Handbook of Clinical Neurology, Vol.

113 (3rd series)

Pediatric Neurology Part III
O. Dulac, M. Lassonde, and H.B. Sarnat, Editors
© 2013 Elsevier B.V. All rights reserved

Chapter 146

Hereditary motor-sensory, motor, and sensory

neuropathies in childhood

PIERRE LANDRIEU1*, JONATHAN BAETS2,3, AND PETER DE JONGHE2,3

1
Department of Paediatric Neurology, Universit Paris Sud, Bictre Hospital, Paris, France
2
Neurogenetics Group, VIB-Department of Molecular Genetics and Laboratory of Neurogenetics,
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
3
Division of Neurology, University Hospital Antwerp, Antwerp, Belgium

INTRODUCTION hereditary diseases are, therefore, considered here in the

first instance.
Hereditary neuropathies are a heterogeneous group of
Categories of neurons mostly involved, according to
disorders that have an overall prevalence of 1 in 2500
clinical and standard EMG examinations, is the most
individuals. There are no good estimations of their prev-
classical element for the initial delineation of genetic
alence in the pediatric population.
neuropathies, in clinical neurology. A subdivision can
There are many ways of categorizing the hereditary be made into three main categories (Dyck, 1984). The
peripheral neuropathies, depending on the starting point
first, and also most prevalent, group is that of hereditary
(clinical presentation, biological mechanism, causal geno-
motor and sensory neuropathy (HMSN). More uncom-
mic rearrangement, and so on), as well as the hierarchy of
mon are the hereditary motor neuropathies (HMN),
the main parameters. If the clinical presentation is logically
characterized by selective involvement of the peripheral
chosen as the starting point in a clinical handbook, the hier-
motor neurons, and their counterparts, the hereditary
archy of the pertinent clinical parameters, both in neuro-
sensory and autonomic neuropathies (HSAN), charac-
logical practice and for classification purposes, must be
terized by a selective involvement of the sensory and/
briefly discussed (Table 146.1). or autonomic neurons. Though each group represents
Primary neuropathies are opposed to the various
a distinct disease spectrum, some areas of overlap exist.
situations in which the neuropathy occurs either as a
In an index case, the neuropathy can initially appear to be
late complication of a chronic hereditary disease, or as
restricted to a specific nerve fiber type, both clinically
a feature relatively secondary in the diagnosis of a multi-
and physiologically, but may extend later to other cate-
systemic congenital syndrome. The present chapter
gories of fiber. In the same family, other cases can pre-
focuses mainly on those entities in which the neuropathy
sent right away as a neuropathy affecting several neuron
is either the only presenting symptom or an early/major
populations.
clinical element. However, for the neurologist facing an
insidious polyneuropathy, the first concern is to ensure
PATHOPHYSIOLOGY OF NERVE
that it is not the unusual presenting symptom of a
FIBER DEGENERATION:
general disease, whether acquired or hereditary. This
ELECTROPHYSIOLOGICAL
rare situation is suspected in two circumstances: (1)
EXAMINATION
the neuropathy exhibits an unusual course, that is, a reg-
ular aggravation, rarely observed in the initial course of Measurement of nerve conduction velocities (NCVs)
primary neuropathies; (2) there are unusual accompany- and needle electromyography (EMG) in children are usu-
ing symptoms or signs in other organs (brain, skin, diges- ally limited to basic measurements, due to restricted
tive tract, heart, etc.). Neuropathies secondary to general tolerance. It is, however, possible to get a reliable

*Correspondence to: Pierre Landrieu, Service de Neurologie Pédiatrique, CHU Paris sud-Hôpital Bicêtre, 94270 F Paris, France.
