrance”. Low penetrance SNPs will have a small effect on a biochemical pathway and play only a small role in the possible eventual onset of disease. It can be difficult to distinguish environmental from genetic risk factors. Conversely, high penetrance SNPs confer a more direct link between the genotype and clinical signs and symptoms of disease.

The underlying principle of personalised medicine is that by arming the medical practitioner with knowledge of which (low penetrance) SNPs are present within the DNA of each individual patient, the doctor becomes empowered to modify their treatment protocols to accommodate these SNPs.

One of the areas in which these advances are proving particularly exciting is neurology, the umbrella term used to denote structure, function and diseases of the nervous system. Many of the fundamental processes underlying neurological disease remain poorly understood, and advances in genomics and emerging technologies offer opportunities to better define neurological syndromes, understand disease progression, and improve therapeutic interventions. Low penetrance SNPs in genes such as APOE (Alzheimer’s disease), MTHFR and BDNF (depression), DRD2 (addictive behaviour) and COMT (anxiety) all contribute to progression of the indicated phenotype, and all provide some clues to healthcare practitioners on how best to manage the afflicted patient.

Genetics in NeurologyWhilst many neurological diseases are caused by single mutations in genes commonly involved in the normal function of brain, spinal cord or peripheral nervous system, many of the more complex disorders result from an interplay between multiple genetic and environmental factors.2 Thus, patients with unexplained neurological symptoms can sometimes search for years for a diagnosis and treatment. However, the last two decades have brought tremendous progress in terms of both molecular diagnoses, and our understanding of the genes and pathways that are involved in many neurological and psychiatric disorders.3 With these advances, a much greater understanding of the aetiology of many complex neurological disorders is now feasible.2

Recent technological advances, in particular next generation DNA

sequencing techniques, have resulted in rapid identification of genes involved in Mendelian disorders and provided new

possibilities for diagnostic genetic testing.Specifically, it means that diagnostic

genetic testing should now be considered earlier in the diagnostic procedure


Advances in our understanding of the genetic basis of neurological diseases have been aided enormously by the technological advances that have been made in analysing human genomic DNA. Due to high costs and time-consuming procedures, genetic tests have traditionally been performed late in the diagnostic process, only once clinical interventions have already pinpointed a particular gene as being the most likely cause.

Recent technological advances, in particular next generation DNA sequencing techniques, have resulted in rapid identification of genes involved in Mendelian disorders and provided new possibilities for diagnostic genetic testing.2 Specifically, it means that diagnostic genetic testing should now be considered earlier in the diagnostic procedure, as depicted by Toft et al2 in Figure1.

This new approach to genetic testing, where it is utilised as a first line approach to identify the cause of disease, rather than a last resort to confirm a diagnosis, requires a shift in both mindset and expertise of the relevant healthcare practitioner. The healthcare practitioner of the future will require an understanding of not just the pathologies associated with their field of speciality, but also with the underlying genetic risk and predisposing factors that may be contributing to these pathologies. This will enable the individual management of each patient according to their unique genetic requirement.

APoE and Alzheimer’s DiseaseOne of the most extensively researched gene variants is apolipoprotein E (ApoE), a protein well known for its association with the transport of cholesterol and lipids in blood.4 Research into APOE has focussed not only on its role in cardiovascular disease, where the E4 isoform is a major risk factor, but also on

the role it appears to play in other medical conditions such as neurodegenerative and autoimmune diseases.5,6 It is recognised, for example, as one of the most important genetic risk factors for late onset Alzheimer’s disease, with carriers of the E4 allele having a 4- to 12-fold increased risk of developing the disease when compared to non-carriers.7 The E2 allele, conversely, appears to confer some protection against onset of this disease.8 It is not clearly understood how these two isoforms differently affect the risk of AD. One explanation is the differing capacities of the two isoforms to effectively clear Amyloid β from the brain; it is well established that APOE binds directly to the Aβ peptide, but the affinity of the E4 allele appears to be much reduced and individuals with this genotype tend to accumulate Aβ in the brain - a hallmark of Alzheimer’s Disease.

APOE is not a causal factor for diseases such as cardiovascular disease or Alzheimer’s disease. Rather, it is a risk factor for these diseases and as such can play a role in the prevention and management of the disease. For example, the association between APOE4 and poor vascular health

appears to be exacerbated in the presence of certain lifestyle variables, such as obesity, smoking and alcohol consumption. Increased physical activity,9 good vascular health10 and lifetime cognitive activity11 all appear to reduce the negative affect of APOE4 on Aβ and Alzheimer’s disease. These findings all seem to suggest that lifestyle choices become an important tool in the management of Alzheimer’s disease.

