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Women Researchers in NF – Kathryn North

Four Decades On What I Have Learned About Learning in NF1

Kathryn North, AC, BSc, MBBS, MD, DMedSc, University of Melbourne

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1982…An early fascination with birth defects and the neural crest

My first foray into genetics and rare diseases was during my undergraduate medical degree at the University of Sydney. I decided to take a year out from the constant exams and enrolled in a one-year research option available to medical students (Bachelor of Science in Medicine). I was fascinated by birth defects and Smith’s Recognizable Patterns of Human Malformation and was drawn to a project to study the potential effects of thalidomide on neural crest development with the late Professor Janet McCredie.

As part of this study, I worked with the neuropathologists at the Royal Alexandra Hospital for Children in Sydney to review a cohort of babies with multiple birth defects to determine if there were common patterns that could be attributed to perturbations in the development of the nervous system. This research year sparked my lifelong interest in research, in neurology and in genetics. I loved the experience of autonomy to pursue the subjects that interested me, the thrill of discovery, and the discipline of the scientific method.  I returned to the last two years of my medical degree invigorated and knowing exactly what I wanted to do in my medical career.

The clinical experience in paediatrics in the fourth year of my medical degree cemented my desire to work with children and introduced me to Professor Robert Ouvrier, an academic child neurologist who “wrote the book” on childhood disorders of the peripheral nervous system and became a lifelong mentor. I started my paediatric residency at the Royal Alexandra Hospital for Children (now The Children’s Hospital at Westmead) in 1987.

Physician training in Australia is different from many other places, such as the US. We do three years of “basic training” in paediatrics, sit a fellowship exam, and then specialise in a specific area (for me it was initially neurology). I met my first patient with NF1 during my basic training, who presented with a brainstem glioma and hydrocephalus. During that time, I first discovered Vic Riccardi’s seminal paper on NF11 and was immediately fascinated by the disorder – I reread the paper many times. Part of the fellowship exam involved a long case, spending an hour with a family and a patient, and then presenting my findings and recommendations to a panel of examiners. My long case was a child with NF1 and visual impairment due to NF1! I nailed the presentation (thanks to Vic).

I then applied for advanced training in neurology and was awarded a fellowship for two years – and as part of this application, I was required to develop a research project. I proposed the development of a multidisciplinary NF clinic in partnership with Dr Meredith Wilson from the genetics service (and based on Vic Riccardi’s clinic in Texas) – the first of its kind in Australia. I imagined this would provide a small cohort that would allow me to develop appropriate surveillance and characterise the diagnosis and best management of these patients. An NF patient association (NFAA) had recently been established in Australia and I liaised with this group early on. Within six months, I had over 200 patients! 2

1991…It was a very exciting time to be embarking on research into NF1.

Around this time (1991), Peter Bellermann, who led the National NF Foundation in the USA, visited Sydney to establish a partnership with the founder of the NFAA, Syd Staas. Peter and his wife Pamela gave me great advice about setting up a clinic and recommended that I contact Dr Bruce Korf, a neurologist, geneticist, and head of the Clinical Genetics Department at Boston Children’s Hospital, who ran the NF clinic. Bruce and I became “penpals”. Literally… there was no email in those days. And Bruce provided me with a wealth of detailed information based on his experience. The NF1 gene was cloned in 1990, and neurofibromin was identified in 1992. So, I started in the field at a time when there was an explosion of interest in NF1.

My initial research focussed on the clinical phenotype and optic pathway tumours in young children with NF1 – but as I met with each of the families, it soon became apparent that the major concerns for the parents were the behavioural, social and learning difficulties of their children. And this soon became my major focus as well. At that time the literature suggested that intellectual impairment was common in NF1 (up to 50%), and there were no guidelines for assessment or management of cognitive deficits, and little neuroimaging data. In the early 1990’s, MRI scanning was just starting to become available in clinical practice. We did not have an MRI scanner at the Children’s Hospital initially, and our paediatric patients had special sessions at the adult hospital up the road.

