Acta Neuropathol

DOI 10.1007/s00401-016-1645-y

REVIEW

Towards a functional pathology ofhereditary neuropathies

JoachimWeis1 KristlG.Claeys1,2,3 AndreasRoos1,4 HamidAzzedine1
IstvanKatona1 J.MichaelSchrder1 JanSenderek5

Received: 12 May 2016 / Revised: 10 November 2016 / Accepted: 13 November 2016

Springer-Verlag Berlin Heidelberg 2016

AbstractA growing number of hereditary neuropathies

have been assigned to causative gene defects in recent
years. The study of human nerve biopsy samples has contributed substantially to the discovery of many of these
neuropathy genes. Genotypephenotype correlations based
on peripheral nerve pathology have provided a comprehensive picture of the consequences of these mutations.
Intriguingly, several gene defects lead to distinguishable
lesion patterns that can be studied in nerve biopsies. These
characteristic features include the loss of certain nerve
fiber populations and a large spectrum of distinct structural
changes of axons, Schwann cells and other components of
peripheral nerves. In several instances the lesion patterns
are directly or indirectly linked to the known functions of
the mutated gene. The present review is designed to provide an overview on these characteristic patterns. It also
considers other aspects important for the manifestation and
pathology of hereditary neuropathies including the role of

* Joachim Weis
jweis@ukaachen.de
* Jan Senderek
Jan.Senderek@med.unimuenchen.de
1

Institute ofNeuropathology, RWTH Aachen University

Medical School, Pauwelsstr. 30, 52074Aachen, Germany

Department ofNeurology, RWTH Aachen University

Medical School, Pauwelsstr. 30, 52074Aachen, Germany

Department ofNeurology, University Hospitals Leuven

andUniversity ofLeuven (KU Leuven), Leuven, Belgium

Leibniz-Institut fr Analytische Wissenschaften-ISAS-e.V.,

OttoHahnStr. 6b, 44227Dortmund, Germany

FriedrichBaurInstitute, Department ofNeurology,

Ludwig-Maximilians-University, Ziemssenstr. 1a,
80336Munich, Germany

inflammation, effects of chemotherapeutic agents and alterations detectable in skin biopsies.

Keywords CharcotMarieTooth disease (CMT)
Hereditary sensory and motor neuropathy (HMSN)
Hereditary motor neuropathy (HMN) Hereditary sensory
and autonomic neuropathy (HSAN) Inflammatory
neuropathy Chemotherapy

Introduction
An effective approach to unravel disease mechanisms is to
link naturally occurring pathogenic mutations with monogenic disorders. Indeed, a mutant gene that gives rise to a
rare monogenic disorder usually also provides an opportunity to understand the genetic, biochemical, signal transduction and developmental network that underlies similar
common polygenic or acquired phenotypes. One striking
example of how the identification of genes for Mendelian disorders influences our views on the pathophysiology of human disease is hereditary peripheral neuropathy.
The Neuromuscular Home Page of the Neuromuscular
Disease Center, Washington University, St. Louis, MO
(neuromuscular.wustl.edu) currently lists more than 200
forms of hereditary neuropathies. Most of these have
already been assigned to distinct disease genes. Many
neuropathy genes are linked to peripheral nerve development, function or maintenance. The gene discoveries
often supported or extended existing or inferred concepts
of disease such as alterations in myelin development and
structure, length-dependent impairment of axonal transport or defects of the axoskeleton. Other disease genes
unraveled previously unrecognized and unexpected neuropathy mechanisms including nuclear envelope structure,

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mitochondrial dynamics, protein biosynthesis, Ca2+homeostasis, phosphoinositide metabolism, Rho GTPase

signalling and transcriptional regulation (Table1; Fig.1)
[9, 70, 114, 167].
The wide array of neuropathy genes identified so far
illustrates which structural and functional components are
required for building and maintaining the human peripheral nervous system. The study of nerve pathology provides
a unique opportunity to decipher the functions of these
genes and the pathomechanisms related to their mutations.
It establishes genotypephenotype correlations and yields
information about concomitant diseases such as inflammation or microangiopathy that might contribute to the neuropathy phenotype. It also provides a framework for the
interpretation of the consequences of these gene defects in
cell culture and animal models. Moreover, studying biopsies from patients with defined genetic defects gives clues
to the function of the affected genes and their homo- and
paralogs also in the human central nervous system (CNS),
with the additional advantage that nerve and skin biopsies
provide well-preserved biopsy tissue, whereas material
unaffected by autolysis is hardly available for most degenerative human CNS disorders.
The present review focuses on the histological and ultrastructural human nerve biopsy patterns related to hereditary
neuropathy entities and gene defects. These patterns are
discussed in the context of our current understanding of
the functions of the affected genes (and encoded proteins).
In addition, we consider the consequences of mutations
in more than one neuropathy gene in the same individual,
of concomitant inflammation and of confounding factors,
especially chemotherapy, that influence the manifestation
and pathology of hereditary neuropathies.

Clinical aspects andclassifications ofhereditary

neuropathies
Peripheral neuropathy is one of the most common reasons for referrals to neurological clinics [91]. While most
cases are acquired (due to diabetes mellitus, alcoholism or
inflammatory diseases), the prevalence of the largest group
of hereditary neuropathies, CharcotMarieTooth neuropathies (CMT, also called hereditary motor and sensory
neuropathies, HMSN), is about 1:2500 in Northern Europe
[101, 152]. Hereditary neuropathies are classified as CMT
(or HMSN) if motor and sensory systems are both affected,
as hereditary sensory and autonomic neuropathy (HSAN)
if sensory deficits and/or autonomic dysfunctions prevail
and as distal hereditary motor neuropathy (HMN) if the
motor deficit is predominant [38, 57]. Spinal muscular atrophy (SMA) has been clinically and morphologically classified as a pure lower motor neuron disease; however, the

