Neurofibromatosis: General Questions And Discovery Timeline

Here are my first notes and a general timeline for NF research I put together. I end with the questions I want to answer in the book.

Start from the common understanding

History from https://www.amazon.com/dp/B00BLQYQXY/ref=rdr_kindle_ext_tmb#nav-subnav Neurofibromatosis type 1:

Summary area.

Germline mutations in the NF1 tumor suppressor gene. First compiled in 1998, updated in 2012.

MRIs,

As of 2012, “we remain ignorant of the mechanisms underlying the transformations of benign neurofibromas to malignancy.” (Summary)

Epigenetics remains to be explored. Managing tumors better. Drosera, zebrafish and mouse studies.

NF1 mutation has been found to be a cause in multiple sporadic cancers.

NF1 is a member of the “RASopathies” Ras/MAPK signalling pathway within the cell. Locus heterogeneity is present. Another disease Legius, has a germline mutation in the SPRED1 gene and clinical features that overlap NF1.

We don’t know the cell of origin of MPNSTs (malignant peripheral nerve sheath tumors), but it seems to involve micro-RNA expression and CD133 (a cancer stem marker) has been found in human MPNSTs.

Lay organizations for NF1 are pushing research and making clear the social stigma associated with NF1.

History from Vincent Riccardi (the Neurofibroma Institute)

“Recklinologist”

“Wild-type NF1 gene

A patient with NF1 was treated with oral ketotifen for 30 years since infancy. Review of the patient’s course and treatment details establishes a basis for reconsideration of several fundamental precepts about NF1 pathogenesis. The data suggest a distinctive benefit to treating an NF1 patient with an inhibitor of mast cell degranulation before cutaneous neurofibromas are clinically apparent: the neurofibromas appear to be arrested at a very early stage of development

More accurately, we only know that, for a large number of NF1 gene changes, there are many “tumor contributor mutations.” Moreover, it is not even clear whether this attribution applies, on the one hand, to the array of sarcomas and other malignancies associated with NF1 or also, on the other hand, to the neurofibromas that are hallmarks of the disorder. Designating a neurofibroma to be a “tumor” is as much poetry as it is science. Over the long run, the neurofibroma will best be understood as a scar, a type of “wound-healing gone awry.” Ribeiro and colleagues quite convincingly document this consideration, although they perpetuate the notion that the lesion, the neurofibroma, is necessarily a tumor and that diploinsufficiency for Nf1 abrogates a “tumor suppression” function of NF1/Nf1wild-type alleles. Applying a clinical approach to the NF1 disorder, acknowledging that compromised attentiveness is the most consistent cognitive element of the disorder, one can characterize the NF1 gene as an “attentiveness suppressor gene” and appropriately rename Nfn as Attentin. If the clinical approach has any merit at all, it is most likely to be fruitful in this regard: The wild-type NF1 alleles contribute to human performance, with specific regard to functions of the central, peripheral and autonomic nervous systems, particularly when time is of the essence, when response “on the instant” is required for organism and species survival. This conclusion is reinforced by acknowledging the NF1 person’s lean habitus and absence of diabetes,.

Assumption: The more we know about a disease, the more likely we can prevent the disease and provide effective treatment.

My thoughts: diagnosis vs. prognosis. The flu. More rapid vaccine response trumps more knowledge.

Assumption 2: The more we learn about a genetic disease, the more likely we can replace or modify that gene. My thoughts: If a single locus, perhaps, but a wide ranging genetic disease does not replace or modify easily.

Questions the very idea of a gene.

NF1 was von Recklinghausen disease, based on Frederich von Recklinghausen’s 1882 German treatise. But in 1849, Irish physician R.W. Smith published a treatise on the neuroma. So there is some debate over whether it should have been called Smith’s disease.

No research until Borberg Danish study in 1951. Noted 1) tremendous variability with a family, 2) adults are far more numerous than children, and 3) not all the patient’s problems are tumor-related.

Crowe in 1956 reiterated these points, but mixed NF2 in with NF1.

In 1971 Brasfield and in 1972 Das Gupta gave some surgical treatments and discussed the lifelong adult illness.

Riccardi was a genetics fellow at MA general. Chose NF1 as his life career. Went to Baylor and established the Baylor Neurofibromatosis Program (BNFP) in 1976. First patient enrolled 1978, the same year as the establishment of the National Neurofibromatosis Foundation (NNFF) by Courtemanche and Rubenstein. In 1979 first international conference with the National Cancer Institute (NCI).

1981 NEJM published his summary of NF1 up to that time. Cell advances and the compromise of NF1 patients’ academic performance (1984) were also by Riccardi.

1987 NIH separated NF1 and NF2. Assignment of NF1 to the long arm of chromosome 17 was made.

1988 NF, inc. was founded for local autonomy.

1990 the NF1 gene and its product, neurofibromin, identified.

1993 NF2 gene and its product merlin (schwannomin) identified.

1994 First mouse models of NF1.

http://www.freepatentsonline.com/6238861.pdf Neurofibromatosis patented.