E-mail: pierre.landrieu@bct.aphp.fr
1414 P. LANDRIEU ET AL.
Table 146.1 of the neuropathy, whether axonal or demyelinating
Most pertinent clinical parameters for categorizing genetic in nature, or to severe wasting of the marker muscle.
peripheral neuropathies ● The clinical experience reveals many neuropathies
with an intermediate electrophysiology (Davis et
Primary versus secondary occurrence al.,1978): in some patients, NCVs fall within a range
Category of peripheral neurons involved of 25–45 m/s and show an overlap between CMT1
Pathophysiology of the nerve fiber degeneration
and CMT. In the same way, in a single family some
Distinct neuropathological markers
patients may present electrophysiologically as CMT1
Apparent mode of inheritance
Isolated versus syndromic forms while others present as CMT2. Some genetic defects
Period of life are known to underlie these phenotypes, and for
many authors this “intermediate CMT” category
remains clinically useful, even if it does not neces-
sarily refer to a precise pathological interpretation.
measurement even in young children which will help in
● In the child, and especially in the infant, many
orienting the genetic diagnosis. Since sensory signs on
genetic neuropathies can be viewed as a develop-
clinical examination can be very mild, especially in
mental rather than a degenerative disorder. Abnor-
young individuals, NCV studies can be the sole tool to
mal development can affect the myelination
clearly prove or exclude the involvement of sensory neu-
without evidence of segmental demyelination, the
rons. Basic neurophysiological parameters in relation to
axonal growth without evidence of dying back
the growth of the peripheral nerve have been reported in
degeneration, or both processes simultaneously,
several studies (Parano et al., 1993; Garcı́a et al., 2000).
making the NCV values more complex to relate to
NCVs and EMG have been major parameters for
the neuropathological findings (Fig. 146.1).
delineating the various forms of hereditary motor and
● Due to the availability of routine molecular testing
sensory neuropathies in adults. When electrophysiologi-
for several of the known genes, sural nerve biopsy
cal and nerve biopsy studies became routinely available
has become obsolete in most patients, making the
in clinical practice, their results showed a coherent pat-
confrontation between neuropathological findings
tern: prominent Schwann cell pathology leads to segmen-
and NCVs increasingly less often needed in the clin-
tal demyelination and results in marked NCV slowing,
ical discussion.
whereas purely axonal degeneration, when respecting
a sufficient proportion of large myelinated nerve fibers, Distinct electrophysiological features can be also
results in near-normal NCVs. found in the two other groups of hereditary neuropa-
Thus, the most universal and simple parameter for thies. HMN is characterized by a pure motor neuropathy
describing HMSN is the measurement of NCVs, allow-
ing subdivision into two categories (Harding and
Thomas, 1980):
1. demyelinating neuropathies with clearly reduced
NCVs, typically defined as slowing of the motor
NCV for the median nerve < 38 m/s (HMSN1)
2. axonal neuropathies characterized by normal or
moderately slowed NCV > 38 m/s for the motor
median nerve (HMSN2).
This cut-off value of 38 m/s for motor NCV in the
upper limbs has mainly been validated for adult patients
with HMSN, but from experience this subdivision can
also be used in children as young as 1 year. However,
the simplistic superposition of the NCV values with Fig. 146.1. Developmental anomalies in a syndromic congen-
the underlying pathological mechanism is only partially ital neuropathy due to a SOX10 neomutation, in a 6-week-old
operative, especially in children’s hereditary neuropa- infant (superficial branch of the lateral popliteal nerve):
thies, for several reasons: atypical partitioning of the nerve trunk in numerous minifasci-
cles; reduced density of large myelinated axons and hypo-
● It is difficult to distinguish the axonal from the myelination of the myelinated fibers (right: control nerve;
demyelinating type when the action potentials can- original magnification  400). Motor and sensory NCVs
not be elicited or are markedly diminished upon were in the range 5–8 m/s in the median nerve (Pingault
stimulation. This could either be due to the severity et al., 2000).
 HEREDITARY MOTOR-SENSORY, MOTOR, AND SENSORY NEUROPATHIES IN CHILDHOOD 1415
of the axonal type, with normal or only slightly reduced
motor NCV. However, minor sensory involvement has
been reported in some HMN cases (Irobi et al., 2006).
HSAN phenotypes, on the other hand, exhibit a broad
range of electrophysiological features. Often a predom-
inantly sensory axonal neuropathy can be found but
occasional electrophysiological signs of demyelination
can be seen as well. Electrophysiological abnormalities
in motor nerves are sometimes present, illustrating the
overlap between HSAN and HMSN.