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Acta Neuropathol

terms distal SMA (DSMA) and HMN are now used largely
interchangeably.
According to electrophysiological criteria, CMT neuropathies are classified into two main subgroups: the demyelinating type CMT1 (or HMSN I) with reduced nerve
conduction velocities (NCV), and the axonal type CMT2
(or HMSN II) with primarily axonal loss characterized by
normal or only slightly reduced NCV, but decreased amplitudes of motor and sensory nerve action potentials [38, 57].
In practical terms, a motor NCV of 38m/s in upper limb
nerves is commonly used as a threshold for differentiating CMT1 from CMT2. As a rule, histopathological studies reveal segmental demyelination and remyelination with
prominent onion bulb formation in CMT1, while in CMT2
there are signs of axonal degeneration with regenerative
sprouting.
An intermediate CMT subgroup with median MNCV
between 25 and 45m/s has been defined [33, 107]. DejerineSottas syndrome (DSS) or HMSN III is an early-onset,
clinically severe, demyelinating motor and sensory neuropathy with MNCV below 12m/s and marked onion bulb
formation and can, thus, be considered as a severe form
of CMT1 [119]. Further subdivisions of CMT neuropathies are based on the inheritance pattern and the molecular genetic defects. Inheritance in CMT can be autosomal
dominant (AD), autosomal recessive (AR) or X-linked.
By convention, autosomal recessive forms of CMT1 are
sometimes referred to as CMT4 and autosomal recessive
forms of CMT2 are also known as AR-CMT2. Autosomal
dominant and autosomal recessive forms of intermediate
CMT have been named CMTDI and CMTRI, respectively.
Finally, X-linked CMT has also been designated as CMTX.
A modification of the current nomenclature of CMTs and
related disorders which takes into account the causative
gene defects, inheritance patterns and primary pathological phenotype (axonal, demyelinating, or intermediate) has
been proposed recently [94].
Mutations in the same gene may lead to dominant or
recessive inheritance patterns, exemplified by the recent
discovery of MME mutations as a cause of both, autosomal dominant and autosomal recessive CMT2 [6, 60]. In
addition, the clinical spectrum of neuromuscular disorders
associated with certain disease genes may be wider than
initially anticipated. For example, mutations in the gene for
glycyl-tRNA synthetase (GARS) may result in CMT2 and
HMN/DSMA [2, 37], and mutations in the TRPV4 gene
encoding an ion channel protein may cause CMT2, congenital non-progressive DSMA or scapuloperoneal SMA
(SPSMA) [5]. In addition, certain disease genes (e.g., MPZ
or GJB1, see below) may be associated with both axonal
and demyelinating neuropathies.
Although CMT neuropathies are considered non-syndromic conditions, additional involvement of other organs

Acta Neuropathol
Table1Neuropathy genes
classified by their known or
inferred functions

1. Myelin proteins
PMP22

CMT1A, CMT1E, HNPP, DSS, CHN

MPZ/P0

CMT1B, DSS, CHN, CMT2I, CMT2J, CMTDID

2. Cytoskeleton, nucleoskeleton and nuclear envelope

NEFL

CMT1F, CMTDI, CMT2E

LMNA
CCT5

AR-CMT2A (CMT2B1)a,b
HSAN with spastic paraplegia

INF2

CMTDIEb

DST
3. Transcriptional regulation

HSAN7b

EGR2

CMT1D, DSS, CMT4E, CHN

SOX10

MORC2

Peripheral demyelinating neuropathy, central

dysmyelination, Waardenburg syndrome, and
Hirschsprung disease (PCWH)b
CMT2Z

IGHMBP2

CMT2S, SMARD1 (HMN6)

DNMT1
IKBKAP

HSAN1Eb
HSAN3 (RileyDay syndrome)

SETX

HMNa

PRDM12

HSAN8

HINT1

CMT2 (neuromyotonia and axonal neuropathy)

MED25
4. Protein biosynthesis

AR-CMT2B (CMT2B2)b

GARS

CMT2D, HMN5A

AARS
YARS

CMT2Nb
CMTDIC

KARS

CMTRIB, HNPPb

MARS
5. Protein modification, folding and degradation

CMT2Ub

HSPB1

CMT2F, HMN2B

HSPB3

HMN2C

HSPB8

CMT2L, HMN2A

LRSAM1

CMT2P

TRIM2

CMT2R

HSJ1

DSMA5, CMT2

GAN

Giant axonal neuropathy 1

6. Intracellular transport
GJB1

CMTX1

SH3TC2/KIAA1985

CMT4C

RAB7

CMT2B, HSAN1

DNM2
DYNC1H1

CMT2M, CMTDIBa
CMTO, SMALED1b

DCTN1

HMN7Ba,b

KIF1A

HSAN2Ca,b

LITAF

CMT1C

NDRG1

CMT4D/HMSNL

KIAA1840
BICD2

CMT2Xa
SMALED2

7. ER membrane shaping
FAM134B

HSAN2B

ATL1

HSAN1Da

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Acta Neuropathol

Table1continued

ATL3

HSAN1F

TFG

CMT2a
CMT2, HMN5Aa,b

BSCL2
8. Mitochondrial dynamics
MFN2

CMT2A, HMSN5A, HMSN6, CMT2A2B

GDAP1

CMT4A, CMT2K, CMTRIA

9. Mitochondrial energy production

DHTKD1
PDK3

CMT2Qb
CMTX6

HK1

CMT4G/HMSNR

10. Sphingolipid biosynthesis

SPTLC1

HSAN1A

SPTLC2

HSAN1C

11. Phosphoinositide metabolism

MTMR2

CMT4B1

SBF2/MTMR13

CMT4B2

SBF1/MTMR5

CMT4B3
CMT4Ja,b

FIG4
12. Rho GTPase signalling
PLEKHG5

DSMA4, CMTRIC

ARHGEF10

Slow nerve conduction velocities, thin myelin

FGD4

CMT4H

13. Interaction with the extracellular environment

FBLN5
MME

CMT1b
CMT2T

GNB4

CMTDIF

NGF

HSAN5

NTRK1
DHH

CIPA/HSAN4, HSAN5b
46,XY partial gonadal dysgenesis with minifascicular neuropathyb

WNK1

HSAN2Ab

PRX

CMT4F, DSS

14. Ion channels

CMT2C, SPSMA, congenital non-progressive
DSMA (HMN8)b
CIP, HSAN2D, primary erythermalgia, PEPDb

TRPV4
SCN9A
15. Various
PRPS1 (purine metabolism and nucleotide biosynthesis)

CMTX5b

AIFM1 (mitochondrial-mediated apoptosis)

CMTX4b

SMARD1 spinal muscular atrophy with respiratory distress type 1, SMALED1 spinal muscular atrophy with
lower extremity predominance type 1, SMALED2 spinal muscular atrophy with lower extremity predominance 2, CIPA congenital insensitivity to pain with anhidrosis, CIP congenital insensitivity to pain, PEPD
paroxysmal extreme pain disorder
a

Mutations in this gene can also cause other neuromuscular disorders

Mutations in this gene have been related to non-neuromuscular conditions

such as CNS, eyes, skeletal muscle, etc. may be observed

[94]. Apart from this, a large, heterogeneous group of other
hereditary diseases feature peripheral neuropathy as a prominent or prevailing component of the clinical picture. These

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conditions include familial amyloid neuropathy (FAP), giant

axonal neuropathy (GAN), polyglucosan body disease, and
neuropathies associated with metabolic disorders such as
metachromatic leukodystrophy and Refsum disease.

