SYMPOSIUM: NEUROLOGY
Inherited peripheral
neuropathies: what does
a paediatrician need to
know?
Anirban Majumdar
Abstract
Collectively, inherited peripheral neuropathies (IPN) are relatively com-
mon in children. They have a combined estimated incidence of 1 in
2500 live births. Therefore, it is likely that most paediatricians and
many healthcare professionals working in primary care settings will
encounter children with IPN during their careers. This article outlines
when to suspect an IPN, the common manner of presentation and
how to diagnose and classify these conditions in children. It offers
advice on the differential diagnosis, the genetic aspects of childhood
IPN and the importance of genetic counselling. The modern aspects
of diagnosis, which often use next generation sequencing to rapidly di-
agnose both common and rare IPNs, are considered. The common
surveillance measures and treatment modalities together with the
basic science developments that underpin future treatments for IPNs
are discussed.
Keywords Charcot Marie Tooth (CMT); Hereditary motor sensory
neuropathy (HMSN); Inherited peripheral neuropathy; Next generation
sequencing (NGS)
Introduction
Inherited peripheral neuropathies (IPN) are relatively common
and the incidence is estimated to be 1 in 2500 live births with a
prevalence of 10e30 per 100 000 in the European population.1
IPN are mostly genetic in nature and usually have a positive
family history. The age of onset of an IPN can be very wide and
may present from infancy to late adulthood.
In adult patients the typical clinical presentation will be with a
loss of sensation, paraesthesia of the feet or hands together with
a foot drop and weakness of the hands. As IPNs are length-
dependent disorders, it is typically the longest nerves in the
body (the nerves to the legs and arms) that are usually affected
first. The disease progression in adults presenting to clinic is
almost invariably slow as IPNs are chronic conditions.
In children, there are some notable differences in how IPNs
present.
Firstly, in some childhood-onset IPNs the presentation and
clinical manifestations may start very early in life. There may not
always be a positive family history as the child may either pre-
sent with a de-novo variant or there may be a case of non-
Anirban Majumdar BMBS BMed Sci FRCPCH MSc, Consultant Paediatric
Neurologist, Bristol Children’s Hospital, Bristol, UK. Conflicts of
interest: none declared.
PAEDIATRICS AND CHILD HEALTH 32:10
paternity. If the IPN is of a late-onset type then the child,
despite having the genetic variant implicated in the IPN, may not
have any symptoms or signs until they are much older or even an
adult.
How do children with IPNs present to the paediatrician?
Children may present to the general paediatrician in an outpa-
tient setting with the typical clinical features of an IPN that an
adult patient may have. The diagnosis is relatively straightfor-
ward when the child has a clear history of difficulty walking,
pain and tiredness after walking or running, toe walking, high
stepping gait, and evidence of a foot drop. Physical examination
may reveal a change in shape of the feet with pes cavus, thinning
of the muscles of the lower limb especially tibialis anterior and
the calf muscle complex or an upper limb tremor or long finger
flexion contractures and with a loss of reflexes in the lower
limbs.
Most of the time there will be a positive family history which
will involve several affected generations in an autosomal domi-
nant manner. This history and examination findings are typical
of the commonest IPN; Charcot Marie Tooth type 1A (CMT1A).
However, the presentation is not always so straightforward,
particularly in the IPNs of childhood. Other types of IPN will
present with a constellation of varying neurological signs and
symptoms. These can present in different ages from infancy to
late childhood and with all manners of inheritance such as
autosomal recessive, or X-linked. High diagnostic suspicion
needs to be maintained if the child has atypical features of
CMT1A.
What are the common differentials in children presenting
with features of suspected IPN?
One of the earliest features in the history and examination is that
of toe walking. The vast majority of toe walkers turn out to be
idiopathic however a considerable number do have a diagnosis
of IPN.
IPN is not the only pathological cause of toe walking. The
paediatrician should also consider the possibility that the child
may have cerebral palsy (i.e. bilateral spastic diplegia), a he-
reditary spastic paraparesis (HSP) or a dystonia. There will often
be very specific features in the history and examination which
will confirm or refute these differential diagnoses. For example,
in children with bilateral spastic diplegia there may be a history
of hypoxic ischaemic injury to the preterm brain leading to a
periventricular leucomalacia. Moreover, lower limb reflexes will
often be increased.
If such an abnormal neonatal history is negative but the
clinical picture is reminiscent of a bilateral spastic diplegia then
the possibility of a HSP arises. Dystonias may also present with
toe walking. Commonly this is associated with twisting of the
feet, hands and ankles. In general dystonias tend to be unilateral
and may be intermittent or dynamic in response to movement.
There are a large number of potential diagnostic avenues that
can be explored if the initial history and examination is not
suggestive of a typical IPN. Although the common differentials
are discussed above, IPNs may be part of a multi-systemic dis-
order rather than a pure genetic neuropathy.2
368 Crown Copyright Ó 2022 Published by Elsevier Ltd. All rights reserved.
 SYMPOSIUM: NEUROLOGY

How do we classify the different types of neuropathies?