So, I wrote my first research grant. My goal was to characterise the neuropsychological, language and motor deficits, and cranial MRI findings in a cohort of children with NF1 aged 8-16 years (the age range chosen so that general anaesthetic was not required for the MRI). I was awarded the princely sum of $30,000 from the Ramaciotti Foundation and used this to fund sessions for neuropsychology, language, and occupational therapy assessments. I could only afford to study 40 patients, so I decided not to include a control group (beginner’s error). I convinced the Head of Radiology to be a collaborator (beginner’s luck) and the MRI scans were done as part of routine patient care, i.e. at no cost (we have a government funded health system in Australia). These studies formed the basis of my doctoral thesis completed in 1993.3

A “Sliding Door” moment

I was due to complete my neurology training in 1993. At that time in Australia, it was customary for specialist trainees to do a period of training or postdoctoral training overseas (we called it the BOSCB…Been OverSeas then Came Back). In 1992, with the guidance of my mentor, Robert Ouvrier, I organised a series of interviews for neurology training positions at Boston Children’s, Columbia Presbyterian in New York, Johns Hopkins and University of Texas Medical Center. After my first set of neurology interviews in Boston, I met up for lunch with my “pen pal” Bruce Korf, who I had never met in person. After half an hour or so, he said to me, “Why are you doing more training in Neurology – you’ve done that. Why don’t you train in Genetics? I could organize a series of interviews for you this afternoon.” And he did.

To cut a long story short, I joined the Harvard Genetics Program as a fellow in July 1993.

Training in Genetics in Boston was one of the best experiences of my career. I attended NF clinics and completed a number of research projects with Bruce and also expanded my interests in inherited neuromuscular disorders. I got my first experience in molecular genetics with Alan Beggs and Lou Kunkel and learned my way around the laboratory, developing a full suite of laboratory techniques. I was awarded a $10,000 scholarship from the NNFF to support my attendance at conferences, which included international NF meetings in San Diego and Vienna, to present my research on cognitive deficits and neuroimaging in children with NF1. This was the beginning of decades of collaboration and friendship across the global NF community. I feel privileged to have known and worked with so many NF luminaries that I met almost 30 years ago…Bruce Korf (of course), Vic Riccardi, Dave Viskochil, Nancy Ratner, Peggy Wallace, Ros Ferner, Sue Huson, Gareth Evans, David Gutmann, Roger Packer, Meena Upadhyaya, Eric Legius…to name a few.

1996…Back to Australia

I returned to the Children’s Hospital in Sydney as the first recipient of a Clinician-Scientist Award – which provided protected time for research and eventually led to an academic appointment with the University of Sydney. The NF clinic continued and expanded during my time overseas under the leadership of Dr Meredith Wilson, and in 1996, we broadened this clinical service to a Neurogenetics Clinic. NF1 and NF2 remained major focuses, eventually following over 1500 families with NF1.

We established an NF education research clinic in parallel to the medical clinic to meet the needs of the children with learning difficulties and to embark upon expanded studies of cognitive deficits in children with NF1 (Table 1). Over the subsequent decade, we developed a talented team of PhD students and post docs – including Jonathan Payne, Mimi Berman, Natalie Pride, Belinda Barton- many of whom are still working in the field of NF1 today. Our team became part of the international DOD-funded NF Clinical Trials Consortium (the only non-US site at that stage) and we embarked on the largest multicenter clinical trial of statins for neurobehavioural deficits in children with NF1 (with Maria Acosta, Karin Walsh, Nicky Ullrich, Pam Wolters, Michael Fisher, Teena Rosser…again to name a few). This trial produced Class I evidence that lovastatin does not improve clinical outcomes and that there is no convincing evidence for off-label treatment, which was occurring before this study.4 This study also led to recommendations to improve the reproducibility of cognitive outcome measures in clinical trials to improve study design.5

TABLE 1: SUMMARY OF OUR RESEARCH FINDINGS IN CHILDREN WITH NF1 (1996-2012)

  • Intellectual function is static in individuals with NF1 over time – from primary school age into young adulthood.6
  • The relationship between the presence or number of MRI T2H and cognitive deficits in children with NF1 (8-18 years) remains controversial. However, it appears lesions in the thalamus are associated with significantly lower intellectual functioning.