By providing the clinician with relevant genotype information, they in turn could provide more patient-specific advice that would assist APOE4 carriers with managing their own risk. In addition to providing useful clinical information, genetic tests have been shown to be a powerful motivator to encourage behaviour modification.12 Thus, access to this information becomes empowering to the patient as there are simple

clinicalExamination

Biochemicalbloodtests

Emgandneurography

mRIofmuscles

musclebiopsy

genetictestingofsinglegene

Finaldiagnosis Nodiagnosis

Emgandneurography

mRIofmuscles

musclebiopsy

clinicalExamination

genetictestingofgenepanel



AcURRENttEStINgStRAtEgY

BNEwtEStINgStRAtEgY

Figure 1. Current and new strategies for genetic testing. (A) Genetic testing of single mutations or genes was traditionally being performed late in the diagnostic process. (B) With the

diminished cost and rapid turnaround times, gene panels and exome sequencing can now be performed earlier in the diagnostic process.

APOE is not a causal factor for diseases such as cardiovascular disease or

Alzheimer’s disease. Rather, it is a risk factor for these diseases and as such can play a role in the prevention and

management of the disease. For example, the association between APOE4 and poor

vascular health appears to be exacerbated in the presence of certain lifestyle

variables, such as obesity, smoking and alcohol consumption.


interventions available to them to assist in reducing the risk burden.

In considering the incorporation of APOE testing into a routine screening programme it would be worth considering the role to be played by a genetic counsellor. The increased anxiety that knowledge of this genotype and its associated risks could create, would need to be balanced with their heightened responsiveness to healthy lifestyle interventions. Furthermore, identifying an APOE4 allele will have implications for the direct relatives of the individual tested, raising ethical concerns that would need to be addressed.

Whilst APOE presents a good example of utilising genotype knowledge in the management of disease risk, availability of genotype information for the gene methylene tetrahydrofolate reductase (MTHFR) represents an opportunity for the healthcare practitioner to directly modify their treatment strategies. It has been shown13,14 that in patients with inadequate response to SSRIs who also contain genetic markers indicative of poor folate metabolism, the addition of L-Methyl folate as an adjunctive therapy improved responsiveness to medication. In this instance genotype data becomes highly useful to the long-term treatment strategy of the healthcare practitioner. For the more accurate and rapid diagnosis, enhanced management strategies and improved therapeutic outcomes, it is becoming increasingly relevant to gain insight into the genetics underpinning many neurological illnesses. The lower cost, faster turnaround times and greater access to interpretative tools has made genetic technologies accessible to a broad range of medical practitioners. What is required going forward is extensive education for these practitioners on how and when to best utilise genetic testing in practice, and the legal, ethical and social implications of such testing.

References1. T. Brody, “Biomarkers,” in Clinical Trials, Second Edition,

Elevier, 2016, pp. 377-419.2. M. Toft, “Advances in genetic diagnosis of neurological

disorders,” Acta Neurologica, vol. 129, pp. 20-25, 2014. 3. H. Y. Zoghbi and S. T. Warren, “Neurogenetics: Advancing the

“Next-Generation” of Brain Research,” Neuron, vol. 68, no. 12, pp. 165-173, 2010.

4. S. Villeneuve, D. Brisson, N. L. Marchant and D. Gaudet, “The potential applications of Apolipoprotein E in personalized medicine,” frontiers in aging neuroscience, vol. 6, 2014.

5. R. W. Mahley and Y. Huang, “Alzheimer disease: multiple causes, multiple effects of apolipoprotein E4, and multiple therapeutic approaches,” Annals of Neurology, vol. 65, pp. 623-625, 2009.

6. P. B. Verghese, J. M. Castellano and D. M. Holtzman, “Apolipoprotein E in Alzheimer’s disease and other neurological disorders,” Lancet Neurology, vol. 10, pp. 241-252, 2011.

7. E. H. Corder, A. M. Saunders, W. J. Strittmatter, D. E. Schmechel and P. C. Gaskell, “Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimers’s disease in late onset families,” Science, vol. 261, pp. 921-923, 1993.

8. E. H. Corder, A. M. Saunders, N. J. Risch, W. J. Strittmatter, D. E. Schmechel and P. C. Gaskell, “Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer’s disease,” Nature Genetics, vol. 7, pp. 180-184, 1994.

9. R. Gueguen, S. Visvikis, J. Steinmetz, G. Siest and E. Boerwinkle, “An analysis of genotype effects and their interactions by using the apolipoprotein E polymorphism and longitudinal data,” American Journal of Human Genetics, vol. 45, pp. 793-802, 1989.

10. C. Ferrari, W. L. Xu, H. X. Wang, B. Winblad, S. Sorbi and C. Qiu, “How can elderly apolipoprotein E epsilon4 carriers remain free from dementia?,” Neurology, vol. 50, pp. 669-677, 2013.

11. M. Wirth, S. Villeneuve, L. J. Renaud, S. Marks and W. Jagust, “Gene-environment interactions: lifetime cognitive activity, APOE genotype and beta-amyloid burden,” Journal of Neuroscience, vol. 34, pp. 8612-8617, 2014.