Commonest genetic variants in CMT amongst European
There is a long history in the classification of IPN. As evidenced ancestry
from the name, CMT peripheral neuropathies were described by
J Charcot, P Marie and H Tooth and other authors, in the 19th CMT 1A/HMSN 1 due to chromosome 17p PMP22 (peripheral myelin
century. In 1968 Dyck et al.3 then classified hereditary motor protein gene-22) deletion
sensory neuropathy (HMSN) into six different types. In 1980 HNPP (Hereditary Neuropathy with liability To Pressure Palsy)
Thomas and Harding4 using a nerve conduction velocity due to chromosome 17p PMP 22 duplication
threshold of 38 m/s were able to further distinguish HMSN into GJB1 (Gap junction beta-1 protein, also known as connexin 32)
type I (Demyelinating) and type II (Axonal). The terms CMT and MPZ (Myelin Protein Zero)
HMSN are used interchangeably. MFN2 (Mitofusin 2)
Very recently the inheritance pattern and the genetic variant GDAP1 ( ganglioside induced differentiation associated protein 1) -
itself has been incorporated into the classification system for IPN. in the Spanish/Italian population
It complements but has not completely replaced the clinical
Box 1
classification systems. This is because of the degree of
complexity and overlap that may exist. There are, however, ex-
amples of genetic heterogeneity where some gene variants may What should a paediatrician do once an IPN has been
cause different phenotypes. De novo cases occur in approxi- diagnosed?
mately 1/5 of all IPNs.
Once a diagnosis including genetic classification of an IPN has
In 2015 Magy5 proposed a new nomenclature to deal with the
been made then a paediatrician should consider a referral for
extensive clinical and genetic heterogeneity displayed by IPNs.
genetic counselling so parents can make informed reproductive
Their proposal was in the classification the following should be
choices for any future children they may wish to have. A sub-
considered; the clinical phenotype, whether it was demyelinating
sequent referral to either a clinical geneticist or a paediatric
or axonal, the mode of inheritance and the genetic variant itself.
neurologist with expertize in neuromuscular disorders should be
The key questions that a general paediatrician should ask are:
considered.
 Does the phenotype fit with an IPN in such that they have the
A referral to a physiotherapist, orthotist, and an occupational
motor, autonomic or sensory system affected?
therapist should also occur. Normally in children, the foot shape
 What is the mode of inheritance or has the affected child the
change into a pes cavus, is a late occurrence. However where this
only affected member of the family?
is clinically apparent then a referral to orthopaedic surgery
 What is the actual genetic variant?
should also be considered.
 Does the genetic variant fit with the neurophysiological
If the child is at a transitional age then the young adult should
features of axonal or demyelinating?
be transitioned to adult neurology/neuromuscular/physio-
It is sometimes possible to predict the likely genetic variant
therapy services promptly. In most centres in the UK the diag-
even when the answers to key questions are not known. This is
nostic service and advice on subsequent management of most
because many of the genes implicated in IPNs can be predicted
IPNs are conducted through the neuromuscular/neurology
merely from the inheritance pattern and the neurophysiology
department.
tests. CMT in most patients is due to a handful of genetic variants
The keys to successful paediatric management of IPNs are
(see Box 1).
summarized in Box 2. These require considerable interdisci-
plinary care and communication between different team mem-
How Next Generation Sequencing (NGS) technology
bers and departments is crucial.
changed the diagnosis and classification of IPN
NGS has accelerated the diagnostic pathway and decreased costs What is the long-term prognosis for IPNs?
for the diagnosis of many IPNs. It has done so by effectively
IPNs are long-term chronic and slowly progressive conditions.
bypassing the step in the diagnostic algorithm of neurophysi-
Currently there are no cure was for this group of conditions but
ology. Given the relative expense and the invasive nature of
slowing down the effects of the disease is usually the main
neurophysiological testing, especially in children, once the
treatment goal. It is important to recognize that due to the un-
phenotype has been identified, NGS is undertaken next.
usual and rare IPN variants often presenting in childhood, the
We know from IPN databases that in European populations
natural history of the particular IPN may not be known and
the commonest pathological genetic variant will be either a
therefore predictions on the speed of progress and future
chromosome 17p PMP22 duplication or deletion (approximately
disability would have to be taken with caution.
80%). Testing for chromosome 17p PMP 22 dosage is the logical
second step. Should this step then return negative results, it is at
The science and pathology of IPNs, what does a
that point NGS for the rarer IPN variants are recommended.
paediatrician need to know?
Undertaking such genetic tests is less time-consuming, comfort-
able for the patient and cheaper in terms of costs when compared The science behind IPNs have progressed very rapidly in the last
to a formal neurophysiological test of nerve conduction velocity. 10 years and this has been particularly noticeable since the
Most laboratories now implement such an algorithm as illus- advent of NGS technology.6 This discussion is beyond the scope
trated in Figure 1. of this article however there are several reviews which discuss