Children with NF1 have:

  • A lowering of Full-Scale IQ (FSIQ) with only a slight increase in the prevalence of intellectual disability.
  • Problems with judging the position of objects in space, organizing and drawing material in a spatial configuration, and matching shapes visually.
  • Problems with planning, forming abstract concepts and utilizing feedback (deficits in executive function).7
  • Difficulties with sustaining and switching attention.

Many different types of cognitive deficits contribute to academic failure in children with NF1:

  • 37% of children with NF1 have a FSIQ score more than one standard deviation (SD) below the population mean.
  • Up to 52% have one or more type of learning disability.8
  • Approximately 38% satisfy the DSM-IV diagnostic criteria for attention deficit hyperactivity disorder (ADHD), and ADHD is highly comorbid with specific learning disability (SLD).9
  • The presence of ADHD is a major contributor to the development of poor social skills in children with NF1.10

Early predictors of later learning difficulties.

  • Children with NF1, as young as 30 months of age, demonstrate early signs of mental, motor, and language delay, indicating two years of age as the appropriate time to perform an initial developmental assessment to identify children at risk of neurodevelopmental difficulties and intervene early.11,12

2013…North moves South

I relocated to Melbourne in 2013 to take on the position of Director of Murdoch Children’s Research Institute. While there was great care for patients with NF1 through the Neurology and Genetics Services at the Royal Children’s Hospital and Victorian Clinical Genetics Service, we worked with those departments and Royal Melbourne Hospital to establish multidisciplinary children’s and adult NF clinics.  A/Prof Jonathan Payne also moved to Melbourne and we continued our research focus on the cognitive deficits associated with NF1 in partnership with the Sydney team and an ever-expanding Melbourne group of researchers in neurogenetics, oncology, neuroimaging and neuropsychology. Our research over the last decade has increasingly focussed on exploring the mechanisms underlying the NF1 cognitive phenotype and the development of early and targeted therapies (Table 2).

TABLE 2: SUMMARY OF OUR RESEARCH FINDINGS IN CHILDREN WITH NF1 (2013-2023)

  • There is a high rate of phonological dyslexia in children with NF113,14, and we have demonstrated that an 8-week home-based phonics training program improves word reading and comprehension. 15
  • We have helped define the broader social communication and autistic phenotype seen in ~50% of children with NF1.16-18
  • In the general population, males are affected more commonly than females (approx 4:1),19 In children with NF1, males and females are affected in equal proportion.17 The social communication and interaction traits in NF1 are similar to those found in autism within the general population. In NF1, there is an additional distinctive profile of restricted interests and repetitive behaviours, with a notable insistence on sameness.16
  • We have identified a novel clinical feature of NF1 – central auditory deficits marked by abnormal timing and amplitude of neural signals and lower afferent fiber density in the brainstem.20 These manifest as difficulties understanding speech, particularly in noisy environments. We subsequently piloted a remote microphone listening device, which improves the signal-to-noise ratio of the teacher’s voice relative to background noise, leading to improved functional communication skills in the classroom.21
  • We have identified abnormal functional networks in the prefrontal and parietal cortices for several cognitive abilities, including inhibitory control and sustained attention, 22,23 providing a potential biomarker to assess response in clinical trials.

Into the future…

To date, investigations into the disease mechanisms leading to the effects of NF1 on brain development and function have primarily been carried out in animal models. Preclinical trials based on a heterozygous mouse model (Nf1+/-) have shown that genetic and pharmacological interventions inhibiting RAS transforming activity can reverse molecular abnormalities and rescue the mouse behavioural phenotype.24,25 These studies provided much optimism for clinicians, researchers, and patients with NF1. However, attempts to replicate these findings in human clinical trials have been frustratingly ineffective.4 Thus, apart from stimulant medication for ADHD in NF1,26,27, there are currently no evidence-based drug treatments for the neurodevelopmental disorders in NF1.