12. [D. E. Nielsen and A. El-Sohemy, “Disclosure of Genetic Information and Change in Dietary Intake; A Randomized Controlled Trial,” PLOS One, vol. 9, no. 11, 2014.

13. G. I. Papakostas, R. C. Shelton, J. M. Zajecka, T. Bottiglieri, J. Roffman, C. Cassiello, S. M. Stahl and M. Fava, “Effect of Adjunctive l-Methylfolate 15 mg Among Inadequate Responders to SSRIs in Depressed Patients Who Were Stratified by Biomarker Levels and Genotype: Results From a Randomized Clinical Trial,” Journal of Clinical Psychiatry, vol. 75, 2014.

14. J. M. Zajecka, M. Fava, R. C. Shelton, L. W. Barrentine, P. Young and G. I. Papakostas, “Long-Term efficacy, safety and tolerability of L-Methyl Folate Calcium 15mg as Adjunctive Therapy with Selective Serotonin Reuptake Inhibitors: A 12 month open label study following aplacebo-controlled Acute Study,” Journal of Clinical Psychiatry, vol. 77, no. 5, pp. 654-660, 2016.

Take Home points

• Personalised medicine gives medical practitioners the tools to manage each patient according to their unique genetic requirements

• Low penetrance genetic variants can contribute to the onset and severity of complex diseases, but also arm both patient and healthcare practitioner with tools to prevent, manage or treat these disease

• Advances in genetic testing technologies means that this information is much more accessible, and genetic tests can be performed earlier in the diagnostic process

• The implementation of widespread genetic tests raises ethical questions that would need to be addressed

• There appears to be a significant knowledge gap for healthcare practitioners on the use and interpretation of genetic data


Huntington Disease in South Africa: A genetics perspective

Prof Amanda Krause MBBCh, PhD ([email protected] )Medical Geneticist/Associate Professor, Head: Division of Human Genetics

National Health Laboratory Service (NHLS) & The University of the Witwatersrand, Johannesburg

untington disease is one of the commonest inherited neurodegenerative disorders. It is characterised by a progressive motor disorder, cognitive decline and psychiatric manifestations. Choreiform movements are the main motor manifestation but dystonia and

rigidity also occur. Memory loss and impaired executive functioning are typical. Marked personality changes, depression and suicidal tendencies also characterise the disease. On MRI, caudate nucleus and putamen atrophy are seen, with neuronal loss predominantly in the cerebral cortex. Huntington disease typically presents in the third to fourth decade of life, but can present as early as childhood and in individuals in their seventies. On average, death occurs 15-20 years after onset. The clinical features can vary significantly between individuals, particularly those who present outside of the typical age range. It is important for clinicians to be aware of this variability, so that less typical cases are recognised.

Huntington disease is inherited in an autosomal dominant fashion. Thus, once a family member is diagnosed with the condition, other at-risk family members should be recognised. Typically, an individual will have inherited the condition from one of his parents. Siblings and children of an affected individual are each at ½ or 50% risk of developing the condition. Importantly, new mutations do occur, so the absence of family history does not exclude the diagnosis.

In view of the severity of the disease, at-risk asymptomatic individuals may choose to be tested to determine whether they carry the genetic mutation. Such individuals need to go through a predictive testing protocol, which includes consultations with a genetic counsellor, neurologist, psychiatrist and psychologist prior to genetic testing. This ensures that individuals are adequately prepared for their results, show no early signs of disease and fully understand their risks and the disease implications, so that their consent for testing is fully informed.

Huntington disease is typically caused by a trinucleotide repeat expansion mutation in the HTT gene. The mutation is unstable so that changes in the number of repeats occur from generation to generation. Typically repeat numbers increase, rather than decrease, and expansions are more likely in paternal transmissions. Expansion from one generation to the next is termed anticipation. If an individual inherits a gene copy with > 40 repeats, they will develop Huntington disease. If there are 36-39 repeats, the disease is not fully penetrant. Importantly, if an individual has 29-35 repeats, they themselves will not develop the disease, but are at risk of having children with repeat sizes in the disease range and thus of developing Huntington disease.

In individuals with African ancestry, an important genetic difference occurs. Of those patients who test positive for HD,

about 2/3 have mutations in the HTT gene described above. However, another 1/3 have mutations in a second gene called JPH3.1 The mutations in JPH3 are also triplet repeat expansions with similar disease ranges to HTT. The disease was first described in an African American family in 20012 and is referred to as Huntington-disease-like 2 (HDL2). Only 69 cases of HDL2 have been clinically described in the literature since 2001, all with African ancestry.3 The great majority of these have been described from South Africa, and more specifically from in and around Gauteng. It is unclear at present whether this represents a true distribution or merely reflects ascertainment bias. However, it is clear that when referring patients with African ancestry for diagnostic genetic testing for HD it is important to test for expansions in both the HTT and the JPH3 genes.

