Systematic Review of N-of-1 Studies in Rare Genetic Neurodevelopmental Disorders

Müller, Annelieke R.; Brands, M.M.M.G.; Ven, Peter M. van de; Roes, Kit C. B.; Cornel, Martina C.; Wijburg, Frits A.; Daams, Joost G.; Boot, Erik; Eeghen, Agnies M. van

doi:10.1212/wnl.0000000000011597

Cited by 41 publications

(33 citation statements)

References 56 publications

(99 reference statements)

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“…N-of-1 studies are randomized, controlled, multiple crossover trials in single patients. 138 Pooled data from multiple N-of-1 trials can produce robust treatment effect estimates. 139 The N-of-1 study design offers an approach for providing evidence-based, personalized medicine.…”

Section: Discussionmentioning

confidence: 99%

Epilepsy in the mTORopathies: opportunities for precision medicine

Moloney

Cavalleri

Delanty

2021

Brain Communications

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The mechanistic target of rapamycin (mTOR) signalling pathway serves as a ubiquitous regulator of cell metabolism, growth, proliferation and survival. The main cellular activity of the mTOR cascade funnels through mTOR complex 1, which is inhibited by rapamycin, a macrolide compound produced by the bacterium Streptomyces hygroscopicus. Pathogenic variants in genes encoding upstream regulators of mTOR complex 1 cause epilepsies and neurodevelopmental disorders. Tuberous sclerosis complex is a multisystem disorder caused by mutations in mTOR regulators TSC1 or TSC2, with prominent neurological manifestations including epilepsy, focal cortical dysplasia and neuropsychiatric disorders. Focal cortical dysplasia type II results from somatic brain mutations in mTOR pathway activators MTOR, AKT3, PIK3CA and RHEB and is a major cause of drug-resistant epilepsy. DEPDC5, NPRL2 and NPRL3 code for subunits of the GTPase-activating protein (GAP) activity towards Rags 1 complex (GATOR1), the principal amino acid-sensing regulator of mTOR complex 1. Germline pathogenic variants in GATOR1 genes cause non-lesional focal epilepsies and epilepsies associated with malformations of cortical development. Collectively the mTORopathies are characterised by excessive mTOR pathway activation and drug-resistant epilepsy. In the first large-scale precision medicine trial in a genetically-mediated epilepsy, everolimus (a synthetic analogue of rapamycin) was effective at reducing seizure frequency in people with tuberous sclerosis complex. Rapamycin reduced seizures in rodent models of DEPDC5-related epilepsy and focal cortical dysplasia type II. This review outlines a personalised medicine approach to the management of epilepsies in the mTORopathies. We advocate for early diagnostic sequencing of mTOR pathway genes in drug-resistant epilepsy, as identification of a pathogenic variant may point to an occult dysplasia in apparently non-lesional epilepsy or may uncover important prognostic information including, an increased risk of sudden unexpected death in epilepsy in the GATORopathies or favourable epilepsy surgery outcomes in focal cortical dysplasia type II due to somatic brain mutations. Lastly, we discuss the potential therapeutic application of mTOR inhibitors for drug-resistant seizures in GATOR1-related epilepsies and focal cortical dysplasia type II.

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Section: Discussionmentioning

confidence: 99%

Epilepsy in the mTORopathies: opportunities for precision medicine

Moloney

Cavalleri

Delanty

2021

Brain Communications

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“…Traditionally, the ideal setup for therapy trials, preferred by the FDA, Health Canada, and European Medicines Agency, is randomized, double blind, and placebo controlled, although particularly for ultra-rare disorders, novel trial designs have been adopted. 46 , 47 In the adolescent and adult VWM population, progression is generally slow, and given the absence of other treatment options, double-blind placebo-controlled trials are preferable (consortium 9/9). With early onset, the disease course is more predictable and generally fast.…”

Section: Clinical Trials In Vwmmentioning

confidence: 99%

Therapy Trial Design in Vanishing White Matter

et al. 2022

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Vanishing white matter (VWM) is a leukodystrophy caused by recessive variants in the genes EIF2B1-EIF2B5. It is characterized by chronic neurologic deterioration with superimposed stress-provoked episodes of rapid decline. Disease onset spans from the antenatal period through senescence. Age at onset predicts disease evolution for patients with early onset, whereas disease evolution is unpredictable for later onset; patients with infantile and early childhood onset consistently have severe disease with rapid neurologic decline and often early death, whereas patients with later onset have highly variable disease. VWM is rare, but likely underdiagnosed, particularly in adults. Apart from measures to prevent stressors that could provoke acute deteriorations, only symptomatic care is currently offered. With increased insight into VWM disease mechanisms, opportunities for treatment have emerged. EIF2B1-EIF2B5 encode the 5-subunit eukaryotic initiation factor 2B complex, which is essential for translation of mRNAs into proteins and is a principal regulator of the integrated stress response (ISR). ISR deregulation is central to VWM pathology. Targeting components of the ISR has proven beneficial in mutant VWM mouse models, and several drugs are now in clinical development. However, clinical trials in VWM pose considerable challenges: low numbers of known patients with VWM, unpredictable disease course for patients with onset after early childhood, absence of intermediate biomarkers, and novel first-in-human molecular targets. Given these challenges and considering the critical need to offer therapies, we have formulated recommendations for enhanced diagnosis, drug trial setup, and patient selection, based on our expert evaluation of molecular, laboratory, and clinical data.

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“…In fact, the patient presents with key aspects of the disorder and has a mutation that is very likely to disrupt protein function. The addition of new cases to the literature of this condition are important ( 27 ), not only to expand the understanding of this rare syndrome, but also in the hope of working toward potential treatments.…”

Section: Discussionmentioning

confidence: 99%

Case Report: A Novel GNB1 Mutation Causes Global Developmental Delay With Intellectual Disability and Behavioral Disorders

et al. 2021

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Diseases of neurodevelopment mostly exhibit neurological and psychiatric symptoms that go from very mild to extremely severe. While the etiology of most cases of neurodevelopmental disease is still unknown, the discovery of underlying genetic causes is rapidly increasing, with hundreds of genes being currently implicated as disease-causing. Here, we report a clinical case of a patient with a previously undiagnosed syndrome comprising severe global developmental delay, intellectual disability, and behavioral disorders (such as attention-deficit/hyperactivity disorder, autism spectrum disorder and recurrent bouts of aggressive behavior). After genetic testing, a pathogenic variant was detected in the GNB1 gene, which codes for the G-protein subunit β1. The detected variant (c.217G>A, p.A73T) has not been previously reported in any of the 58 published cases of GNB1 encephalopathy. However, it localizes to the mutational hotspot in exons 6 and 7 in which 88% of all missense mutations occur. An in silico model predicts that this mutation is likely to disrupt the WD40 domain of the GNB1 protein, which is required for its interaction with other G-proteins and, consequently, for downstream signal transduction. In conclusion, we reported an additional GNB1 encephalopathy patient, bearing a novel mutation, taking another step toward a better understanding of its clinical presentation and prospective development of treatments for the disease.

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Systematic Review of N-of-1 Studies in Rare Genetic Neurodevelopmental Disorders

Cited by 41 publications

References 56 publications

Epilepsy in the mTORopathies: opportunities for precision medicine

Epilepsy in the mTORopathies: opportunities for precision medicine

Therapy Trial Design in Vanishing White Matter

Case Report: A Novel GNB1 Mutation Causes Global Developmental Delay With Intellectual Disability and Behavioral Disorders

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