Acta Neuropathol
Hereditary neuropathies: Genes and pathomechanisms

Nuclear envelope
(LMNA)

Nucleotid biosynthesis
(PRPS1)

Intracellular transport,
endosomes
(SH3TC2, RAB7)

Rho GTPase signalling

(PLEKHG5, ARHGEF10,
FGD4)

Heat shock proteins

(HSPB1, HSPB8,
HSJ1)
Protein degradation
(LRSAM1, TRIM2,
GAN)

Transcriptional regulation
(EGR2, SOX10, SETX)

Myelin proteins
(PMP22, MPZ, Cx32)

Sphingolipid
biosynthesis
(SPTLC1, 2)
Phosphoinositide
metabolism
(MTMR2, SBF2)

Amino acid processing

(GARS, YARS, AARS,
MARS, KARS)

ER membrane shaping
(FAM134B, ATL1,
ATL3, TFG, BSCL2)

Cytoskeleton
(NEFL, Gigaxonin)

Axonal transport
(DCTN1, DYNC1H1)

Mitochondrial dynamics
(GDAP1, MFN2)
Energy production
(DHTKD1, PDK3, AIFM1
HK1)

Extracellular matrix interaction

(PRX, GNB4)

Fig.1Hereditary neuropathies: genes and pathomechanisms (based on Weis and Senderek, 2014 [180]

Neuropathy genes andpathology patterns

The following chapters provide an overview of distinct
forms of inherited neuropathies and their causative gene
defects that lead to prototypical morphological changes
detectable in nerve and skin biopsies.
Selective lack, loss, or preservation ofcertain nerve
fiber populations insensory nerves
MFN2, MME, KIAA1840 and MORC2 mutations leading
to CMT2 as well as mutations in the BSCL2 gene leading
to distal hereditary motor neuropathy predominantly affect
large myelinated fibers in the sural nerve [6, 28, 60, 100,
149, 166] (Fig.2b). For two cases of CMT2 due to MORC2
mutation, a peculiar patchy, focally accentuated loss of
nerve fibers has been described [149]. Prominent loss of
large and small myelinated nerve fibers along with relative
preservation of unmyelinated axons has been reported in
neuropathies caused by myelin protein zero (MPZ) [163],
Gap junction beta-1 protein/connexin-32 (GJB1) [59] and
Lamin A/C (LMNA) gene mutations [158]. Slowly progressive loss predominantly of large sensory axons with
preservation of the small myelinated and unmyelinated
fibers is a characteristic feature of Friedreichs ataxia due
to mutations in the FXN gene for the iron-binding protein

frataxin [68, 128] (Table2). A similar pattern of preferential degeneration of large myelinated nerve fibers has been
found in patients with posterior column ataxia and retinitis pigmentosa caused by mutation of the feline leukemia
virus subgroup C cellular receptor (FLVCR1) gene, which
is involved in iron homeostasis [122].
Subtotal loss or lack of myelinated fibers in a sural nerve
biopsy with remarkable preservation of unmyelinated axons
has been described by one of us (JMS) in a sporadic case
of sensorymotor neuropathy [138]. Prominent loss of large
and small myelinated fibers restricted to the sensory system combined with a relative preservation of unmyelinated
nerve fibers is seen in HSAN1 due to SPTLC1 mutations
and in HSAN2A caused by WNK1 gene defects [64, 181].
All nerve fiber populations in the sural nerve are equally
reduced in number in the HSANs due to ATL1, ATL3 [54],
RAB7 [65], DNMT1 [10] and FAM134B [78] gene mutations. Incomplete development and/or early degeneration
mainly of small myelinated sensory axons and of unmyelinated nerve fibers is found in HSAN III (familial dysautonomia; Riley-Day syndrome; inhibitor of kappa light
polypeptide gene enhancer in B-cells, kinase complexassociated protein (IKBKAP) gene mutations) and in neuropathies caused by mutations in the genes encoding nerve
growth factor (NGF), its high affinity receptor neurotrophic
tyrosine kinase receptor type 1 (NTRK1) [116, 181] and of

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Acta Neuropathol

Fig. 2a Myelinated nerve

fibers in the normal sural nerve.
Semithin section, toluidine blue;
scale bar 12m. b Loss of large
myelinated fibers in CMT2 in a
case with a mutation in MFN2,
showing only few remaining
large fibers (arrows). Semithin
section, toluidine blue; scale
bar 12m. c Normal myelinated and unmyelinated (lower
right corner) nerve fibers. EM;
scale bar 2m. d Schwann cell
processes forming empty collagen pockets indicative of the
loss of non-myelinated fibers
in a case of CMT1 due to MPZ
mutation; scale bar 1m

Table2Preferential loss of sural nerve fiber populations in hereditary neuropathies

Affected gene

Large myelinated nerve fibers

Small myelinated nerve fibers

Unmyelinated nerve fibers

MFN2, MME, KIAA1840, MORC2

+++

++

+++

+++

+++

+++

MPZ, GJB1, LMNA

SPTLC1, WNK1
ATL1, ATL3, RAB7, DNMT1, FAM134B
TTR
BSCL2
IKBKAP, NGF, NTRK1, PRDM12

+++

+++
++

++
+

+++

+++

+++

++

+++

+++, severe reduction; ++, moderate reduction; +, minor reduction; , no reduction; ?, no information found

transcriptional regulator PR/SET domain 12 (PRDM12)

[29]. Predominant loss of small myelinated and of unmyelinated nerve fibers is also a distinctive feature of early
stages of hereditary amyloid neuropathy due to transthyretin (TTR) mutations [118].
Alterations ofunmyelinated nerve fibers
As mentioned above, unmyelinated sensory and autonomic
nerve fibers are reduced in number or absent along with
myelinated sensory nerve fibers in several forms of HSAN,
whereas motor axons are largely preserved in this group of
neuropathies. Empty Remak bundles showing complete

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or partial loss of unmyelinated nerve fibers are often associated with increased numbers of so-called empty collagen pockets and indicate degeneration of unmyelinated
fibers (Fig.2d; Table3). In these structures, processes of
non-myelinating Schwann cells do not wrap axons, but
bundles of collagen fibers instead. Abnormally extended
and branched processes of Schwann cells of unmyelinated
nerve fibers are a prominent and characteristic feature of
CMT4C due to SH3TC2 (KIAA1985) mutations [44, 145]
(Fig. 6a). They have also been described in intermediate
CMT due to INF2 mutations [19]. However, the pathology
of unmyelinated nerve fibers in most hereditary neuropathies is still largely unexplored.

Acta Neuropathol
Fig. 3a Longitudinal section of a normal myelinated
axon showing low density of
organelles. EM; scale bar 2m.
b Focal axonal accumulation
of mitochondria and other
degenerating organelles in a
myelinated nerve fiber in a case
of NEFL neuropathy (from
Elbracht etal. Clin Neuropathol
2014 [39], with permission);
scale bar 2m. c Prominent
axoplasmic reticulum profiles
(arrows) in INF2 neuropathy;
scale bar 2m. d Giant axons
(arrows) in giant axonal neuropathy (GAN mutation); scale
bar 20m

