Author's Accepted Manuscript

An Unusual Cause of Peroneal Neuropathy

G. Bradley Schaefer MD, FAAP, FACMG, Amitha L.Ananth MD, Yaping Yang Ph.D, Seema R. Lalani M.D.,Ph.D, Timothy B. Lotze MD

PII: S1071-9091(14)00049-7DOI: http://dx.doi.org/10.1016/j.spen.2014.05.002Reference: YSPEN496

To appear in:Semin Pediatr Neurol

Cite this article as: G. Bradley Schaefer MD, FAAP, FACMG, Amitha L. Ananth MD,Yaping Yang Ph.D, Seema R. Lalani M.D., Ph.D, Timothy B. Lotze MD, An Unusual Causeof Peroneal Neuropathy,Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2014.05.002

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Commentary for Seminars in Pediatric Neurology  Submitted by: G. Bradley Schaefer, MD, FAAP, FACMG Professor of Genetics and Pediatrics Founding Director, Division of Medical Genetics    University of Arkansas for Medical Sciences Committee for the Future Endowed Chair in Medical Genetics    Arkansas Children's Hospital Section Chief, Division of Genetics and Metabolism    Department of Pediatrics  1 Children's Way Slot 512‐22 Little Rock, AR 72202   Phone:        501/364‐2971 Facsimile:  501/364‐1564 email:          SchaeferGB@uams.edu    

 Article Reviewed: 

An Unusual Cause of Peroneal Neuropathy

Amitha L. Ananth, MD1 Yaping Yang, Ph.D2

Seema R. Lalani, M.D., Ph.D2 Timothy B. Lotze, MD1

This article by Dr. Ananth and colleagues reports a patient being evaluated for

symptoms consistent with a peripheral neuropathy. In addition, the patient developed an aterio-

venous fistula. Genomic testing subsequently identified a COL31A mutation – which is known to

be associated with Ehlers-Danlos syndrome of the vascular type.

This case highlights several important features of the “new genomics” and its application

in clinical medicine. Clearly the advent of whole exome sequencing (WES) as a clinically

available test has already had a dramatic impact on clinical medicine. Nowhere is this more

evident than in child neurology. WES is a powerful tool and has greatly improved the diagnostic

yield for many previously un-diagnosable conditions. The data is emerging, and it is still a little

too early to make firm predictions. However, fairly consistent yields are being noted by most

persons ordering these tests. When WES is performed in the setting of a patient who has had a

thorough evaluation using conventional testing methods and protocols – i.e. the “diagnostic

dilemmas”, the yield appears to be about 25-30%. This is notable from two aspects. 1) It is

indeed exciting and rewarding for clinicians to get answers for families that have waited a long

time for a diagnosis. 2) Still, 30% seems like less than was expected. Surely if all of a person’s

genes can be sequenced, the answers to most unknown diagnoses would be found. The fact

that this isn’t the case highlights the fact that there are still may more etiologies out there that

are not “simple mutations”. The answers yet to be discovered are going to involve more

complex genetic mechanisms such as epigenetics, metabolomics pathways, multiply interacting

genes, and gene-environment interactions. It is nice to know that clinicians are still going to

have jobs for a while longer!

The ‘role’ that WES is ultimately going to play is still being worked out. The information

noted above states the diagnostic yield of such testing – when all other means have been

exhausted. The question arises: “When does WES become a “first tier testing modality”? While

the answer to this question is still a moving target, it is safe to say that that time is already upon

us for certain scenarios. Many of the child neurologists that I talk to already comment on how

genomic testing has changed their practice. For instance most already recognize that the role of

procedures such as muscle biopsies are being ordered at a much less frequent rate – mainly

because of the availability of genomic diagnostics as an alternative.

It is important to point out that testing a person’s entire genome is not as straightforward

as checking a serum level of some metabolite. Such testing is fraught with many ethical and

legal issues for which there are often not clear answers. Clinicians must be rigorous in adhering

to ‘best-practice’ standards in using these tests. Careful and complete informed consent must

be provided to every patient for every such test. If the clinician is unable or unwilling to do so,

the test simply should not be performed.

Finally, the discovery of new and novel diagnoses that come out of testing like WES also

presents new challenges in interpretation. The case reported here highlights such challenges.

As the authors point out, this is “the first reported case” of the association of a peripheral

neuropathy in a patient with Ehlers Danlos syndrome (EDS) of the vascular type. In such

situations, care has to be taken in the interpretation of novel situations. The authors do a nice

job in discussing previous reports of neuropathies in EDS. They also broach the possibility that

these are related. Still, caution has to be taken in all assumptions. In reality, it currently cannot

be determined what the relationship is between these two diagnoses in their patient. Several

possibilities exist: 1) There is some pathogenic link between the two – which is an option

considered by the authors. 2) It is also possible that the patient actually has two different

disorders. Another discovery with advanced genomic diagnostics is that sometimes patients

have more than one genetic change. Thus some complex phenotypes are explained by multiple

genetic abnormalities. My experience over the past 5 years suggests that this is a lot more

common than would ever have been anticipated. 3) A coincidental relationship could exist. 4)

There could be some common regulatory abnormality. Clearly more experience is going to be

needed before the medical community has a firm grasp on many of these complex

interpretations.