PAEDIATRICS AND CHILD HEALTH 32:10 369 Crown Copyright Ó 2022 Published by Elsevier Ltd. All rights reserved.
 SYMPOSIUM: NEUROLOGY

Clinical suggestion of PMP22 HMSN1/

neuropathy HNPP
• Weakness of hands, wrist
and feet
Negative NCS
• Pes cavus
•
• Loss of sensation
• Family history Demyelinating
Gene Panel Axonal
Intermediate
Negative

Sequential
Is it acquired? WES/ WGS genetic
Alcohol
studies
Diabetes, trauma, etc

Variant
identified?
No genetic studies
needed
Is the variant pathogenic ?

Figure 1 Algorithm used historically (light grey) and the current recommendations (purple).

treatment are set to benefit from these emerging technologies and

Management of IPN, the role of the paediatrician treatments.

Accurate diagnosis Conclusions

Manage pain and discomfort
Monitor foot shape
Monitoring for scoliosis
Maintain ambulation
Assessment of tremor and its effects on writing
Timely referral for orthotics and orthopaedics
Ensuring engagement with the curriculum and school
Box 2
the current thinking around the neuropathology and disease
mechanisms/overlaps in IPNs.
What are the future developments for IPNs?
One of the most exciting developments for IPN is the possibility
of treating some of these conditions at an early age before the
loss of neurons become irreversible and irretrievable. This has
been demonstrated in the utilization of adeno associated viral
vector gene therapy for treatment of spinal muscular atrophy.7
Although spinal muscular atrophy is not an IPN but an anterior
horn cell disorder, it is now clearly possible to treat nerve dis-
orders with emerging gene therapy technologies with consider-
able success. There have recently been further developments in
several neuropathies utilizing similar viral vector approaches.
Neurological conditions that in the past were considered
untreatable are now rapidly being assessed as candidates for
treatment.8 Inherited peripheral neuropathies and their potential
This article is a brief summary of inherited peripheral neu-
ropathies and how it may present to a general paediatrician.
IPNs are common and often present in childhood with very
classical clinical features. In most instances the diagnosis is
straightforward and can be achieved with relative ease on the
basis of standard genetic tests. The advent of NGS testing has
accelerated new and unusual gene discoveries implicated in
IPNs. This has had the effect of reducing the costs of making a
genetic diagnosis. This also has allowed the possibility of
studying new and complex disease mechanisms and overlaps
with other neurological conditions affecting the peripheral
nerve. Finally there are exciting treatments using gene therapy
on the horizon for predominantly genetic conditions such as
IPNs. A
REFERENCES
1 Pisciotta C, Shy ME. Neuropathy. Handb Clin Neurol 2018; 148:
653e65.
2 Rossor AM, Carr AS, Devine H, et al. Peripheral neuropathy in
complex inherited diseases: an approach to diagnosis. J Neurol
Neurosurg Psychiatry 2017; 88: 846e63.
3 Dyck PJ, Thomas PK. Peripheral neuropathy. 4th ed. Philadelphia,
Pa: Elsevier Saunders, 2005.
4 Harding AE, Thomas PK. The clinical features of hereditary
motor and sensory neuropathy types I and II. Brain 1980; 103:
259e80.

PAEDIATRICS AND CHILD HEALTH 32:10 370 Crown Copyright Ó 2022 Published by Elsevier Ltd. All rights reserved.
 SYMPOSIUM: NEUROLOGY

5 Magy L, Mathis S, Le Masson G, Goizet C, Tazir M, Vallat J-M. 8 Bailey RM, Armao D, Nagabhushan Kalburgi S, Gray SJ.
Updating the classification of inherited neuropathies. Neurology Development of intrathecal AAV9 gene therapy for giant
2018; 90: e870. axonal neuropathy. Mol Ther Methods Clin Dev 2018; 9:
6 Rossor AM, Polke JM, Houlden H, Reilly MM. Clinical implications 160e71.
of genetic advances in CharcoteMarieeTooth disease. Nat Rev
Neurol 2013; 9: 562e71.
Acknowledgements
7 Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management
of spinal muscular atrophy: Part 1: recommendations for diagnosis,
I would like to thank Dr Silvia Sanchez Marco for her review of this
rehabilitation, orthopedic and nutritional care. Neuromuscul Disord
article.
2018; 28: 103e15.

PAEDIATRICS AND CHILD HEALTH 32:10 371 Crown Copyright Ó 2022 Published by Elsevier Ltd. All rights reserved.