Alterations ofmotor nerve fibers

Selective degeneration of spinal motor neurons and/or their
axons is a hallmark of spinal muscular atrophies (SMAs)
due to mutation of the RNA binding survival of motor neuron protein (SMN) gene and of the golgin and motor-adaptor protein bicaudal D homolog 2 (BICD2) gene [58, 106,
111, 127]. There can be concomitant, but clinically less
apparent or subclinical involvement of other neuronal cell
populations such as sensory neurons [58]. Histopathological nerve fiber alterations in hereditary motor neuropathies
(HMNs) are largely unexplored due to the limited availability of appropriate tissue specimens.
Focal axonal alterations
Focal accumulations of cytoskeletal elements and organelles as well as autophagic vacuoles are found in several
axonal neuropathies including neuropathies due to MFN2
[166, 169] and NEFL (Fig.3b) mutations [39, 40, 186].
Abnormally positioned, elongated and/or distorted mitochondria are especially frequent in patients with MFN2
mutations (see below); actually, intraaxonal accumulations

of degrading organelles, abnormal mitochondria and

cytoskeletal components as well as abnormally large clusters of regenerating axons should alert to the possibility
of CMT2 [14, 136, 137, 163, 167, 169]. Accumulations
of abnormal mitochondria in axons as well as Schwann
cells have also been reported in mitochondriopathies due
to mitochondrial and nuclear gene defects (for review, see
[172]. Large intraaxonal accumulations of mitochondria,
dense bodies, glycogen granules, neurofilaments and membranotubular profiles are a hallmark of neuroaxonal dystrophies [52, 77, 112, 182]. These so-called spheroids stain
positive for neurofilament, ubiquitin, and alpha-synuclein
[77].
Similar accumulations of neurofilaments leading to an
enlargement of axons are also encountered in neuropathies caused by neurofilament light-chain protein (NEFL)
gene mutations (CMT1F, CMT2E, DI-CMT) [39, 40, 186].
They are even more prominent (Fig.3d) in giant axonal
neuropathy due to GAN mutation [4, 71]. Gigaxonin, the
protein encoded by GAN, is an E3 ligase substrate adaptor and thus is believed to be involved in proteasomal
degradation and/or turnover of intermediate filament proteins (reviewed in [71]). PNS and CNS axons of affected

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Acta Neuropathol

Fig. 4a Large polyglucosan body in a myelinated axon. Semithin

section, toluidine blue; scale bar 10m. b Electron micrograph
revealing the filamentous ultrastructure of the polyglucosan body;
scale bar 1m. c Lack of myelin around larger diameter axons in
a case of congenital amyelination due to a SOX10 mutation [115].
Note that two of the axons (asterisks) show a one to one relationship
with Schwann cell nuclei, indicating that these axons do not belong

to Remak bundles. EM; scale bar 3m. d Increased nodal width in

CMT1 due to an MPZ mutation. EM; scale bar 3m. e Segmental
demyelination in a sural nerve biopsy of a patient with an MPZ mutation. EM; scale bar 2m. f Segmental demyelination followed by
thin remyelination in a patient harbouring a LITAF mutation; arrow
focal myelin folding close to the node of Ranvier. Semithin section,
toluidine blue; scale bar 10m

patients show marked swellings arranged like pearls on

a string; within these swellings, neurofilaments may lack
visible side arms and show dense packing with incomplete
whorl-like arrangement [71]. Organelles and microtubules
are often displaced; autopsy studies revealed a loss of cell
bodies of the affected neuronal populations [71]. Interestingly, altered neurofilament phosphorylation and spacing is
also observed in peripheral nerves of patients with neurofibromatosis type 2 due to mutations of the NF2 gene [144]
and in common CNS conditions associated with axonal
degeneration including Alzheimers and Parkinsons disease [117].
Polyglucosan bodies (Fig.4a, b) are basophilic, strongly
PAS-positive inclusions with a diameter of 10100m.
They are composed of fine branching filaments as well as
granular and amorphous material [82]. In a large series of
sural nerve biopsies, polyglucosan bodies were present in
8.5% of cases [22]. Their frequency was related to age, and
the authors concluded that the presence of a few polyglucosan bodies in sural nerves is a rather common finding

[22]. Intraaxonal polyglucosan bodies are increased in

number in adult polyglucosan body neuropathy and type IV
glycogen storage disease (GSD IV), both due to mutations
of the glycogen branching enzyme 1 encoded by the GBE1
gene. In these disorders, polyglucosan bodies are present
at a high frequency in CNS neurons as well as astrocytes
and may also be found in Schwann cells, muscle fibers and
other cell types [82, 83, 110, 124, 179].

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Alterations ofnerve fiber regeneration

Regenerating nerve fibers sprout within bands of Bngner
[135]. Such clusters are seen in nerve biopsies in many
cases of hereditary neuropathy and have been observed at
particularly high frequency in certain neuropathies including CMTX1 due to GJB1 mutations [171] as well as
CMT2A due to MFN2 mutations [32]. Absence of regenerative nerve fiber clusters has been described in several
hereditary neuropathies including cases of neuropathy due
to LMNA mutations [34].

Acta Neuropathol

Lack or early loss ofmyelin

Focal Schwann cell changes

CMT1A. Tomacula become apparent both in semithin sections and in teased nerve fiber preparations and are thought
to be caused by slippage and redundant folding of myelin
loops [86]. Less regular outfoldings of the myelin sheath
are referred to as focally folded myelin (FFM) and may
lead to a globular appearance of myelinated nerve fibers
(Fig.5e, f). Such alterations may occur in CMT1A and B,
but they are especially prominent and considered to be a
characteristic feature of several autosomal recessive forms
of CMT due to mutations in the myotubularin-related protein 2 (MTMR2; CMT4B1), SET binding factor 1 and 2
(SBF1 and SBF2/MTMR13; CMT4B3 and CMT4B2), and
periaxin (PRX; CMT4F) genes [7, 55, 66, 104, 146].
Lack or loss of compaction of the layers of the myelin sheath leads to uncompacted or decompacted myelin
(Fig. 5c). These alterations usually affect the major dense
line of outer myelin layers corresponding to the cytoplasmic component. They are encountered in CMT1B [47]
and in several forms of demyelinating autosomal recessive
CMT (CMT4). A similar pattern, affecting the intermediate
line which corresponds to the original extracellular space,
may be caused by deposition of immunoglobulins between
the myelin layers in disorders associated with monoclonal
gammopathy [165].
Abnormal widening and extensions of the adaxonal
Schwann cell cytoplasm and other abnormalities of the
innermost layers of the Schwann cell plasma membranes
are characteristic for the X-chromosomal form of CMT
(CMTX) due to mutation of the GJB1 gene encoding the
connexin-32 protein [140] (Fig.5d).

De andremyelination

Schwann cell onion bulb formations

Segmental demyelination is a frequent finding in CMT of

the demyelinating type, CMT1. It is defined as the loss of
myelin in one or several internodes, the territory of one
myelinating Schwann cell between two nodes of Ranvier,
and is often followed by remyelination. The process usually starts at the node of Ranvier (paranodal demyelination)
and involves activation of monocytes/macrophages as well
as fibroblasts (for review, see [136]). Regenerated myelin
sheaths of remyelinated nerve fibers usually do not reach
the thickness of the preexisting myelin, making them readily identifiable in teased fiber preparations and in longitudinal semithin sections for long periods of time after active
demyelination has taken place (Fig.4e, f).