2005 NNFF changes its name to the “Children’s Tumor Foundation.”

NF specialists: Japan, Niimura: Canada, Friedman;European NF Association,

Major advances: 1) full body MRI evaluation, tracking advances of neurofibroma growth. Riccardi notes that neurofibromas grow primarily by budding rather than enlarging, so recommends a full surface examination of neurofibromas.

2) genetic technology has made possible both patient and pre-implantation screening. Genetic phenotype relations (Pasmant, Vogt,

3) Somatic mosaicism, heterogeneity and genotype-phenotype variation makes it entirely reasonable to do a complete genomic analysis for every NF1 patient. Currently there are few adult NF1 centers when NF1 patients are primarily adults. Research has continued to focus on neurofibromin without considering transcription factors like mi-RNAs especially miR-10b (Chai).

4) Gliomas contribute to illness and early death. (Gutmann)

5) Widespread skeletal involvement, DA Stevenson, Understanding the commonalities of cartilage and bone in relation to melanocytes and Schwann cells will be especially rewarding.

6) Mast cell contributions to NF1, Riccardi pointed to mast cell involvement in neurofibromas. The difference between encapsulated and diffuse, fascicular vs extra-fascicular can be predicted by the number of mast cells present (Tucker, 2011). Mouse models support the idea (Staser, 2011). Treatment with ketotifen, a mast cell stabilizer, were modestly successful.but weren’t continued (Riccardi 1993).

7) Intellectual compromise has been helpful. Silva, 1997, Li, 2005, Shilyansky, 2010, using the mouse NF+/- model have seen statins as helpful. Krab took research to patients (2008) with simvastatin, helped by van Engelen 2008. Inattentiveness Brown 2010, 2011, Ribeiro (2011). Riccardi believes the issue is Prosody, European NF Association paper in 2007. They have attention but do not use it. Other studies focus on brain function in relation to cAMP, ATP, and GTP. Riccardi thinks stress of all kinds activates the NF1, which can adapt more quickly 3-nitrotyrosine experiment, 1980.

Riccardi notes that the NF1 variation does not occur among wild animals but does occur among domesticated animals like cows. The exception is a bicolor damselfish, but that seems to be infected by a virus or virus-like material. Riccardi suggests that inattention is not a Darwinian trait. He finishes on a note that we should be focusing on how to maximize the wild-strain NF1.

  1. Complex NF

Multiple tumor issues including epilepsy.

Multiple sclerosis which is progressive.

Bowing of the long bones, usually tibia.

Sphenoid wing dysplasia.causes pulsating exophthalmos (no mention of pituitary involvement).

  1. Monozygomatic (identical) twins show 30-40% variation in their genetic expression. The NF1 mutation takes place in the blastocyst stage. The neoplasms of twins requires a secondary hit event on the NF1 allele, making these sporadic. Almost half of NF1 children have tumors discovered on MRI, but the twin studies haven’t been done.

The elephant man may have had NF1 or Proteus syndrome. Most recent research indicates Proteus, but final DNA analysis has not been done.

Take the common understanding to its conclusion.

The bottom line is that NF1 is a fairly newly established diagnosis, one that is in flux and will likely be absorbed into another genetic disease definition. As we move forward, it is clear that while NF1 is a clear diagnosis, it does not determine a patient’s prognosis.

Look for any holes in the common understanding.

When we look at a genetic disease, we look for absolutes. Dwarfism, once diagnosed, does not vary widely. Down’s Syndrome, once diagnosed again has a set range of expectations regarding prognosis. But NF1 patients have a wide ranging prognosis, varying from a normal life span to one cut short in adolescence from rare cancers. It is the heterogeneity of the NF1 prognosis that makes the genetic origin less than useful. How can a parent plan when we have no idea what to expect? Monitoring the patient is wise, but means waiting for genetic failure to occur rather than working to prevent it.

The focus on the faulty genes in NF1 fails to address the reality of one faulty and one good gene. No

Ask yourself, if you had this, what would you want?

A way to test: The Digit Span subtest from the Wechsler scales was given the highest ratings of the performance measures due to its good psychometrics, feasibility, utility across a wide age range, and extensive use in previous research. The Conners scales achieved the highest ratings of the behavioral questionnaires for similar reasons.

Greater understanding. Genetics vs. prognosis

An estimated lifetime cancer risk for patients with NF1 was 59.6%. The 5-year survival of patients with cancer and NF1, excluding nervous tissue cancers, was worse than that of comparable patients with cancers without NF1 (54.0% v 67.5%; P = .01).

A plan of approaching the illness. What can I expect? How can I prevent it?

Hope of improvement. Is it possible that I can improve?

Who and What

What is it?

What causes it?

How did I get it?

Are my loved ones at risk?

How is it treated?

Does treatment vary widely?

How can I get the best treatment?

What else is there?

Are there any alternative treatments with any research behind them?

Are there any alternative theories about how to treat it?

What can I do?

Tell me some simple things that might help.

Give me a plan.