Distinct neuropathological markers. Since EMG find-
ings can accurately predict the underlying primary patho-
logical process in most hereditary neuropathies, the need
for a nerve biopsy becomes limited mostly to the rare
cases in which diagnosis of an acquired (inflammatory)
neuropathy remains uncertain. However, it is well known
that the morphological abnormalities in hereditary neu-
ropathies are much more diverse and sometimes patho-
gnomonic in the very young age group, compared to
the more monomorphic abnormalities observed in late-
onset forms (Schr€ oder, 2006). For example, myelin out-
foldings or redundant myelin loops can sometimes orient
towards a specific group of genes (Fig. 146.2).
Inheritance pattern in the family is an important ele-
ment for further subdivision of hereditary neuropathies.
As a rule, inherited peripheral neuropathies are trans-
mitted as monogenic disorders with high penetrance.
Autosomal dominant (AD), X-linked as well as autoso-
mal recessive (AR) forms have been described. Caution
Fig. 146.2. Myelin outfoldings in a case of demyelinating
CMT4. This finding points to several candidate genes, in the
first place those coding for myotubularin-related proteins
(bar ¼ 1 mm, Ax ¼ axon).
should be taken when interpreting this information in a
given pedigree. Especially in early onset neuropathies,
there is a substantial degree of de novo dominant muta-
tion that in essence presents as an isolated patient
within the family. In small kinships this can be difficult
to distinguish from recessive forms that are also com-
mon in early onset Charcot–Marie–Tooth (CMT) dis-
ease. On the other hand, if the vast majority of gene
defects behave either in a dominant or a recessive
way, a few notable exceptions need to be taken into
account for genes that can support both inheritance
patterns.
Syndromic versus nonsyndromic forms is another
major element to consider in pediatrics. A syndrome is
the nonrandom association of clinical and paraclinical ele-
ments, not linked to each other by a sequential process,
allowing identification of a clinical entity. A congenital
syndrome is a syndrome in which at least one element is
a developmental (i.e. with fetal onset) anomaly. As the ner-
vous system is a complex, multisystemic organ, two major
types of syndromes can be delineated in neurology:
1. Purely neurological syndromes, associating dys-
functions in different nerve cell populations, are
encountered both in adult and pediatric neurology.
They are numerous and generally classified in ref-
erence to the main initial symptom.
2. Syndromes associating both neurological and extra-
neurological anomalies are more specific to the
pediatric population and very rare for most.
The physician must be aware that no clear-cut frontier
exists between syndromic and non-syndromic disorders,
thus examining and re-examining the patient remains a
basic law in pediatrics. Some neuropathies initially con-
sidered as nonsyndromic can exhibit new findings along
their course, sometimes including extraneurological
ones. For practical reasons, some of them are here main-
tained in the category of primary neuropathies.
Period of life is a clinical category familiar to pedia-
tricians, as each exhibits its specific range of diseases.
As regard the peripheral neuropathies, the most relevant
pediatric category is the congenital neuropathies, i.e.
expressing in the perinatal period or in early infancy.
Many of them are syndromic, very specific to pediatric
practice and linked to genes different from those of clas-
sical neuropathies.
NEUROLOGICAL AND GENETIC
CLASSIFICATIONS OF HEREDITARY
NEUROPATHIES
No unifying classification or diagnostic algorithm is capa-
ble of taking into account at the same time all the relevant
clinical elements, permitting the regular introduction of
1416 P. LANDRIEU ET AL.
new genetic entities and staying simple. Historically,
hereditary neuropathies were first classified by neurolo-
gists according to neurological parameters, then were clas-
sified by geneticists according to succinct neurological
parameters in combination with novel genetic findings.
