The ‘overarching theme’ of this year’s 4th Congress of the European Academy of Neurology (EAN), which was held from 16–19 June 2018 in Lisbon, Portugal, was neurogenetics, a rapidly expanding field. This theme was reflected in numerous presentations, workshops and symposia. In this article, we highlight a selection of the workshops and presentations that reflect the latest research and the potential within this area.
A focused workshop entitled ‘Novel genetic techniques in neurological practice – time for responsible clinical and research implementation’ provided an insight into the application, interpretation and limitations of next-generation sequencing (NGS).1 Conventional molecular testing of patients with genetic disorders has relied primarily on single-gene or panel testing, or microarrays. However, up to 50% of patients fail to receive a molecular diagnosis after such testing and enter into a lengthy and expensive diagnostic process.2 The use of NGS has decreased the cost of DNA sequencing; downstream data analysis, storage and interpretation account for most of the expense. In patients with nonspecific neurological disorders, for which a number of genetic causes might exist, three options are available. Whole genome sequencing or whole-exome sequencing (WES) have shown promise. However, unexpected variants might be found that are of uncertain significance and are unrelated to the initial sequencing indication. Targeted-panel NGS employs a series of disease-focussed genes. By focusing on the genes most likely to be involved, these panels are more cost-effective and minimise the need for data analysis. One key difficulty in the design of these panels is defining the appropriate list of genes for a particular phenotype due to the heterogeneity of clinical presentations. There are still drawbacks to the current sequencing technologies and these may be overcome by future developments, such as long read and nanopore technology.3
A poster presentation described the diagnostic yield of NGS studies in neurological disorders at a tertiary centre in Portugal. Of 192 patients included, a definitive molecular diagnosis was made in around a third (35.4%). The main neurological syndromes identified were: intellectual disability/autism (45.8%), epilepsy (12%), dementia (9.9%) and muscle disease (9.4%). A further 19.8% of patients had findings of clinical undetermined significance.4 A Greek study of 109 patients reported a 46.8% diagnostic rate for WES, identifying epilepsy/epileptic encephalopathies (29.3%), muscle disorders (19.3%), developmental disorders (13.8%) and motor neuron disease/spastic paraparesis (8.3%).5 These studies did not address cost-effectiveness but highlighted the potential of NGS technique.
Neurogenetics can be an important tool for the identification of rare neurologic disorders. Symptoms of these disorders can be difficult to recognise, delaying diagnosis and prompt treatment initiation. For example, new mutations have been found in hypomyelination with atrophy of the basal ganglia and cerebellum, a rare leukodystrophy.6 In addition, genetic analysis is allowing the identifications of new phenotypes of known conditions, for example, a new distinct phenotype of spastic-ataxia with hypomyelination that is negative for previously known hypomyelinating genes.7
For more common neurologic disorders, such as epilepsy, Alzheimer's disease and Parkinson's disease (PD), neurogenetics is facilitating the identification of hereditary forms, allowing those affected to be informed of the risks earlier. A case study described the first known cases of early onset PD related to the S107L mutation in the glucocerebrosidase gene (GBA1).8 Another example is familial dementia, which is diagnosed by single gene analysis. However, identification of a single genetic cause is difficult due to phenotypic overlap between the different subtypes, locus heterogeneity, and variable accessibility of genetic tests. An Italian study described a custom-designed NGS panel that identified pathogenic and novel pathogenic variants in 55 of 300 patients (18.33%), in common and rare genes. Researchers also identified a novel possible risk factor in one patient, known genetic risk factors in seven patients, and previously reported variants of uncertain significance in 10 patients.9
Genetic variants of known conditions can also help target therapy to the individual. A Portuguese study highlighted advances in the recognition of new causative genes of paediatric epileptic encephalopathies in 10 children, all presenting with treatment-refractory seizures in the new born period and all evolving to global developmental delay. The use of NGS allowed individualised treatment directed to the dysfunction of specific proteins and has laid the foundations for future genetic treatment.10 In addition, a South Korean study identified new genetic variants associated with wearing-off and levodopa-induced dyskinesia (LID) within 5 years after PD onset.11 The occurrence and clinical features of wearing off and LID are very heterogeneous among patients with PD, and this is a potentially important finding.