In both HD and HDL2, there is a broad but strong negative correlation between repeat length and age of onset and severity of the disease. Unfortunately, this is not particularly useful on an individual basis to predict disease onset or severity. When diagnostic testing is performed, very accurate sizing of repeats is essential. Laboratories performing such testing should perform quality controls regularly and align their sizing with international protocols.

After testing for HD and HDL2, a group of patients remain in all cohorts who have clinical features suggestive of HD, but who test negative for known phenocopies. This group of patients requires further study, in order to improve diagnostic efficiency.

The clinical phenotype of HDL2 appears broadly similar to that of HD from the published clinical case reports, but it has been gathered from only 69 case reports.3 In these reports, chorea was noted in 84%, dementia in 74% and Parkinsonism in 37%. Psychiatric features were reported in 93% of cases. Patients with chorea had lower expanded repeat lengths compared to patients without chorea. Nineteen out of 20 MRIs were reported as abnormal with findings similar to HD.

Importantly, no systematic studies have been done on a cohort of HDL2 patients. Such a cross-sectional study is currently underway in Johannesburg to characterise the clinical, radiological and haematological features of HDL2 and to compare them to HD. This study will determine whether there are significant clinical differences between the two diseases.

HDL2 had been classified as a neuroacanthocytosis syndrome on the basis of finding acanthocytes in 4/13 cases in the literature. Three of these cases were related. In the South African prospective study comparing 13 HD and 12 HDL2 cases against 21 unaffected controls, acanthocytosis was not identified in either HDL2 or HD patients.4 These results, suggest that screening for acanthocytosis will not help establish the


diagnosis of HD or HDL2, nor differentiate between the two disorders and raises the question whether HDL2 should continue to be placed within the neuroacanthocytosis syndromes.

Importantly longitudinal studies are also required to study the disease course of HDL2 and compare it to HD. Patients with HDL2 who have features dissimilar to HD may exist but may not yet have been recognised.

Recent estimates place the HD disease frequency in European populations between 10.6 - 13.7 per 100,000 individuals.5 Huntington disease prevalence is known to differ geographically. HD has been reported to be rare in African populations, although both HD and HDL2 are clearly documented in African populations. Based on an analysis of molecular diagnostic records, recent minimum estimates of disease frequency are: 5.1, 2.1 and 0.25 (per 100,000 individuals) in South African individuals of European, mixed and African ancestry respectively. These minimum estimates suggest that disease frequencies are significantly higher than those previously reported in South Africa.6 Huntington disease should be considered and diagnostic testing performed in patients with suggestive clinical features.

Despite the genetics of Huntington disease having been elucidated a number of decades ago now, the molecular and cellular mechanisms underlying the disease pathogenesis in Huntington disease remains relatively poorly understood. The Huntington protein has been proposed to have many roles. It is required in early embryonic development, is a scaffold protein and has been implicated in many intra-cellular roles such as transcriptional regulation and apoptosis. In the presence of the expansion, the protein is expanded to include a long polyglutamine tract. There appears to be loss of function of the normal protein and a toxic gain of function of the mutant huntingtin protein which contributes to the disruption of multiple intracellular pathways.

It is fascinating that the JPH3 protein appears to have little overlapping structure or function with huntingtin, but expansions in this gene produce similar clinical effects. The protein encoded by this gene is a component of junctional complexes and is composed of a C-terminal hydrophobic segment spanning the endoplasmic/sarcoplasmic reticulum membrane and a remaining cytoplasmic domain that shows specific affinity for the plasma membrane. The pathogenic mechanism of JPH3 expansion mutations appears to include a gain of function of JPH3 RNA transcripts as well as a loss of JPH3 expression.7,8

Currently, there are no curative therapies for Huntington disease, although a wide range of potential therapeutics are under investigation in both animal models of HD and in human clinical trials. Inhibitors of apoptosis, excitotoxicity, huntingtin aggregation, huntingtin proteolysis, huntingtin phosphorylation, inflammation, oxidative damage, phosphodiesterase activity, histone deacetylase inhibitors, and transglutaminase activity are under investigation, as well as compounds that modulate mitochondrial function, chaperone activity, transcription, and neurotrophic support. Preliminary

results from the IONIS trial presented at the end of 2017,9

show promising results for a drug aimed at RNA-mediated silencing of the abnormal Huntington gene. Importantly, drugs developed for HD will not necessarily be effective for HDL2. It would thus be important for efforts to be made locally to ensure that HDL2 therapies are developed in parallel to those for HD.