In recent years, stem cell technologies have opened new opportunities to explore novel treatment options for cognitive deficits in NF. Patient-derived induced pluripotent stem cells (iPSC) are the only experimentally tractable system for studying human neurodevelopmental biology and offer a powerful platform for disease modeling and drug discovery.

We and others have developed patient-derived stem cell neuronal models of NF1.28-30 In addition, we have developed stem-cell derived human brain organoids that have been successfully used to identify developmental perturbations associated with autism.31,32 Our goal is to identify pathways that are potential treatment targets and to use our human preclinical models for high-throughput drug screening to identify medications that reverse disease-associated phenotypes.

For most children, the ability to develop, maintain, and understand social relationships and engage in daily activities comes naturally. However, for many children born with NF1, this is not the case. Impairments linked to NF1 can lead to significant lifelong negative impacts on peer relationships, quality of life, literacy, educational attainment, and career choices. My ultimate dream is that our research over more than 30 years will lead to early identification of children with NF1 at risk of cognitive deficits, and the ready availability of early, targeted and effective interventions.

Kathryn North AC BSc(Med) MBBS MD DMedSc FRACP FAHMS
Director, Murdoch Children’s Research Institute

Flemington Road Parkville
Melbourne Victoria 3052 Australia
T +61 3 8341 6226
F +61 3 9348 1391
E kathryn.north@mcri.edu.au
 www.mcri.edu.au