In many demyelinating neuropathies including CMT1A

and 1B, myelinated and demyelinated nerve fibers are surrounded by one or several layers of abnormal, flattened,
degenerating Schwann cells and their processes (Fig.6).
These so-called Schwann cell onion bulb formations are
thought to result from an initial proliferation of Schwann
cells that try to remyelinate a demyelinated axon. Because
only one of them subsequently captures the internode, the
others recede to the periphery [14]. Several cycles of deand remyelination as well as ample deposition of collagen
and other extracellular matrix components between the
Schwann cell layers can lead to an impressive size of the
onion bulbs [141], which has led to the designation complex onion bulbs in certain cases [88, 89, 175]. During
these cycles, Schwann cell basal laminae often detach and
can form redundant layers. In the extreme form, the onion
bulbs largely or exclusively consist of left over basal lamina
and other extracellular matrix components [14]. As mentioned above, such basal lamina onion bulb formations are

Congenital amyelination or hypomyelinating neuropathy

is characterized by complete or subtotal lack of myelin as
well as other Schwann cell abnormalities. Such patterns are
observed in neurocristopathies caused by mutations in the
gene for the transcription factor SOX10 (Fig.4c) [115] and
in neuropathies due to certain mutations in myelin protein
zero (MPZ), peripheral myelin protein 22 (PMP22) and
early growth response 2 protein (EGR2) genes [18, 167].
Absent myelination may be associated with increased numbers of Schwann cells around the naked axons. Subsequent
degeneration of these Schwann cells leads to the formation
of onion bulbs of Schwann cell processes and their basal
laminae (basal lamina onion bulbs) around these axons
[42, 56].
The congenital cataracts, facial dysmorphism and neuropathy (CCFDN) syndrome due to mutations in the C-terminal domain phosphatase of RNA polymerase II, subunit
A (CTDP1) gene [168] is associated with hypomyelination;
in older CCFDN patients, de- and remyelination as well as
axonal degeneration is observed [160]. At the mild end of
the phenotypic spectrum, individuals with asymptomatic
congenital hypomyelination due to a single Rho guaninenucleotide exchange factor 10 (ARHGEF10) gene mutation
show disproportionately thin myelination, slowed nerve
conduction velocities, moderately reduced axon numbers
and mild denervation of muscles [170].

Tomacula andother focal myelin alterations

Concentric and eccentric myelin thickening associated with
axonal constriction in so-called tomaculous fibers (Fig.5a)
is especially frequent in HNPP, but may also occur in

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Fig. 5a Concentric myelin thickening (tomaculum) in HNPP. Semithin section, toluidine blue; scale bar 15m. b Concentric accumulation of Schwann cell basal laminae (basal lamina onion bulb; arrows)
at a node of Ranvier in CMT due to MPZ mutation. EM; scale bar
3m. c Incomplete compaction of the innermost myelin layers in
the same case. EM; scale bar 2m. d Accumulation of membranous

material at the axon-Schwann cell interface in CMTX1 due to GJB1

mutation. EM; scale bar 2m. e Cross and f longitudinal sections of
a sural nerve biopsy of a patient with SFB2 mutation showing marked
focal myelin folding. The axon is labelled with an asterisk. Arrow
node of Ranvier. EM; scale bar in e 2m, in f 5m

a frequent feature of congenital hypomyelination neuropathy (CHN), DSS and autosomal recessive CMT (CMT4)
[44] (Fig.5b).
At the other end of the spectrum, the onion bulbs may
consist of numerous vital Schwann cells. Such formations
are a frequent feature of neuropathies in neurofibromatosis,
especially neurofibromatosis type 2 [155]. In nerve fascicles of these patients, Schwann cells may also be grouped
in clusters not showing onion bulb architecture. The
Schwannoid cells within these so-called tumorlets often
show dysmorphic features such as altered nuclear morphology and nucleuscytoplasm ratios [155, 177]. In addition,
nerve biopsies of patients with neurofibromatosis type 2
may reveal atypical onion bulb formations as illustrated in
Fig.6c.

Other Schwann cell alterations inhereditary neuropathies

13

Abnormal cytoplasmic accumulations of beta-actin have

been observed in Schwann cells in nerve biopsies of patients
with CMTDIE due to INF2 mutation [93]. Neurolipidoses
such as sphingolipidoses and gangliosidoses as well as
certain leukodystrophies lead to characteristic inclusions
detectable by electron microscopy in Schwann cells and
other cell populations. These deposits includeamong
otherstuff stone bodies in metachromatic leukodystrophy, lipid inclusions in NiemannPick type A and Tangier
disease, banana bodies within myelinating and non-myelinating Schwann cells in Farber disease and bilaminar or
trilaminar structures composed of linear profiles in adrenoleukodystrophy/adrenomyeloneuropathy [14, 50, 113].

Acta Neuropathol
Fig. 6a Schwann cell onion
bulb (black arrow), abnormal
processes of non-myelinating
Schwann cells (arrowheads)
and Schwann cell basal lamina
proliferation (white arrow) in
CMT4C due to SH3TC2 mutation. EM; scale bar 2m. b
Semithin section of a CMT1A
sural nerve biopsy showing
Schwann cell onion bulbs (black
arrows) around normally and
thinly myelinated axons as well
as obsolete onion bulbs without
axons (white arrows). Toluidine blue; scale bar 10m. c
Atypical onion bulb formations with (black arrow) and
without (white arrow) central
myelinated axon in a case of
neurofibromatosis type 2 and
peripheral neuropathy due to
NF2 mutation. Semithin section,
toluidine blue; scale bar 15m

Secondary axonal degeneration

In advanced stages of most predominantly demyelinating
neuropathies, axonal loss is encountered in nerve biopsies.
It is generally considered a reactive phenomenon resulting
from secondary degeneration of the axons that have been
stripped of their protective Schwann cell covering and
may be accompanied by signs of nerve fiber regeneration.
Axonal degeneration after formation of onion bulbs results
in a denervated or obsolete onion bulb [99]. Moreover,
unmyelinated axons may be present in the Schwann cell
layers of onion bulbs which might originate from sprouting of the parent central axon within the bulb and/or belong
to neighboring unmyelinated nerve fibers that have been
incorporated into the bulb [99]. Pseudo-onion bulbs are
defined as clusters of regenerating myelinated and unmyelinated nerve fibers that are surrounded by Schwann cell
processes, adopting an onion bulb-like shape [99]. They
correspond to later stages of axonal regeneration within a
band of Bngner (Table3).