In conclusion, Huntington disease occurs in South Africa in individuals of different ancestries, and the condition should be considered in those with suggestive signs and symptoms. Testing is definitive if an HTT or JPH3 mutation is identified. Other rare phenocopies are yet to be characterised. The diagnosis of Huntington disease has significant implications for the extended family and referral to a genetic centre for counselling is indicated. In view of the clustering of HDL2 cases in South Africa, there are unique opportunities to characterise these patients systematically, so that all patients have equal access to management and state of the art care.

References1. KRAUSE A, MITCHELL CL, ESSOP F, TAGER S, TEMLETT J, et al.

(2015) Junctophilin 3 (JPH3) expansion mutations causing Huntington Disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype. Am J Med Genet B Neuropsychiatr Genet 168B, 573-85.

2. MARGOLIS RL, O’HEARN E, ROSENBLATT A, WILLOUR V, HOLMES SE, et al. A disorder similar to Huntington’s disease is associated with a novel CAG repeat expansion. Ann Neurol. 2001;50(3):373-80.

3. ANDERSON DG, WALKER RH, CONNOR M, CARR J, MARGOLIS RL. AND KRAUSE, A (2017). A Systematic Review of the Huntington Disease-Like 2 Phenotype. Journal of Huntington Disease 6, 37-46.

References4-9availableonrequest.

Take Home points

• Huntington disease is one of the commonest inherited neurodegenerative disorders, but marked clinical variability, particularly at the extremes of age, may make diagnosis difficult

• Siblings and children of an individual with Huntington disease are each at 50% risk of developing the condition

• At-risk individuals need to go through a predictive testing programme prior to testing

• A triplet repeat expansion mutation causes Huntington disease

• In people with African ancestry Huntington disease may be caused by HTT or JPH3 expansion mutations causing HD or HDL-2

• The clinical phenotype of HDL-2 is similar to HD but requires further studies

• Huntington disease occurs in all populations• Therapies developed for Huntington disease may not

be suitable for all patients, depending on their genetic mutation


Ethical implications of genetic testing for dread diseases

Ms Elsabe Klinck B.Iur, LL.B, BA Hons (German), BA Applied PsychologyManaging Director: Elsabe Klinck & Assocates (Pty) Ltd

Johannesburg

here are limited legal or ethical rules specifically related to genetic testing in South Africa. The only specific rules are those of the HPCSA pertaining to Genetic Counsellors.

However, the general ethical and legal rules on consent, confidentiality and the likes apply equally to situations of genetic testing, whether for dread disease, or any other condition.

Informed consentThe most important aspect of genetic testing is, as with any other healthcare service, the right to provide informed consent, prior to any testing, and the duty on service providers to provide sufficient information to allow an informed decision.

The National Health Act (“NHA”) has governed the criteria set for informed consent since its inception in 2003, requiring users of healthcare services (i.e. patients or those consenting on their behalf) to have “full knowledge”. Of specific importance is that the implications of the test in this case, and the refusal thereof, be explained.

Section 6 of the NHA reads as follows:1. Every health care provider must inform a user of—

a. the user’s health status except in circumstances where there is substantial evidence that the disclosure of the user’s health status would be contrary to the best interests of the user;

b. the range of diagnostic procedures and treatment options generally available to the user;

c. the benefits, risks, costs and consequences generally associated with each option; and

d. the user’s right to refuse health services and explain the implications, risks, obligations of such refusal.

2. The health care provider concerned must, where possible, inform the user as contemplated in subsection (1) in a language that the user understands and in a manner which takes into account the user’s level of literacy.

A key part of the discussion is the patient’s health status, and factors, such as genetics, that could influence such status. It should also be noted that section 6(1)(a) provides for circumstances where such health status could be withheld from the patient. However, unless this is clear in the interest of the patient, withholding information on a person’s health status should be exercised in narrow circumstances, and with concurrence of an ethics committee. This is as the Constitution of South Africa, 1996, gives persons the right to freedom and security of their bodies, as well as the right of access to information.

Pitching the discussing at the correct level bearing in mind language and literacy, and, also relevant social circumstances,

is important so that the patient can indeed make an “informed” decision.

The HPCSA’s Booklet 9 on Informed Consent, dated May 2008, contains a section on genetic testing (section 17). It sets the scene within which the decision to undergo genetic testing is made, and which includes not only the advantages in terms of “effective care”, but also the serious implications that could flow from false tests, but also positive tests from social and financial perspectives:

Screening or testing of healthy or asymptomatic people to detect genetic predispositions or early signs of debilitating or life threatening conditions can be an important tool in providing effective care. However, the uncertainties involved in screening or testing may be great, for example the risk of false positive or false negative results. Some findings may potentially have serious medical, social or financial consequences not only for the individuals, but for their relatives. In some cases the fact of having been screened or tested may itself have serious implications.