The classification proposed here (Table 146.2) is a version
of the classification more universally used, adapted for
pediatric needs. CMT, in the genetically based classifica-
tion, is the imperfect counterpart of HMSN in the previ-
ous, clinically oriented classification, which explains
several illogical points. For example, HMSN type III,
which referred to a severe, early demyelinating neuropa-
thy in a patient with nonaffected parents, has not been
retained in the CMT classification. So its transposition into
the CMT subtypes has to be found either in the recessive
forms (CMT4) with slow NCVs, in the severe CMT1 result-
ing from a de novo dominant mutation, or in the eponymic
Dejerine–Sottas disease that some authors continue to
use outside of any classification. Hereditary motor
Table 146.2
General classification of hereditary peripheral
neuropathies in childhood
I Hereditary neuropathies secondary to general diseases
II Primary neuropathies
IIa Hereditary motor sensory neuropathies
(HMSN) ¼ CMT
CMT1 (slow NCV, AD): a, b, c
CMT2 (normal/intermediary NCV)
CMT4 (AR)
CMT4 with slow NCV
CMT4 with normal/intermediary NCV
CMT X (various types of X-linked HMSN)
IIb Distal hereditary motor neuropathies (HMN)
HMN II
HMN IV
HMN V/Silver syndrome
HMN VI
HMN VII
ALS4
(spinal muscular atrophies SMA)
HMN (distal)
IIc Hereditary sensory (þ/ dysautonomic)
neuropathies (HSN)
HSAN I (AD):
HSAN II (AR, familial dysautonomia, Riley–Day
syndrome)
HSAN III (AR congenital sensory neuropathy)
HSAN IV (AR, HSN with anhiydrosis)
HSAN V
III Syndromic neuropathies, congenital neuropathies.
Syndromic neuropathies with late onset
Congenital neuropathies
AD, autosomal dominant; AR, autosomal recessive; NCV, nerve con-
duction velocities.
neuropathies have been distinguished from spinal muscu-
lar atrophies clinically by the distal predominance and
genetically by the usual AD transmission, but unavoidable
overlaps exist between the two categories.
FROM PHENOTYPE TO GENOTYPE,
AND VICE VERSA
Though a correct clinical evaluation is capable of orient-
ing the genetic testing, the neurologist needs to take into
account the extensive genetic heterogeneity that under-
lies any peripheral neuropathy. Conversely, for a given
gene, he must be aware that some mutations can be
responsible for distinct clinical presentations, including
some without a neuropathic trait.
I RULING OUT A NEUROPATHY
SECONDARY TO A HEREDITARY
GENERAL DISEASE
Monogenic metabolic diseases
A “metabolic disease”, for the physician, refers to any
disease in which the primary diagnosis is based upon bio-
chemical markers in body fluids and/or enzymological
markers in cells amenable to investigation. They are usu-
ally classified according to the deficient biological
function.
In only a few cases, the peripheral neuropathy is a
major or even the first presenting feature. The paradigm
is metachromatic leukodystrophy, in which some juve-
nile forms present as a progressive demyelinating poly-
neuropathy. Actually, almost all metabolic diseases
resulting in a neurodegenerative disorder can, sooner
or later, involve the lower motor neuron and the auto-
nomic or sensory ganglia (see Ch. 148, Metabolic neurop-
athies and myopathies).
LYSOSOMAL STORAGE DISEASES (SPECIFIC HYDROLASE
DEFICIENCIES) COMPLICATED BY PERIPHERAL
NEUROPATHY
See Table 146.3 (see also Chs 164, 174–177).
OTHER LYSOSOMAL DISEASES
Niemann—Pick disease type C results from an aberrant
traffic of exogenous cholesterol. Mutations in NPC1,
an integral membrane glycoprotein of the late endo-
some, or in NPC2, a small endoluminal protein of lyso-
somes, result in the lysosomal storage of a complex
mixture of unesterified cholesterol and glycosphingoli-
pids. Neuronoaxonal peripheral degeneration is a late,
unconstant complication.