Alterations offascicular architecture

andof the neural connective tissue
Hypoplasia of perineurial structures associated with amyelination has been observed as a consequence of mutation
of the differentiation gene SOX10 [115]. A surplus of fascicles (minifascicular neuropathy; similar to minifascicle
formation in neuromas [139]), is caused by mutation of the
desert hedgehog (DHH) gene in patients with 46,XY partial
gonadal dysgenesis [102, 120, 130, 159, 162, 176]. Multiple mucosal neuromas are a regular feature of multiple
endocrine neoplasia type 2B (MEN2B) due to mutations
of the RET protooncogene, but have also been described in
a patient with normal RET gene lacking other features of
MEN2B [120]. These patterns have to be discerned from a
surplus of perineurial cells in the context of perineurioma.
This neoplastic lesion of peripheral nerves is characterized
by onion bulb formations composed of cells with perineurial differentiation including epithelial membrane antigen
(EMA) immunoreactivity [130]. Few cases of multiple

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Table3Summary of characteristic nerve pathologies in hereditary neuropathies

Characteristic nerve fiber changes in hereditary neuropathies

Prototypic gene defects/disorders

Preferential loss of certain nerve fiber populations

Axonal alterations
Altered neurofilament phosphorylation and spacing
Accumulations of neurofilaments/giant axons

See Table2
Neurofibromatosis type 2
NEFL, GAN

Spheroids

Neuroaxonal dystrophy: PLA2G6, C19ORF12

Polyglucosan bodies

GBE1

Mitochondrial abnormalities, focal axonal accumulations

of mitochondria and of other organelles
Axonal atrophy
Particularly large clusters of regenerating nerve fibers

MFN2, GDAP1

Absence of regenerative nerve fiber clusters

LMNA

Myelin/Schwann cell alterations

Absence of myelin
Widening of nodes of Ranvier
Paranodal demyelination
Segmental de- and remyelination
Uncompacted/widely spaced myelin

CMT2 (all forms)

MFN2

Congenital amyelinating/hypomyelinating neuropathy

(SOX10, MPZ, EGR2)
Prominent in CMT4C (SH3TC2), but also found
in other forms of CMT1
CMT1 (all forms)
CMT1 (all forms)
MPZ

Widening and abnormal segmentation of the adaxonal Schwann cell

cytoplasm
Abnormal paranodal loops

GJB1

Focally folded myelin, (FFM)/globular neuropathy

Prominent in CMT4B1 (MTMR2), CMT4B2 (SBF2) and CMT4B3

(SBF1), also found in other CMT1 forms
HNPP, sometimes in CMT1
CMT1 (all forms), sometimes in HNPP
CMT1 (all forms)

Tomacula
Schwann cell onion bulb formation
Abundant redundant and detached Schwann cell basal laminae
Basal lamina onion bulbs
Complex Schwann cell onion bulbs
Giant onion bulbs, Schwannoid cell clusters
Abnormal deposits in Schwann cells
Alterations of unmyelinated nerve fibers
Empty Remak bundles, collagen pockets
Abnormally extended and branched processes of Schwann cells of
unmyelinated nerve fibers
Alterations of fascicular architecture and of the neural connective tissue
Reduced number of nerve fascicles/abnormal or incomplete
perineurial covering
Increased number of fascicles
Multiple mucosal neuromas
Multiple perineuriomas, perineurial dysplasia
Endoneurial fibrosis, endoneurial deposition of mucoid substances
Amyloid

perineuriomas as well as hypertrophic perineurial dysplasia have been reported [159] one of which had a possible
positive family history [102]. Endoneurial fibrosis and

13

PRX

Prominent in CMT4C (SH3TC2), but also other forms of autosomal

recessive CMT1 (CMT4)
Prominent in CMT4F (PRX)
Neurofibromatosis type 2
Metachromatic leukodystrophy (MLD), adrenoleukodystrophy/adrenomyeloneuropathy (ALD, AMN), Fabry disease, neurolipidoses
Many CMT and HSAN forms
CMT4C (SH3TC2), also found in intermediate CMTDIE (INF2)

SOX10
Minifascicular neuropathy in cases with 46,XY partial gonadal dysgenesis (DHH)
Multiple endocrine neoplasia type 2 (RET) and related disorders
Familial perineuriosis
CMT1 (all forms)
Familial amyloid neuropathy (TTR), PrP systemic amyloidosis syndrome (PRNP)

deposition of mucoid material in the endoneurial extracellular space are prominent in many cases of demyelinating
neuropathy. Together with the formation of Schwann cell

Acta Neuropathol

onion bulbs mentioned above, these extracellular matrix

alterations may lead to a marked thickening of the nerves
(hypertrophic neuropathy) [176].
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding alphagalactosidase. In nerve biopsies, abnormal granular, osmiophilic inclusions are found predominantly in perineurial
and vessel wall cells. These inclusions produce a so-called
Maltese cross birefringence in polarized light microscopy
of unfixed tissue and show a variable ultrastructural morphology [14]. Extracellular granular osmiophilic deposits
are associated with cells of blood vessel walls in peripheral nerves of patients with CADASIL (cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy) due to mutations of the NOTCH3 gene
encoding a transmembrane receptor protein [143]. Peculiar
intranuclear granular inclusions in epineurial perivascular
cells are apparent in neuroferritinopathy caused by mutations in the FTL gene encoding the ferritin light polypeptide [134].

Paradigmatic neuropathy genes andtheir

functions ata glance
Genes predominantly associated withan axonal
phenotype
Mitofusin 2 (MFN2)
One of the most frequent axonal types of CMT neuropathy
is CMT2A caused by mutations of the MFN2 gene [185].
Mitofusin 2 is located in the outer mitochondrial membrane. Mutations alter the equilibrium between fusion and
fission of the mitochondrial net and are thought to affect
intra-axonal mitochondrial transport and bioenergetics
including the OXPHOS system [24]. Clinical presentation
may vary from rapid progression in early infancy to adult
onset with slow progression, occasionally with optic atrophy [80], pyramidal features, tremor, and parkinsonism
[41]. Histopathologically, the number of myelinated fibers
is reduced depending on the onset and duration of the disease [142] and larger myelinated fibers may be preferentially affected [166] (Fig.2b). Regenerating axons may be
located in large clusters. EM revealed distinct changes of
axonal mitochondria including condensation, swelling, and
interruption of the outer mitochondrial membrane, predominantly at the site of paranodal axonal protrusions where
mitochondria may accumulate [169]. Occasional mitochondria contain homogeneous or filamentous material [169].
Unusually swollen mitochondria were noted in endoneurial fibroblasts [169] and atypically branched cristae were
observed in Schwann cell mitochondria [153].

Neurofilament lightchain polypeptide (NEFL)

