Introduction

Neurofibromatosis (NF) is a syndrome for developing conditions of tumours in the peripheral and central nervous system (CNS) i.e., the brain, nerves carrying signals between the brain and spinal cord, and the spinal cord. These tumours can either be benign or malignant.

This article focuses on the types of neurofibromatosis, its cognitive implications on especially children and therapeutic interventions to overcome these.

Types of Neurofibromatosis

There are three types of Neurofibromatosis:

• Neurofibromatosis 1 (NF1): Also known as Recklinghausen’s disease, it is the most common form of disorder with an occurrence of about 96%.¹ It is usually inherited from generations through the genes but can be caused due to genetic mutations in the NF1 gene as well. Major symptoms include multiple brown spots in the skin regions like the armpits, groin, and iris.  It can further cause heart conditions and behavioural disabilities in children²
• Neurofibromatosis 2 (NF2): It is a genetically inherited disorder with autosomal dominance. The mutated gene is called NF2. These patients develop schwannomas on the nerves and spinal cords, meningiomas, and ependymomas at a young age. Major symptoms include hearing loss, vision loss or cataracts, and numbness of muscles at an early age¹
• Schwannomatosis (SWN): SWN is the rarest type of neurofibromatosis. The genetic mutations can be linked with the SMARCB gene, but the definite cause is not known. With a normal life expectancy, symptoms of SWN include chronic pain, numbness of muscles, and tingling sensations^1,2

Diagnosis

To diagnose NF, doctors look for the following symptoms:

• Light brown spots on the skin, might look like birthmarks
• Peak-sized bumps in cutaneous skin
• Tumour in the optic pathway
• Short stature and larger head size
• Freckling in armpits
• Learning disabilities and poor memory 

Cognitive impairments due to NF

Cognitive disabilities are mostly found in children with NF1. Prevalent signs can be poor academic performance, writing abilities, incorrect spellings, organizational skills, and difficulties in mathematics. These children can also be affected by autism (29%) and attention deficit hyperactivity disorder (ADHD) (38%). Researchers have identified memory impairments and language-based disabilities in these children.^3,4

• Intelligence and attention

Generally observed, children with NF1 have lower intelligence quotient (IQ) (91) as compared to average children (99). They are diagnosed with divided attention, deficits in visual perception skills, and basic functioning like planning and thinking concepts.³ These results were gained based on Wechsler intelligence scale and Rey complex figure tests to learn their cognitive and written skills. 

Attention deficit is also linked with NF1 type as seen in up to 50% of patients.³ NF1 children with ADHD exhibit poor attention, low performance, and learning difficulties. It increases the intensity of cognitive impairments for NF1-type children when diagnosed with ADHD. Hence cognitive disabilities can be linked to various difficulties like ADHD, autism, and behavioral/emotional problems. 

• Role of Ras activation and cAMP for cognition

Scientists have confirmed that due to NF1, the patients lack neurofibromin which is responsible for inducing Ras hyperactivity and ERK signaling.⁵ By conducting tests like Morris water maze tests on NF1 mutant mice, studies proved that high Ras activity is linked with cognitive deficits in NF1 mice. The unregulated activity of Ras is directly related to cognitive dysfunction. 

Similarly, cAMP activation is also interlinked with learning and memory deficits. Therefore, Ras and cAMP are targets associated with cognitive impairments in NF. Recent advancements for treating these dysfunctions are primarily focusing on molecular signaling mechanisms behind NF further specified with individual abnormalities in children.⁴

• Social/behavioural problems 

Based on results from clinical trials on children with NF1, reports have shown that apart from cognitive decline, these children prominently show social and behavioural problems majorly. These are intense in the patients with autism along with NF1 with further links directly to the quality of life. Finding a direct link between these behavioural problems and cognitive decline is quite difficult as some children might have only behavioural problems without any cognitive dysfunctions or vice versa.⁶

Therapeutic targets

There are several studies conducted to improve cognitive decline in NF1 patients. Drugs like methylphenidate (MPD) and simvastatin can reverse learning deficits in mouse models but lack the same effects in humans. MPD has been successful in decreasing ADHD symptoms hence a growing research focus but recent focus is being conducted on the molecular pathways related to the cognitive problems to treat NF1 and its symptoms.³

1. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels: 

As mentioned above in this article, cognitive impairments are a prominent feature diagnosed in patients suffering from NF1. Molecular mechanisms are not completely known yet, but studies have suggested various molecular targets like Ras activity or cAMP activation as underlying pathways of interest.⁷ One of these targets is the HCN channels due to its direct relation with hippocampal GABAergic neurons and cortical interneurons. 

Studies have shown that NF1 communicated to HCN1 hence affecting the functions of HCN channels making it a potential drug target for cognitive functions. It is known that Ras/ERK signalling is independent of HCN signalling, but both serve as important targets for learning deficits caused by NF1.⁷

2. Mitogen-activated protein kinase inhibitor (MEKi) therapy:

Research conducted on 59 NF1 patients from 5 - 27 years of age showed that behavioral functions were found regulated over the span of 48 weeks in the MEKi trial. A high level of performance-based improvement was seen in visual and working memory starting from the 24th week, further showing an increase till the 48th week. With more research to be continued on MEKi, it proves to be an ideal target for cognitive problems in NF1 patients in the future.⁵

3. Surgery and drug treatments:

As well known, NF1 cannot be cured completely, but the treatments are based on reducing the intensity and time period of signs and symptoms. One of such treatment approved by the National Health Service (NHS) is selumetinib (Koselugo). This drug is approved for children aged 2 years and older and helps decrease tumour cell growth.²

Similarly, surgical removal is a conventional method for cancer causing tumours. Chemotherapy and surgical operations for bone malfunctions are also suggested depending on the severity of symptoms.²

FAQs

What triggers neurofibromatosis?

Neurofibromatosis is caused by to deregulation of the NF1 gene located on chromosome 17. It is responsible for producing a protein called neurofibromin which is related to cell division in the CNS.

Are neurofibromas cancerous?

NF1 and NF2 types are generally caused due to genetic inheritance, hence usually developing as non-cancerous.  Aggressive growth can be cancerous hence it is advised to get medical checkup regularly.

Is it a life-threatening condition?

Developing NF is most commonly seen to be non-life threatening. But in rare cases of plexiform neurofibroma becoming malignant, it can lead to a patient passing away.

Are there medications to stop tumours due to NF?

An approved medication called selumetinib is available in the UK for children. It has been shown to reduce the growth of plexiform neurofibromas in children. It has also improved the quality of life and pain caused due to NF.  Its side effects include nausea, vomiting, or skin irritation.

Summary

Neurofibromatosis is an autosomal dominant inherited disorder which links to various cognitive impairments in children. It is unlikely for NF to start in adulthood, about 30 years of age, as its signs can be observed in early childhood. As it is an incurable disease, treatments like speech, occupational, and motor therapies are seen to be effective for children.