The HPCSA then sets out the considerations that healthcare practitioners must abide by, namely:• The decision must be one that is “properly informed”. • The decision must (as is indeed the legal requirement for

children) be in the individual's interest. • Identify, provide and focus on the information the person

wants or ought to have.• Explain clearly:

- The purpose of the screening or test; - The likelihood of positive or negative findings and the

possibility of false positive or negative results; - The uncertainties and risks attached to the screening or

testing process; - Any significant medical, social or financial implications

of screening or testing for the particular condition or predisposition; and

- Follow up plans, including the availability of counselling and support services.

Children and consent to genetic testingParents, and even adoptive parents, are sometimes anxious as to whether their child or children may have inherited some disease or condition.

Specific provisions on the consent relating to children must be adhered to. An overarching principle, on which even the wishes of parents or guardians may be overridden, is the best interest of the child. Where a genetic test would not be in the best interest of a child, a court of law can stop such a test from occurring. This will happen if a healthcare professional refuse to do the test, and/or a genetic counsellor advise against this.


In general, the Children’s Act of 2005, with its associated Regulations published in 2010, govern all aspects of medical treatment. Medical treatment is not defined in the Act or regulations, but is deemed to include all diagnostic testing, including therefore genetic testing.

According to section 129(2) of the Children’s Act, a child can consent to treatment, unassisted, when s/he is 12 years of age or older, and:

b. the child is of sufficient maturity and has the mental capacity to understand the benefits, risks, social and other implications of the treatment.

The assessment as to whether the child is able to understand the implications of a genetic test is therefore an important assessment to be made. This is recommended to be made with the assistance of a child psychologist or psychiatrist, with concurrence of a genetic counsellor with experience in paediatrics. If the child is found to not be able to understand the implications of a genetic test, and the implications of the outcomes thereof, the parent(s), caregiver or legal guardian should consent to the test. All healthcare professionals involved in an assessment as to the child’s maturity to understand the implications of the tests, should carefully document their assessments, conclusions and the facts that led to those conclusions.

Parents, guardians or caregivers may consent to a genetic test on behalf of a child younger than 12 years of age, but, as stated above, the best interest of the child must be the overriding factor. Where healthcare professionals are unsure as to whether the genetic test would be in the best interest of the child, they should approach psychologists, psychiatrists and their local social worker, to assist in the process. In the end, the courts, as the upper guardians of all children, could make a decision as to whether a genetic test, refused by healthcare professionals on the basis of the best interest of the child, would indeed be in the child’s best interest.

The Children’s Act‘s section 7(1) sets out the factors to be considered in this regard:

a. the nature of the personal relationship between—i. the child and the parents, or any specific parent; andii. the child and any other care-giver or person relevant

in those circumstances;b. the attitude of the parents, or any specific parent,

towards—i. the child; andii. the exercise of parental responsibilities and rights in

respect of the child;c. the capacity of the parents, or any specific parent, or of

any other care-giver or person, to provide for the needs of the child, including emotional and intellectual needs;

d. the likely effect on the child of any change in the child’s circumstances, including the likely effect on the child of any separation from—i. both or either of the parents; orii. any brother or sister or other child, or any other care-

giver or person, with whom the child has been living; e. the practical difficulty and expense of a child having

contact with the parents, or any specific parent, and

whether that difficulty or expense will substantially affect the child’s right to maintain personal relations and direct contact with the parents, or any specific parent, on a regular basis;

f. the need for the child—i. to remain in the care of his or her parent, family and

extended family; andii. (to maintain a connection with his or her family,

extended family, culture or tradition;g. the child’s—

i. age, maturity and stage of development;ii. gender;iii. background; andiv. any other relevant characteristics of the child;

h. the child’s physical and emotional security and his or her intellectual, emotional, social and cultural development;

i. any disability that a child may have;j. any chronic illness from which a child may suffer;k. the need for a child to be brought up within a stable

family environment and, where this is not possible, in an environment resembling as closely as possible a caring family environment;

l. the need to protect the child from any physical or psychological harm that may be caused by—i. subjecting the child to maltreatment, abuse, neglect,

exploitation or degradation or exposing the child to violence or exploitation or other harmful behaviour; or

ii. exposing the child to maltreatment, abuse, degradation, ill-treatment, violence or harmful behaviour towards another person;

m. any family violence involving the child or a family member of the child; and

n. which action or decision would avoid or minimise further legal or administrative proceedings in relation to the child.

2. In this section “parent” includes any person who has parental responsibilities and rights in respect of a child.

If a parent unreasonably refuses a genetic test, the Minister of Social Development may consent instead of the parent in terms of section 129(7) of the Children’s Act. Parents, guardians or care-givers may also not refuse consent on the basis of religion or other beliefs, unless there are medically acceptable alternatives available to the child. Therefore, if the genetic test is necessary in order to commence treatment, or to decide on the correct treatment, a parent, caregiver or guardian cannot refuse to provide such consent.