Since NEFL mutations directly affect the intermediate filament network of neurons, NEFL mutations are supposed to
lead to primarily axonal neuropathy. This is reflected by the
axonal loss and the above mentioned focal axonal swellings
and organelle accumulations encountered in sural nerve
biopsies of NEFL mutation cases (Fig.3b). Surprisingly,
however, NEFL mutation may also manifest as a predominantly demyelinating type of neuropathy; neuropathies due
to NEFL mutations therefore may be classified as either
CMT1F, CMT2E, or DI-CMT [39, 40, 186].
Genes predominantly associated witha demyelinating
phenotype
Peripheral myelin protein 22 (PMP22) This was the first
neuropathy gene to be identified [84, 121]. Duplications,
deletions and rare point mutations of PMP22 lead to various types of neuropathy with predominant Schwann cell
pathology (CMT1A; CMT1E; Hereditary Neuropathy with
liability to Pressure Palsy, HNPP; DejernieSottas Syndrome, DSS; Congenital Hypomyelination Neuropathy,
CHN, see above). CMT1A due to PMP22 duplications is
by far the most frequent hereditary neuropathy. PMP22
deletions andrarelypoint mutations lead to HNPP.
PMP22 is a cell membrane glycoprotein; proposed functions include Schwann cell maturation, myelination, myelin maintenance and adhesion of myelin lamellae [45]. In
nerve biopsies of CMT1A patients, de- and remyelinated
axons and classical Schwann cell onion bulb formations are
frequent. A small number of cases with PMP22 mutations
including the typical duplication [11] and the p.Arg159Cys
point mutation [49] may show a predominantly axonal
(CMT2-like) phenotype.
MPZ (P0) Myelin protein zerois a major transmembrane peripheral nerve myelin glycoprotein of the immunoglobulin superfamily. Mutations in MPZ can cause a
similar spectrum of demyelinating neuropathies as PMP22
mutations, including CMT1B, DSS and pressure-induced
neuropathy [69, 87, 174]. Myelin protein zero acts as a
homophilic adhesion protein that is thought to serve important functions in myelin development and compaction as
well as myelin maintenance. Accordingly, nerve biopsies of
CMT1B patients may show uncompacted myelin lamella,
especially inner and outer lamella (Fig.5c); abnormal myelin in- and outfoldings might result in a globular neuropathy pattern [164]. As in CMT1A signs of repeated de- and
remyelination including Schwann cell and basal lamina
onion bulb formations as well as axonal loss and endoneurial fibrosis are present.
Intriguingly, certain MPZ mutations are not associated
with a predominantly demyelinating phenotype, but cause

13

a mixed axonal and demyelinating (intermediate dominant

CMT, ID-CMT [92]) or even predominantly axonal, often
late-onset neuropathy (CMT2I) [25, 73, 151]. In nerve biopsies of such cases, no large Schwann cell onion bulb formations are found. There is a reduction predominantly of large
myelinated nerve fibers, and clusters of regenerating nerve
fibers are frequent. Some of these clusters are surrounded
by concentrically arranged Schwann cell processes, forming
so-called pseudo-onion bulbs [148]. It is unclear so far
why certain MPZ point mutations cause a primary axonal
phenotype. One possibility is the interference of these mutations with Schwann cellaxon interactions [151].
Connexin 32 (Cx32) The connexin 32 (Cx32) protein is
encoded by the GJB1 gene, which is localized on chromosome Xq13. Hemizygous or heterozygous GJB1 mutations
are the most frequent cause of X-linked CMT (CMTX1).
Few cases of an HNPP-like phenotype have been reported
[17]. Cx32 is a gap junction protein expressed by Schwann
cells and other cell populations. Cx32 appears to be
involved in the trafficking of small molecules through the
layers of the Schwann cell plasma membranes at sites of
non-compacted myelin, that is, at SchmidtLanterman
incisures and at nodes of Ranvier. GJB1 mutations are
thought to lead to loss of Cx32 functions. Morphologically, GJB1 mutations are associated with reduced myelin
thickness and loss of predominantly large myelinated nerve
fibers and clustered small, regenerated myelinated nerve
fibers. In line with the proposed functions of Cx32, characteristic abnormal widenings and extensions of the adaxonal
Schwann cell cytoplasm and other abnormalities of the
innermost layers of Schwann cell plasma membrane have
been described (reviewed in [140]) (Fig.5d). In addition,
abnormal axonal inclusions and other axonal alterations
have been found in myelinated nerve fibers of CMTX1
nerve biopsies [140]. These changes might be mostly secondary, even though for several patients carrying GJB1
mutations a predominantly axonal phenotype has been
described [16, 131, 147, 183].
SH3TC2 Autosomal recessive mutations in the gene
encoding SH3 domain and tetratricopeptide repeat-containing protein 2 (SH3TC2) cause CMT4C. This early-onset
progressive neuropathy is one of the most common forms
of autosomal recessive CMT [184]. Patients present with
distal muscle weakness and wasting, distal sensory deficits
as well as precocious and rapidly progressive scoliosis or
kyphoscoliosis and foot deformities [8, 145]. Characteristic
sural nerve pathology includes hypomyelination with excess
Schwann cell and basal lamina onion bulbs, peculiar supernumerary extensions of the cytoplasm of non-myelinating
Schwann cells and abnormal nodes of Ranvier (Fig.6a) [3,
44, 75, 145]. Several studies indicate that SH3TC2 protein
serves important functions in the endocytic recycling pathway which is important for myelination [3, 123, 156].

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Acta Neuropathol

Intermediate/mixed axonal anddemyelinating

neuropathies
As mentioned above, a mixed axonal and demyelinating
phenotype is observed in patients harboring certain mutations in genes that intuitively would be assigned to a primary axonal or demyelinating neuropathy. The NEFL and
the MPZ genes are prime examples of this phenomenon.
Both encode for major structural proteins of the axon
and Schwann cell, respectively. NEFL is not expressed in
Schwann cells, and MPZ is not expressed in neurons and
their axons. And yet, mutations in both genes may lead to
an intermediate neuropathy or even demyelinating (NEFL)
and axonal (MPZ) neuropathy (see above). Autosomal
dominant mutations in the INF2 gene encoding inverted
formin-2 protein are known to cause focal segmental glomerulosclerosis (FSGS) or FSGS combined with intermediate CMT (CMTDIE) [19]. CMTDIE patients present with
a typical CMT phenotype consisting of progressive distal
muscle weakness and atrophy, reduced tendon reflexes and
foot deformities. Nerve conduction velocities denote an
intermediate type of neuropathy with moderate slowing
combined with signs of axonal loss. In some of the CMTDIE patients anomalies of the central nervous system and
mental retardation as well as sensory hearing loss are found
[19]. Neuropathological studies of sural nerve biopsies
revealed varying degrees of axonal loss as well as severe
de- and remyelination with formation of multilayered onion
bulbs and supernumerary elongated cytoplasmic expansions of non-myelinating Schwann cells [19, 85, 93, 126].
In addition, occasional focally folded myelin layers were
linked to INF2 nerve pathology [126]. While INF2 mutations are unlikely to contribute to neuropathies without kidney disease [19], they are detectable in 75% of patients suffering from FSGS-CMT [85, 125, 161]. In line with a role
of INF2 in actin dynamics and its known association with
the endoplasmic reticulum (ER), actin aggregation [93]
and a prominent or even proliferated ER [126] was found
in axons (Fig.3c), Schwann cells and perineurial cells of
FSGS-CMT patients.

Prion protein andhereditary neuropathy

Prion protein (PrP) is widely implicated in spongiform
encephalopathies that occur in both animals and humans
with intra- and inter-species transmissibility. Demyelinating neuropathy has been described in rare familial cases of
CreutzfeldtJakob disease (CJD) caused by mutations in
the prion protein (PRNP) gene [1, 105]. In Prnp knockout
mice, a late-onset demyelinating neuropathy was reported
[20, 108]. Neuropathy was triggered by specific depletion
of Prnp expression in neurons, but not in Schwann cells,

Acta Neuropathol

suggesting that prion protein derived from neurons is

required for myelin maintenance in peripheral nerves [20].
Recently, a truncating PRNP mutation was identified in a
large family with a PrP systemic amyloidosis syndrome
[96, 97]. Patients presented with late-onset (4th decade)
autosomal dominant axonal sensory neuropathy, diarrhoea,
nausea, autonomic failure, neurogenic bladder and urinary
tract infections. The neuropathy was length dependent,
and the disease progressed for over 20years until death
[9597]. PrP amyloid was deposited in the CNS including
cerebral blood vessel walls and in peripheral nerves, skeletal muscle, skin and internal organs. In peripheral nerves,
abnormal PrP immunoreactivity was mainly found between
nerve fibers [96, 97].