Salla disease is a free sialic acid storage disorder
resulting from mutations in a presumptive sialic acid
 HEREDITARY MOTOR-SENSORY, MOTOR, AND SENSORY NEUROPATHIES IN CHILDHOOD 1417
Table 146.3
Lysosomal storage diseases (specific hydrolase deficiencies) complicated by peripheral neuropathy

Peripheral
neuropathy Biochemical
Disease characteristics Other organs markers (urine) Deficient enzyme

Metachromatic Demyelinating CNS Sulfocerebrosides Arylsulfatase A

leukodystrophy
Krabbe disease Demyelinating CNS Galactocerebroside b-Galactosylceramidase
Niemann–Pick A Demyelinating CNS, liver Sphingomyelinase
Gaucher Axonal CNS, macrophages Glucocerebroside b-Glucocerebrosidase
(type 2)
Tay–Sachs Distal axonal CNS b -Hexosaminidase
(late forms)
Fabry Neuropathic pains Heart, kidney a-Galactosidase A
Gut
b-Mannosidosis Demyelinating CNS, skin, bone Mannose-rich b-Mannosidase
oligosaccharides
a-Mannosidosis Immune, CNS, Mannose-rich a-Mannosidase
hearing, bone oligosaccharides
Mucopolysaccharidoses Carpal tunnel Bone Specific MPS Specific hydrolases
(MPS 1–7) syndrome
Schindler/Kanzaki Neuroaxonal CNS O-linked a-N-acetylgalactosaminidase
dystrophy Skin glycopeptides

transport protein. Sialic aciduria is the main biochemical
marker. Peripheral neuropathy, a secondary manifesta-
tion compared with the severe mental retardation, is at
least in part due to demyelination (Varho et al., 2000).
PEROXISOMAL DISORDERS
Disorders of peroxisome biogenesis, of which > 12
genetic subtypes have been identified by complementa-
tion studies, are responsible for a large phenotypic
range: Zellweger syndrome, neonatal adrenoleukodys-
trophy (ALD), and infantile Refsum disease, among
others (see Ch. 163). A peripheral component could be
partly responsible for the major hypotonia frequently
observed in these babies (Baumgartner et al., 1998),
but a peripheral neuropathy has not been clearly demon-
strated in any of the few neuropathological studies.
In X linked ALD, due to mutations in ABCD1, a gene
that encodes an ABC half-transporter involved in the
transmembranous traffic of VLCFA, a peripheral neu-
ropathy, mixing axonal degeneration and demyelination,
is sometimes associated with the degeneration of the
long tracts of the CNS. This picture of adrenomyelo-
neuropathy usually begins beyond adolescence.
Classic Refsum disease shows an accumulation of phy-
tanic acid in plasma- and lipid-containing tissues. Most
cases are due to a deficiency in a peroxisomal enzyme,
phytanoyl-CoA 2-hydroxylase (PAHX). The clinical
picture progressively includes retinitis pigmentosa, blind-
ness, anosmia, deafness, and ataxia. The peripheral neu-
ropathy rarely begins in childhood. It is dominated by
sensory features and results both from a Schwann cell dis-
order and from axonal degeneration.
In deficiency of peroxisomal D-bifunctional protein,
the progressive neurodegenerative syndrome begins in
childhood. A peripheral neuropathy is present which
results in a severe reduction of myelinated fibers in
the nerve biopsy (Schr€oder et al., 2004).
MITOCHONDRIAL OXPHOS DEFICIENCY
(see also Ch. 168)
A peripheral neuropathy is frequently encountered in
the course of the mitochondrial cytopathies, character-
ized by unique or multiple mtDNA deletions, which bear
the classical denominations of Kearns–Sayre syndrome,
progressive external ophthalmoplegia þ, multiple
mtDNA deletions syndromes, etc. Most of them occur
in a sporadic way, whereas rare cases are due to inherited
mutations affecting nuclear genes involved in the repli-
cation of mtDNA (POLG; Twinkle, ANT1, OPA1). The
clinical onset of the neuropathy is rarely before the juve-
nile period. Frequently the sensory fibers are more
involved clinically than the motor fibers. The pathologi-
cal picture is dominated by axonal degeneration, but
1418 P. LANDRIEU ET AL.
segmental demyelination is also present (Santoro et al.,
2006). In some cases, however, the neuropathy is a major
presenting feature, prompting some authors to delineate
separate entities like SANDO (sensory ataxic neuropa-
thy, dysarthria, and ophthalmoparesis) and MIRAS
(mitochondrial recessive ataxia syndrome).
A few syndromes begin in infancy. Infantile-onset
spinocerebellar ataxia (IOSCA), an autosomal recessive
disorder originally described in Finland, includes a
peripheral axonal neuropathy with a sensory predomi-
nance. It has been related to special mutations of Twin-
kle (a helicase specific for mtDNA), offering a good
example that the same gene can carry both dominant
and recessive mutations which result in different pheno-
types (Nikali et al., 2005).