A thorough assessment of the child’s circumstances, relationship with, and capacity of the parents, mental development, as well as health status (chronic conditions and/or disability), is therefore required.

Foster parents have the right to be informed of “any fact or occurrence” that may “substantially affect the foster placement (section 66(3)), which would include the results of genetic testing, where such would impact on the ability of the foster parents to care for the child, in the child’s best interest.


ConfidentialityOf the same grave importance as informed consent, is confidentiality. A key aspect of confidentiality is that the person whose information it is, has the right to control such information. This means that the person has the right to decide on disclosure: To whom, when, and in which settings.

There are, under the NHA’s section 14(2), only under three circumstances can healthcare information can be disclosed, namely:

a. With the patient’s written consent;b. When a law authorise a disclosure;c. When a court orders a disclosure.

There is no general law authorising the disclosure of genetic conditions, save for cancers, which has to be reported to the NHLS under the Regulations on the Cancer Registry, published as Government Notice R 380 of 26 April 2011.

This means that, prior to any disclosure, a healthcare professional should obtain the written consent patient, or child patient of 12 years or older. This consent must contain:• Details as to whom the disclosure can be made;• Details as to the extent of the disclosure (what exactly can,

and cannot be disclosed relating to the patient’s visit or stay at a health facility, the diagnosis, treatment, prognosis, etc.);

• The duration for which the consent to disclosure is valid;• Any other matter pertaining to the implications of a

disclosure, such as how follow-up questions by the person to whom the disclosure is made, should be handled.

Provisions contained in the soon-to-be-implemented Protection of Personal Information (“POPI”) Act, should also be borne in mind, namely that health information, and information on children are special information, subject to more stringent privacy protections. Further processing of personal information is also limited by the initially consent obtained, for example, further research on a genetic condition can only take place with the patient’s consent, even if such further research will not identify the patient, but will be based on identified or identifiable information, such as a patient record or file.

HPCSA Rules: Genetic counsellors as medical scientistsBased on the above, the importance of involving generic counsellors in the pre-consent, consent and post-consent processes, as well as when disclosures are considered, is evident.

Genetic Counsellors are governed by the HPCSA as part of the profession of medical scientists. Genetic Counsellors are required to enter a two-year internship when they register for a M.Sc. degree in Genetic Counselling. One of these years is during their Master’s degree, and one year thereafter. The internship must be completed in an HPCSA accredited training facility under the supervision of an appropriate HPCSA registered group of genetic counsellors and medical geneticists.

The scope of the profession of genetic counsellors has been set in Government Notice No 579 of 22 May 2009. The scope of practice of genetic counsellors make it clear that, as with all medical scientists, genetic counsellors perform an auxiliary and supporting service to medicine and do not diagnose nor treat patients for a medical condition.

The genetic counsellor has a pre-screening role, by addressing consents of the presence of a genetic disorder in a family. Apart from providing information on risk assessment, the science and education, the genetic counsellor should work with medical practitioners and other professionals, such as social workers, psychologists, etc. The scope of practice of genetic counsellors, as published by the HPCSA in May 2013, includes: • Providing genetic counselling to anyone who is concerned

about or referred as a result of the presence of a genetic disorder/s in him or herself or in the family.

• Collecting and interpreting comprehensive patient information, including medical, genetic and psychosocial family histories.

• Making appropriate and accurate genetic risk assessments, offering options for dealing with these risks and referrals to other agencies, as appropriate.

• Educating regarding the medical, genetic and scientific aspects of the condition/s and the associated risks.

• Using therapeutic short term counselling and communication skills to address the psychosocial needs of patients and their families and to assist them in making the best possible adjustment to the disorder.

• Requesting appropriate genetic tests, as indicated, in association/consultation with a medical practitioner.

• Liaising, in the form of consultations, discussions, written reports and referrals, with of the healthcare professionals to provide optimum services.

• Planning, organising and delivering professional and public education in genetic healthcare.

• Serving as a genetic health care resource for professionals and the general public.

• Participating in research in the field of genetic counselling, where possible.

Genetic tests as medical devicesWith amendments to the Medicines and Related Substances Act, 1965 (“Medicines Act”), in effect from 1 June 2017, diagnostic tests (which are medical devices) have been included in the regulatory framework previously only applicable to medicines. All IVDs – i.e. in vitro diagnostic tests, are subject to this framework, as well as a set of regulations promulgated in December 2016.

Companies providing such tests as importers and/or local manufacturers, have had to apply for licences in August 2017, and the South African Health Products Regulatory Authority (SAHPRA) is in the process of awarding licences. Distributors have to apply for licences before or on 24 February 2018. This means that the suppliers of such tests have to be duly licenced, for such tests to be validly and lawfully used in South Africa.