Skin biopsy findings inhereditary neuropathies

Skin biopsy coupled with immunohistochemistry using
the pan-neuronal marker PGP9.5, is a reliable and minimal invasive method for the assessment of unmyelinated
sensory fibers in the epidermis as well as myelinated fibers
in the dermis. In the last decade, skin biopsies have been
increasingly used in the diagnostics and research of hereditary peripheral neuropathies [154]. The quantification of
the epidermal nerve fibers and other features (e.g., innervation of Meissner corpuscles) can be used in the evaluation
and follow up of sensory axonal degeneration [109]. In particular, a loss of sensory innervation in the skin is present
in HSANs [43, 62]. Besides the changes in intra-epidermal
innervation, alterations in sudomotor, vascular and pilomotor innervation can specifically be observed and quantified
in skin biopsies of patients with autonomic neuropathies
[35]. Axonal swellings in the epidermal small nerve fibers
filled with accumulated vesicles are thought to represent
early signs of axonal degeneration [79, 178]. Myelinated
fibers can be observed in higher density in glabrous skin
samples. Alterations of the nodes of Ranvier of these fibers
(changes in internodal length, nodal asymmetries, segmental demyelination) can be observed in hereditary as well
as in acquired neuropathies [129]. Changes of the level of
certain myelin proteins (PMP22, MPZ, MBP) as a result of
disease causing mutations (PMP22 duplication in CMT1A,
deletion in HNPP) can be quantified with immunoelectron
microscopy to correlate them with the clinical phenotype
[74, 81].

Hereditary neuropathies anddouble trouble

Patients harboring mutations in more than one CMT
gene have been reported, including cases with combined
EGR2/GJB1 [30], PMP22 (duplication)/GJB1 [63] and

PMP22 (duplication)/LITAF [98] mutations. In addition,

genetic studies of the promotor region of SH3TC2, which
is controlled by the transcription factors CREB and SOX10,
unraveled particular SNP genotypes as potential modifiers of disease severity of CMT1A [21]. Furthermore, the
co-occurrence of CMT and muscular dystrophies or other
neuromuscular disorders has been occasionally described:
CMT1A and facioscapulohumeral muscular dystrophy
(FSHD) [23, 133], X-linked CMT and Becker muscular
dystrophy [12], CMT neuropathy and myotonic dystrophy
type 1 [63], and HNPP and adrenomyeloneuropathy [63].
The phenotypes are generally more severe compared to
cases with mutations in a single gene.

Hereditary neuropathies andinflammation

Hereditary neuropathies are usually associated with nerve
biopsy changes that are equally distributed within the
fascicles and over the whole cross-sectional area of an
affected nerve. However, edema, lymphocytic infiltrates
and focally accentuated involvement of fascicles, which
are characteristic of chronic inflammatory demyelinating
polyneuropathy(CIDP), have also been described in some
cases of CMT [46]. Occasionally, sporadic and familial
inflammatory neuropathies were linked to PMP22 or GJB1
mutations [51, 76, 88, 173]. Moreover, immunological
studies in a group of CMT1A patients revealed serological
changes including anti-PMP22 autoantibodies indicative
of a superimposed autoimmune component [48]. Moreover, upregulated MHC class II expression was found to be
a common feature in CMT nerve biopsy samples [157].
Established mouse models for inherited demyelinating neuropathies, such as heterozygous Mpz deficient mice, show
a mild increase of CD8+ lymphocytes and macrophages
in peripheral nerves [150] and an immunodeficient genetic
background ameliorated the phenotype of myelin mutant
mice [132]. Extended cellcell contacts between endoneurial macrophages and fibroblasts were found in CMT mouse
models and human CMT nerve biopsies and were linked to
colony-stimulating factor-1-mediated macrophage activation [53]; further pathomechanisms linked to the immune
system in CMT mouse models have been reviewed recently
[90]. Finally, occasional patients with CMT1A, CMT1B,
CMT1X or CMT4C have been reported to respond to antiinflammatory or immunomodulatory treatment resulting in
amelioration of symptoms [36, 51, 67, 175].

Hereditary neuropathies andchemotherapy

Chemotherapeutic agents and other medication can
severely aggravate or exacerbate a coexisting hereditary

13

neuropathy [15]. For example, acute neurotoxicity of the

antimicrotubule agent vincristine has been observed even at
low doses in patients with CMT1A [26, 31, 61] or CMT
due to EGR2 mutation [103]. Vincristine-induced neuropathy can be the initial presentation of CMT [27] or HNPP
[72]. Recently, predisposition to chemotherapy-induced
peripheral neuropathy related to treatment with another
antimicrotubule agent, paclitaxel, was found to be associated with CMT gene variants, in particular variants in the
PRX and ARHGEF10 genes [13].

Concluding remarks
The number of patients with hereditary neuropathies is
likely to grow as ever-improving molecular genetic testing
strategies will continue to assign cases previously labelled
sporadic or idiopathic to distinct gene defects. This
should also become relevant for so far etiologically often
unexplained peripheral neuropathies in the growing elderly
population. At the same time, next-generation sequencing
techniques are generating vast numbers of candidate gene
mutations that need to be verified or excluded by careful
genotypephenotype correlation including nerve biopsy
studies. We should also expect to witness discovery of
an increasing number of gene alterations that predispose
to the clinical manifestation of a neuropathy when they
occur together with other genetic factors (e.g., hypomorphic mutations in neuropathy genes) or other endogenous
and exogenous influences (e.g., ageing, autoimmunity or
treatment with neurotoxic drugs). Analysis of archival and
newly obtained nerve biopsies will remain a mainstay for
scrutinizing these pathomechanisms.
Acknowledgements The authors are grateful to Mrs. H. Mader, Mrs.
E. Beck and Mrs. C. Krude (Institute of Neuropathology, RWTH
Aachen University Medical School) for technical assistance and to
Mr. M. Meyenberg (Dept. of Cardiology, RWTH Aachen University
Medical School) for artwork. This study was supported by grants from
the German Research Foundation (DFG WE1406/13-1, to JW), the
German Ministry for Education and Research (BMBF 01GM1511D,
to JW, IK and JS), the Fritz-Thyssen-Stiftung (Az. 10.15.1.021MN,
to JS) and the Interdisciplinary Center for Clinical Research (IZKF)
within the Faculty of Medicine of RWTH Aachen University (N5-3,
to JW, and N5-4, to JS). JW, IK and JS are members of the German
CMT-Network which is supported by the German Federal Ministry of
Education and Research (BMBF). JW is also a member of the German Motor Neuron Disease Network (MND-Net) sponsored by the
BMBF and the German Society for Muscle Diseases (DGM).

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