References

  1. Riccardi VM. Von Recklinghausen Neurofibromatosis. New England Journal of Medicine 1981; 305: 1617-27.
  2. North K. Neurofibromatosis type 1: review of the first 200 patients in an Australian clinic. J Child Neurol 1993; 8(4): 395-402.
  3. North K, Joy P, Yuille D, et al. Specific learning disability in children with neurofibromatosis type 1: significance of MRI abnormalities. Neurology 1994; 44(5): 878-83.
  4. Payne JM, Barton B, Ullrich NJ, et al. A randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1. Neurology 2016; 87: 2575-84.
  5. Payne JM, Hearps SJC, Walsh KS, et al. Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1. Ann Clin Transl Neurol 2019; 6: 2555-65.
  6. Hyman SL, Gill DS, Shores EA, et al. Natural history of cognitive deficits and their relationship to MRI T2-hyperintensities in NF1. Neurology 2003; 60(7): 1139-45.
  7. Payne JM, Hyman SL, Shores EA, North KN. Assessment of executive function and attention in children with neurofibromatosis type 1: Relationships between cognitive measures and real-world behavior. Child neuropsychology: a journal on normal and abnormal development in childhood and adolescence 2011; 17: 313-29.
  8. Hyman SL, Shores EA, North KN. Learning disabilities in children with neurofibromatosis type 1: subtypes, cognitive profile, and attention-deficit-hyperactivity disorder. Developmental medicine and child neurology 2006; 48: 973-7.
  9. Hyman SL, Shores EA, North KN. The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology 2005; 65: 1037-44.
  10. Barton B, North K. Social skills of children with neurofibromatosis type 1. Developmental medicine and child neurology 2004; 46: 553-63.
  11. Lorenzo J, Barton B, Acosta MT, North K. Mental, motor, and language development of toddlers with neurofibromatosis type 1. The Journal of Pediatrics 2011; (158): 660-5.
  12. Lorenzo J, Barton B, Arnold SS, North KN. Developmental trajectories of young children with neurofibromatosis type 1: a longitudinal study from 21 to 40 months of age. The Journal of Pediatrics 2015; 166(4): 1006-12.e1.
  13. Watt SE, Shores A, North KN. An examination of lexical and sublexical reading skills in children with neurofibromatosis type 1. Child neuropsychology: a journal on normal and abnormal development in childhood and adolescence 2008; 14: 401-18.
  14. Arnold SS, Payne JM, McArthur G, North KN, Barton B. Profiling the word reading abilities of school-age children with neurofibromatosis type 1. Journal of the International Neuropsychological Society 2021; 27: 484-96.
  15. Arnold SS, Barton BA, McArthur G, North KN, Payne JM. Phonics training improves reading in children with neurofibromatosis type 1: a prospective intervention trial. Journal of Pediatrics 2016; 177: 217-26.
  16. Chisholm AK, Haebich KM, Pride NA, et al. Delineating the autistic phenotype in children with neurofibromatosis type 1. Molecular Autism 2022; 13(1): 3.
  17. Chisholm AK, Lami F, Haebich KM, et al. Sex- and age-related differences in autistic behaviors in children with neurofibromatosis type 1. J Autism Dev Disord 2022.
  18. Payne JM, Walsh KS, Pride NA, et al. Social skills and autism spectrum disorder symptoms in children with neurofibromatosis type 1: evidence for clinical trial outcomes. Developmental Medicine & Child Neurology 2020.
  19. Werling DM, Geschwind DH. Understanding sex bias in autism spectrum disorder. Proc Natl Acad Sci U S A 2013; 110(13): 4868-9.
  20. Rance G, Zanin J, Maier A, et al. Auditory dysfunction among individuals with neurofibromatosis type 1. JAMA Network Open 2021; 4(12): e2134842.
  21. Rance G, Maier A, Zanin J, et al. A randomized controlled trial of remote microphone listening devices to treat auditory deficits in children with neurofibromatosis type 1. Neurol Sci 2022; 43(9): 5637-41.
  22. Pride NA, Korgaonkar M, North KN, Barton B, Payne JM. The neural basis of deficient response inhibition in children with neurofibromatosis type 1: Evidence from a functional MRI study. Cortex; a journal devoted to the study of the nervous system and behavior 2017; 93: 1-11.
  23. Pride NA, Korgaonkar M, North KN, Payne JM. Impaired engagement of the ventral attention system in neurofibromatosis type 1. Brain Imaging and Behavior 2018; 12: 499-508.
  24. Costa RM, Federov NB, Kogan JH, et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 2002; 415(6871): 526-30.
  25. Li W, Cui Y, Kushner SA, et al. The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 2005; 15(21): 1961-7.
  26. Lion-Francois L, Gueyffier F, Mercier C, et al. The effect of methylphenidate on neurofibromatosis type 1: a randomized, double-blind, placebo-controlled, crossover trial. Orphanet journal of rare diseases 2014; 9: 142.
  27. Mautner VF, Kluwe L, Thakker SD, Leark RA. Treatment of ADHD in neurofibromatosis type 1. Developmental medicine and child neurology 2002; 44: 164-70.
  28. Anastasaki C, Wegscheid ML, Hartigan K, et al. Human iPSC-derived neurons and cerebral organoids establish differential effects of germline NF1 gene mutations. Stem Cell Reports 2020; 14(4): 541-50.
  29. Anastasaki C, Woo AS, Messiaen LM, Gutmann DH. Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning. Hum Mol Genet 2015; 24(12): 3518-28.
  30. Bozaoglu K, Shern Lee W, Haebich KM, North KN, Payne JM, Lockhart PJ. Generation of four iPSC lines from Neurofibromatosis Type 1 patients. Stem Cell Res 2020; 49: 102013.
  31. Paulsen B, Velasco S, Kedaigle AJ, et al. Autism genes converge on asynchronous development of shared neuron classes. Nature 2022; 602(7896): 268-73.
  32. Pigoni M, Uzquiano A, Paulsen B, et al. Cell-type specific defects in PTEN-mutant cortical organoids converge on abnormal circuit activity. Hum Mol Genet 2023; 32(18): 2773-86.
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