Following the licensing of entities in the supply chain, the tests will be called up for registration under the Medicines Act and Device Regulations of 2016. If a test is proven to be of good quality, safe and perform as intended, it will be registered for use in South Africa. Existing tests on the market can be continued to be used until such a call-up is made, but is subject to adverse event reporting. This means that false results, test failures and the likes must already be reported, under regulation 17 of the Device Regulations. The form to use to report such events is the same as that used to report medicines adverse events, and can be found on the SAHPRA website: http://mccza.com.

Of critical importance also is the prohibition of advertising of medical devices and IVDs that fall in the category of “class C” or “class D” IVDs. Regulation 21 prohibits the advertisement of these tests to the public. Many, if not all, of the genetic tests would fall within class C or D, and can therefore not be promoted to the public. It can be advertised to healthcare professionals, who’d need to discuss its possible availability and use with patients.

Although specific (branded) tests cannot be advertised, educational activities on genetic conditions, and the availability

of tests relating to such conditions can, and indeed should, be made available to the public at large.

ConclusionGenetic testing requires careful consideration of older ethical rules such as those on informed consent and confidentiality. There are also very specific considerations relating to what should be discussed during informed consent processes, and detailed provisions when children are involved. The tests themselves, and the companies that manufacture, import and distribute the tests are also now subject to a relatively new legal framework.

Healthcare professionals should not only be aware of these legal frameworks, but also work together in teams in order to ensure application of the various legal and ethical provision, with a key role set for genetic counsellors.

References1. See “HPCSA Regulations” under “Scope of the Profession” at

http://sashg.org/information-and-education/.2. See “HPCSA Regulations” under “Scope of Practice for

Genetic Counsellors” at http://sashg.org/information-and-education/.

As a healthcare professional (HCP), you can effortlessly complete all your CPD compliance requirements on the SAMA accredited, Medical Practice Consulting (MPC) Online Education System, without having to leave the comfort of your own home or practice.

The MPC System provides a comprehensive CPD compliance solution that offers accredited CPD events, journals and courses, as well as industry leading CPD management services such as automatic issuing and secure storage of all your CPD certificates within the MPC CPD Manager.

What sets the MPC CPD Manager apart is its unique functionality that enables HCPs to elec-tronically submit your CPD activity records directly to the HPCSA at the click of the button when audited.

All this functionality is available at no cost on MPC.

Healthcare professionals can acquire CPD points with this newsletter by completing an online multiple-choice questionnaire on www.mpconsulting.co.za. All queries should be directed at [email protected] | 012 001 0452.

Register today on www.mpconsulting.co.za.


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DisclaimerThe content contained in this publication contains medical or health sciences information and is intended for professional use within the medical field. No suggested test or procedure should be carried out unless, in the reader’s judgement, its risk is justified. Because of rapid advances in the medical sciences, we recommend that the independent verification of diagnoses and drug dosages should be made. Discussions views, and recommendations as to medical procedures, products, choice of drugs, and drug dosages are the views of the authors. The views expressed by the editor or authors in this newsletter do not necessarily reflect those of the sponsors or publishers. The sponsors, publishers and editor will not be liable for any damages or injuries of any kind arising from the use or misuse of information provided in this publication and do not support the use of products for off label indications.

2018 Congresses

Event/Congress Date Venue Contact

South African Society of Anaesthetists (SASA 2018)

4-8 April

Cape Town International Convention Centre, Cape Town

www.sasacongress.com

Stroke & Hypertension Congress 2018

3-5 August

Protea Hotel Stellenbosch, Stellebosch

www.strokeandhy-pertension2018.co.za/

PainSA 2018 18-20 May

Emperor’s Palace Convention Centre, 64 Jones Road, Johannesburg

[email protected]

34th World Congress of Internal Medicine (WCIM 2018)

18-21 October

Cape Town International Convention Centre, Cape Town

www.wcim2018.com

Congress Calendar 2018

References: 1. Clark BG, Jue SG, Dawson GW, et al. Loprazolam - A Preliminary Review of its Pharmacodynamic Properties and Therapeutic Efficacy in Insomnia. Drugs. 1986:31(6):500-516. 2. Dormonoct® 2 mg package insert. 3. Salkind MR, Silverstone T. The Clinical and Psychometric Evaluation of a new Hypnotic Drug, Loprazolam, in General Practice. Curr Med Res Opin. 1983;8(5):368-374. 4. McInnes GT, Bunting EA, Ings RMJ, et al. Pharmacokinetics and Pharmacodynamics Following Single and Repeated Nightly Administrations of Loprazolam, a new Benzodiazepine Hypnotic. Br J Clin Pharmac.1985:19:649-656. 5. Botter PA. A comparative Double-blind Study of Loprazolam, 1 mg and 2 mg, Versus Placebo in Anxiety-induced Insomnia. Curr Med Res Opin. 183;8(9):626-630.

For full prescribing information refer to the package insert approved by the medicines regulatory authority.

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