In single base mutations of mtDNA, transmitted
through maternal lineage, a peripheral neuropathy does
not occur as an isolated presenting feature. However, it
can be a part of the clinical picture associated both with
the most frequent mtDNA mutations, such as the
8993 T > C (Leigh /NARP mutation), the 3243 A > G
(MELAS), the 8344A > G (MERRF), and with many
rarer mutations.
Deficiencies of respiratory chain complexes related
to mutations in nuclear genes also result in various clin-
ical pictures, some of them including a peripheral neu-
ropathy. No isolated deficiency of a specific complex
seems to be particularly responsible for a peripheral
nerve degeneration. In multiple respiratory chain com-
plex deficiency due to a depletion of mtDNA, a periph-
eral neuropathy has been mostly described in those
related to POLG mutations, some of them resembling
CMT II (Harrower et al., 2008). In other forms linked
to unidentified nuclear genes, presumably coding for
proteins involved in the ribosomal translation or in other
mitochondrial regulations, the peripheral neuropathy is
rarely but possibly a presenting feature, including in
severe neonatal forms (Ferreiro-Barros et al., 2008).
INTERMEDIARY METABOLISMS OF AMINO ACIDS AND
OTHER SIMPLE SUBSTRATES
Various hereditary diseases involve the intermediary
metabolism of simple molecules and are responsible
for the diffusion of abnormal substrates in body fluids.
Sometimes peripheral nerve lesions can occur as a major
presenting symptom. Various mechanisms can be
involved: (1) Direct toxicity of abnormal metabolites
on the neuron or on its axonal extension, usually result-
ing in a sensory-motor axonopathy. This is probably the
major phenomenon in hepatic porphyrias (neurotoxicity
of d-aminolevulinic acid). (2) Energetic crisis in the
peripheral nerve cell, resulting directly from the meta-
bolic defect. This is probably the case in pyruvate
dehydrogenase (PDH) deficiency and in diseases causing
a secondary deficiency of PDH (see Ch. 169) or of the
mitochondrial respiratory chain. Here the neuropathy
is usually a mixture of axonal degeneration and Schwann
cell dysfunction. (3) Multiple factors are involved in
more complex situations such as disorders of folate
remethylation, the most frequent being methylenetetra-
hydrofolate (MTHF) reductase deficiency (see Ch. 184).
DISORDERS OF POSTTRANSLATIONAL GLYCOSYLATION
The carbohydrate-deficient glycoprotein (CDG) syn-
dromes are a family of autosomal recessive disorders
in relation to defects of the protein N glycosylation,
which can be observed with isoelectric focusing of serum
transferrine as the most widely used diagnostic test
(see Ch. 179). The most frequent form, CDG-Ia or
phosphomannomutase-2 deficiency, affects many
organs, including the nervous system, in a not very pre-
dictable way. Neurological forms are characterized by
psychomotor retardation, strabismus, cerebellar hypo-
plasia and atrophy, retinitis pigmentosa, and stroke-like
episodes. A slow lower-limb sensory-motor axonal neu-
ropathy is an inconstant complication, rarely observed
clinically before adolescence. In a series of sural nerve
biopsies, the most striking findings were attenuation
of myelin sheaths, multivacuolar myelinoid bodies in
Schwann cells, and axonal degeneration of scattered
unmyelinated fibers (Nordborg et al., 1991).
SPECIFIC SYSTEMIC CARRIERS
a-Tocopherol transfer protein. Various recessive muta-
tions of the TTPA gene are responsible for AVED (ataxia
with vitamin E deficiency), a disease which reveals itself
usually in the late infantile or juvenile period with ataxia,
dystonia, and retinopathy (see Ch. 184). In most patients,
the peripheral neuropathy is clinically absent or moder-
ate, with normal NCVs and sensory potentials. In rare
cases, however, the peripheral neuropathy is an overt
clinical feature, presenting as a sensory, sensory-motor,
or distal motor axonopathy (Zouari et al., 1998; Fusco
et al., 2008). In the neurological complications secondary
to diseases resulting in malabsorption or deficient trans-
port of all liposoluble vitamins (cholestasis, mucovisci-
dosis, A-b-lipoproteinemia), a severe peripheral axonal
neuropathy was more often observed before the era of
systematic preventive measures.
