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TBC1D24-associated phenotypes, including DOORS. Campeau and colleagues2 also show that the crucial function of TBC1D24 extends beyond neuronal cells, to chondrocytes and bone. Why only some TBC1D24 mutations are associated with a chondrocyte and bone phenotype is unknown. The underlying cellular and molecular mechanism for the growing number of TBC1D24-associated phenotypes is far from clear. Whether the explanation is in the TBC1D24 mutations themselves, TBC1D24associated proteins and pathways, or precise timing of TBC1D24 function during development has not been established. The framework for understanding phenotype–genotype correlation is more complicated than was envisaged by Garrod and his early successors. Elucidation of this association will be crucial for deeper understanding in the laboratory and the clinic, and for the development of new treatments. In view of what is known so far about TBC1D24-mutation pleiotropy, studies such as that of Campeau and colleagues2 will provide new opportunities toward achieving this goal. Samuel F Berkovic*, Jozef Gecz Epilepsy Research Centre, Melbourne Brain Centre, Austin Health, 245 Burgundy Street, Heidelberg, VIC 3084, Australia (SFB); and School of Paediatrics and Reproductive Health, The University of Adelaide at the Women’s and Children’s Hospital, North Adelaide, Adelaide SA 5006, Australia [email protected]

We declare that we have no conflicts of interest. 1 2

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Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013; 369: 1502–11. Campeau PM, Kasperaviciute D, Lu JT, et al. The genetic basis of DOORS syndrome: an exome sequencing study. Lancet Neurol 2013; published online Nov 29. http://dx.doi.org/10.1016/S1474-4422(13)70265-5. Cantwell RJ. Congenital sensori-neural deafness associated with onycho-osteo dystrophy and mental retardation (D.O.O.R. syndrome). Humangenetik 1975; 26: 261–65. Qazi QH, Nangia BS. Abnormal distal phalanges and nails, deafness, mental retardation, and seizure disorder: A new familial syndrome. J Pediat 1984; 104: 391–94. Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet 2013; 132: 1077–130. Falace A, Filipello F, La Padula V, et al. TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. Am J Hum Genet 2010; 87: 365–70. Corbett MA, Bahlo M, Jolly L, et al. A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24. Am J Hum Genet 2010; 87: 371–75. Afawi Z, Mandelstam S, Korczyn AD, et al. TBC1D24 mutation associated with focal epilepsy, cognitive impairment and a distinctive cerebro-cerebellar malformation. Epilepsy Res 2013; 105: 240–24. Guven A, Tolun A. TBC1D24 truncating mutation resulting in severe neurodegeneration. J Med Genet 2013; 50: 199–202. Milh M, Falace A, Villeneuve N, et al. Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy. Hum Mutat 2013; 34: 869–72. Barcia G, Fleming MR, Deligniere A, et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet 2012; 44: 1255–59. Schweitzer JK, Sedgwick AE, D’Souza-Schorey C. ARF6-mediated endocytic recycling impacts cell movement, cell division and lipid homeostasis. Semin Cell Dev Biol 2011; 22: 39–47.

Intracranial aneurysms: individualising the risk of rupture The decision of what to do with asymptomatic unruptured intracranial aneurysms is a fairly new problem. Although these aneurysms have been known to exist for centuries through autopsies and for several decades through catheter angiography, their true prevalence did not begin to emerge until the use of non-invasive angiograms became widespread in the recent past. Now we know that nearly 3% of the general population has an unruptured intracranial aneurysm.1 Comparatively, subarachnoid haemorrhages from aneurysmal rupture are relatively uncommon. This discrepancy indicates that many intracranial aneurysms are not destined to rupture. Yet, the consequences of rupture can be devastating.2 Treatment of the aneurysm by craniotomy and clipping or by endovascular coiling www.thelancet.com/neurology Vol 13 January 2014

can effectively eliminate the risk of subarachnoid haemorrhages, but treatment of all unruptured intracranial aneurysms is neither prudent, because of the risk of iatrogenic complications, nor parsimonious, because of the high financial cost.3 Thus, when advising a patient with an asymptomatic unruptured intracranial aneurysm we face a difficult problem. An adequate solution can only be based on individualisation of the rupture risk. In The Lancet Neurology, Jacoba Greving and colleagues4 present their analysis of individual patient data pooled from six prospective cohort studies on the natural history of unruptured intracranial aneurysms (three from Japan, one from the Netherlands, one from Finland, and one from the USA, Canada, and

Published Online November 27, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70272-2 See Articles page 59

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various European countries). The large sample size of the combined population allowed the researchers to refine the estimation of rupture risk at 1 and 5 years, define the strongest predictors of rupture among those evaluated in the original studies, and develop a score (named PHASES) to gauge the individual risk of rupture using readily available information. The information provided is solid and has practical value. I plan to use it when advising my patients, although keeping in mind certain caveats. The PHASES score is calculated from the region of origin of the patient (attributing a higher risk to Finnish and Japanese patients than to all others, although specific information is not available for most world regions), presence of hypertension, patient’s age (dichotomised at 70 years), maximum diameter of the aneurysm (by far the strongest predictor of rupture), previous history of subarachnoid haemorrhage from another aneurysm, and the site of the aneurysm (with a higher risk assigned to aneurysms arising from the anterior cerebral arteries, posterior communicating arteries, or the posterior circulation vessels). Notable absences include smoking (at entry and on follow-up),5 hypertension control, family history of subarachnoid haemorrhage, multiplicity of unruptured intracranial aneurysms, other anatomical and haemodynamic factors of the aneurysm (inflow angle, concentrated inflow jets, complex flow patterns, non-spherical shape, dome-to-neck ratio),6 and, most importantly, evidence of aneurysm growth over time.7 Yet, these Diagnosis of unruptured intracranial aneurysm