Neurogenetics has also provided a rich source of molecular biomarkers. An Italian study investigated microRNAs, small non-coding RNAs that modulate numerous biological functions in various pathological conditions and can be actively released by muscle.12 Upregulation of miR-206, was seen in Becker and facioscapulohumeral muscular dystrophy as well in lipid storage myopathies, suggesting its potential as a biomarker.13
While many of these studies are small and require confirmation in larger studies, they have highlighted the potential of neurogenetics. Gene replacement therapy is also likely to emerge in the field of neurology in the coming years. This intervention holds promise in a number progressive disorders, including spinal muscular atrophy14 and Friedreich's ataxia,15 an inherited disease that causes progressive damage to the nervous system. Prof. Günther Deuschl, president of the EAN, summarised the growth of the field as follows: “Neurogenetics is not a panacea that holds the key to solving every problem. But it does help to reclassify diseases and groups of diseases, and promises to open up new treatment approaches.”16
1. Overarching theme: Novel genetic techniques in neurological practice – time for responsible clinical and research implementation (abstracts FW09_1–3). Eur J Neurol. 2018;25(Suppl 2):642–3.
2. Shashi V, McConkie-Rosell A, Rosell B, et al. The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. Genet Med. 2014;16:176–82.
3. Houlden H. FW09_1 What should the general neurologist know about next generation sequencing (NGS)? Eur J Neurol. 2018;25(Suppl 2):642.
4. Marques-Matos C, Leao M. EPO2087 Diagnostic yield of next-generation sequencing (NGS) technology applied to neurological disorders. Eur J Neurol. 2018;25(Suppl 2):195.
5. Zaganas I, Michaelidou K, Bourbouli M, et al. EPR1118 Utility of whole exome sequencing as a diagnostic tool in different neurologic phenotypes. Eur J Neurol. 2018;25(Suppl 2):343.
6. Hamilton EM, Bertini E, Kalaydjieva L, et al. O125 UFM1 founder mutation in the Roma population causes severe variant of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Eur J Neurol. 2018;25(Suppl 2):31.
7. Chelban V, Alsagob M, Kloth K, et al. O126 Phenotypic and neuroimaging expression of NKX6-2 mutations lead to a new distinct disease with spastic ataxia and hypomyelination. Eur J Neurol. 2018;25(Suppl 2):32.
8. Hertz E, Thörnqvist M, Holmberg B, et al. EPO2081 First clinicogenetic description of Parkinson’s disease related to S107L GBA1 mutation. Eur J Neurol. 2018;25(Suppl 2):192.
9. Bartoletti-Stella A, Stanzani-Maserati M, Caffarra P, et al. EPR1121 Targeted sequencing for the diagnosis of familial dementias. Eur J Neurol. 2018;25(Suppl 2):344.
10. Marecos C, Jacinto S, Dias AI, et al. EPO2091 New genes on infantile epileptic encephalopathies–five years experience of a tertiary center review. Eur J Neurol. 2018;25(Suppl 2):197.
11. Chung SJ, Kim J, Kim K, et al. EPO2082 Common and rare genetic variants associated with wearing-off and dyskinesia in Parkinson’s disease. Eur J Neurol. 2018;25(Suppl 2):192.
12. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.
13. Angelini C, Giaretta L, Pegoraro V, Marozzo R. EPR1115 Micro RNA in muscular dystrophies and metabolic myopathies are useful biomarkers. Eur J Neurol. 2018;25(Suppl 2):341.
14. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377:1713–22.
15. Rummey C, Kichula E, Lynch DR. Clinical trial design for Friedreich ataxia - where are we now and what do we need? Expert Opin Orphan Drugs. 2018;3:219–30.
16. Springer Healthcare. 2018 EAN: Daily Update. Saturday 16 June 2018. Available at: https://medically.roche.com/content/dam/pdmahub/non-restricted/neurology/ean-2018/EAN-Conference-Newsletter-6-16.pdf (accessed 27 June 2018).