Monogenic degenerative diseases
recognizable by nonbiochemical markers
Chediak–Higashi disease is dominated by a disorder of
the immune system and recognized by the presence of
special inclusions in leukocytes. Causal mutations are
 HEREDITARY MOTOR-SENSORY, MOTOR, AND SENSORY NEUROPATHIES IN CHILDHOOD 1419
to be found in the Beige gene (CHS1/LYST), a 430 kD
cytosolic protein of poorly understood function. A slow
peripheral neuropathy of the axonal type frequently
develops during the course of the disease.
Disorders of DNA repair, whatever their type, are
frequently complicated by a neurological degradation
including a peripheral neuropathy (see Ch. 167). In some
disorders (e.g., xeroderma pigmentosum, Cockayne syn-
drome), the diagnosis is facilitated by tests measuring
the process of excision-repair of single DNA strands
on cultured cells submitted to mutagenic stress such
as UV irradiation. Though the microarray technology
will be capable of measuring specific DNA repair activ-
ities, no generic test is currently available in most cases.
The diagnosis remains based upon investigation of can-
didate genes in syndromic neuropathies with some
orienting features (see below).
II PRIMARY NEUROPATHIES
IIa Hereditary motor sensory neuropathies,
Charcot–Marie–Tooth disease
The majority of hereditary neuropathies, both in adults
and in children, present as mixed motor and sensory neu-
ropathies (HMSN). All these forms have been exten-
sively described in adults, whereas studies specifically
focusing on children and adolescents are scarce or non-
existent. The earliest signs and symptoms do not seem to
differ between children and adults but the pace of pro-
gression is clearly different. Inherited neuropathies in
the pediatric age group tend to be more severe, some-
times resulting in early death and often compromising
the reproductive fitness of the more severely affected
patients. The early signs include areflexia, problems in
heel walking, atrophy of intrinsic foot muscles, clawing
of toes, pes cavus or pes varus, Achilles tendon shorten-
ing, peroneal weakness, and stocking hypoesthesia when
the sensory axons are involved. Sensory involvement is
often difficult to detect clinically, especially in children,
but can be documented by electrophysiological studies.
Special clinical attention needs to be given to any addi-
tional features such as pyramidal tract signs, ulcerations,
and autonomic symptoms.
Occasionally, the expression of a HMSN can be
acutely provoked by exposure to neurotoxic drugs.
Over the years several asymptomatic children have
been reported with different forms of inherited neurop-
athies who progressed to almost complete tetraplegia
within days or weeks after exposure to vincristine
(Cil et al., 2009).
A positive family history is the classical hallmark of
HMSN, but its absence does not argue against the
genetic nature of the neuropathy, especially in children.
Many isolated cases represent de novo dominant
mutations and many of them will not be transmitted,
due to the lack of reproductive fitness in severely
affected patients. Recessive forms tend to start early
in childhood and run a more severe course than the dom-
inant forms, and present with delayed motor milestones,
loss of ambulation, and variable associated signs
(Dubourg et al., 2006). In the European population,
AR forms of HMSN account for less than 10% of fam-
ilies, while in communities with a high percentage of con-
sanguineous marriages this proportion may rise to over
40% (Dubourg et al., 2006). Overall there is a lack of
large-scale studies looking into the mutation distribution
and frequency in a pediatric population, making diffi-
cult any prediction regarding the yield of mutation
screening.
The molecular investigation becomes increasingly
important not only for a correct diagnosis, but also
for genetic counseling, pre-implantation diagnosis and
eventually genotype-specific therapies. However, hered-
itary neuropathies show a bewildering genetic heteroge-
neity and routine diagnosis is only available for a few
genes. So far over 40 genes have been implicated and this
number is only expected to grow since more loci have
been identified. Screening of large cohorts of well-
defined phenotypes usually shows that a considerable
number of cases are not explained by mutations in any
of the known relevant genes. Fortunately, easily accessi-
ble parameters such as mode of inheritance, clinical fea-
tures, and additional characteristics often orient towards
a more restricted subgroup, limiting the number of
potential gene defects to be tested.