Individual estimate of rupture risk (PHASES score) Low

High

Smoking cessation Control of hypertension

Smoking cessation Control of hypertension

Clinical and radiological follow-up

Aneurysm treatment

Treat aneurysm if symptoms or evidence of growth

Figure: Proposed algorithm for the management of unruptured intracranial aneurysms

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additional factors also deserve careful consideration. Smoking cessation and control of hypertension might reduce rupture risk.8 Follow-up imaging to exclude aneurysm growth is necessary because growth is strongly associated with increased risk of subarachnoid haemorrhage,7 although the optimum frequency and duration of radiological follow up is not well defined. The Article also incorporates charts offering specific 5-year risk prediction for different populations. Readers should note that the chart that would apply to North America and European countries other than Finland is based on information from the large ISUIA cohort (1691 patients with a median follow-up of 9 years)9 and the much smaller Dutch cohort of the study by Wermer and colleagues (93 patients with a median follow-up of 2·2 years).10 The risk predictions on this chart are therefore mainly derived from the ISUIA cohort, which highlights the limitations of pooling data from heterogeneous cohorts of very different sizes. Nonetheless, the information on this chart is presented in a visually appealing and user-friendly format and represents a refinement of individual risk stratification. The greatest caveat in the interpretation of these risk estimates is that they are based on cohorts of patients for whom treatment of the aneurysm was left at the discretion of the patient’s physician. Patients thought to be at high risk of rupture might have been treated at first recognition of the aneurysm (thus not being entered into the observational cohort) or after developing symptomatic or asymptomatic aneurysm growth without rupture (thus being censored from the cohort in which they had been enrolled). This selection bias affects the reliability of the risk predictions presented in this analysis. If aneurysms deemed at greatest risk of rupture had not been treated, the observed rates of rupture would probably have been higher. Consequently, the rupture rates presented in this pooled analysis might be an underestimation of the actual risks. Yet, this bias should not affect the value of the predictive factors for rupture identified in the proposed model. As correctly pointed out by the investigators, a pure natural history study on the risk of rupture of intracranial aneurysms is impossible because treatment is favoured over observation in a substantial proportion of cases. Whether treatment is truly a better option for www.thelancet.com/neurology Vol 13 January 2014

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all patients with unruptured intracranial aneurysm is a question that could only be answered by a rigorous randomised clinical trial. As the matter stands, we have to rely on our clinical judgment and the best available information about risk of rupture to offer individualised advice to our patients (figure). Such information is provided by Greving and colleagues’ study4 and pragmatically summarised in the PHASES score.

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Alejandro A Rabinstein

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Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA [email protected]

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I declare that I have no conflicts of interest. 1

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Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 2011; 10: 626–36. Rabinstein AA, Lanzino G, Wijdicks EF. Multidisciplinary management and emerging therapeutic strategies in aneurysmal subarachnoid haemorrhage. Lancet Neurol 2010; 9: 504–19.

www.thelancet.com/neurology Vol 13 January 2014

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Brinjikji W, Kallmes DF, Lanzino G, Cloft HJ. Hospitalization costs for endovascular and surgical treatment of unruptured cerebral aneurysms in the United States are substantially higher than medicare payments. AJNR Am J Neuroradiol 2012; 33: 49–51. Greving JP, Wermer MJH, Brown RD Jr, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 2013; published online Nov 27. http://dx.doi.org/10.1016/S1474-4422(13)70263-1. Vlak MH, Rinkel GJ, Greebe P, Algra A. Risk of rupture of an intracranial aneurysm based on patient characteristics: a case-control study. Stroke 2013; 44: 1256–59. Cebral JR, Mut F, Weir J, Putman CM. Association of hemodynamic characteristics and cerebral aneurysm rupture. AJNR Am J Neuroradiol 2011; 32: 264–70. Burns JD, Huston J 3rd, Layton KF, et al. Intracranial aneurysm enlargement on serial magnetic resonance angiography: frequency and risk factors. Stroke 2009; 40: 406–11. Lindekleiv H, Sandvei MS, Romundstad PR, et al. Joint effect of modifiable risk factors on the risk of aneurysmal subarachnoid hemorrhage: a cohort study. Stroke 2012; 43: 1885–89. International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003; 362: 103–10. Wermer MJ, van der Schaaf IC, Velthuis BK, Majoie CB, Albrecht KW, Rinkel GJ. Yield of short-term follow-up CT/MR angiography for small aneurysms detected at screening. Stroke 2006; 37: 414–18.

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Intracranial aneurysms: individualising the risk of rupture.

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