AD DEMYELINATING NEUROPATHIES (CMT1)
CMT1A is due to a 1.5 Mb duplication on chromosome
17p12 containing the peripheral myelin protein 22 gene.
PMP22 is an integral membrane protein produced by
Schwann cells, where it plays a crucial role in the devel-
opment and maintenance of compact myelin. CMT1A
accounts for the vast majority of CMT patients: up to
70% of all CMT patients if AD inheritance is present
and close to 50% of all CMT patients (Houlden and
Reilly, 2006; Szigeti et al., 2006). CMT1A is the only
CMT phenotype that has been systematically studied
in a small cohort of 12 young children (Berciano et al.,
2003). In these at-risk infants (one parent had confirmed
CMT1A), a molecular diagnosis was made irrespective
of the presence of symptoms or signs of neuropathy.
All children developed signs including areflexia,
problems in heel walking, atrophy of intrinsic foot mus-
cles, clawing of toes, pes cavus or pes varus, Achilles
tendon shortening, peroneal weakness, and stocking
hypoesthesia. Not every sign was present in all children.
Despite these signs, only 3 out of 12 children became
1420 P. LANDRIEU ET AL.
symptomatic at the age of 10 years. Serial electrophysi-
ological studies, including motor and sensory NCVs,
motor distal latencies and F-wave latencies, showed
abnormalities in all children by the age of 2 years. Inter-
estingly, NCVs reached their maximum, which are still
severely reduced compared to unaffected children, at
the age of 5 years and remained stable from then on, a
finding that suggests a combination of both dysmyelina-
tion (a developmental problem) and demyelination (a
degenerative process). Within the second decade most
CMT1A patients develop symptoms. CMT1A is often
mild or moderately severe and progresses only slowly
over many years.
Given the high prevalence of CMT1A and the com-
mon occurrence of de novo mutations, molecular
genetic testing should be considered in all children with
a demyelinating neuropathy without another evident
cause.
No specific treatment is currently available. How-
ever, in a transgenic mouse model that shows a huge
overexpression of PMP22, a study has demonstrated a
beneficial effect of ascorbic acid, possibly by lowering
PMP22 levels (Passage et al., 2004). Several clinical trials
of vitamin C in CMT1A are still ongoing (Pareyson et al.,
2006). In children, a recent trial reported no effect over a
period of 1 year (Burns et al., 2009).
Hereditary neuropathy with liability to pressure
palsies is caused by the reciprocal deletion of the same
region on chromosome 17 where the CMT1A duplica-
tion lies. This results in the loss of one copy of the
PMP22 gene. Symptoms of this episodic disorder are
painless, recurrent, focal motor and/or sensory periph-
eral neuropathies. Onset of this disorder is usually in
adolescence but it can be seen occasionally in younger
children. Some degree of phenotypic overlap with
CMT1 exists, obscuring the clinical diagnosis in some
patients (Chance, 2006).
CMT1B, which represents around 5% of CMT1
(Szigeti et al., 2006), is due to mutations in MPZ. Myelin
protein zero is a homophilic adhesion molecule and a
major structural protein of peripheral myelin. CMT1B
also starts in the first or second decade of life. Studies
specifically aimed at children are not available.
A follow-up study in the family that was instrumental
in localizing and cloning the MPZ gene showed that
NCVs were only marginally decreased over many years,
despite a clear increase in disease severity (Bird et al.,
1997). This again highlights that NCVs are a diagnosis
marker but a poor parameter for monitoring disease pro-
gression. Occasionally, CMT1B presents as a CMT2 phe-
notype and is then often associated with abnormalities of
the pupil reflexes. However, this form almost exclu-
sively starts in adulthood (Marrosu et al., 1998; De
Jonghe et al., 1999).
CMT1C, related to mutations in LITAF
(lipopolysaccharide-induced tumor necrosis factor-a is
a protein of uncertain role that participates in the break-
down of various substances), exhibits a classic CMT1
phenotype. CMT1D is related to dominant mutations
in EGR2 (early growth response 2, a transcription factor
with three tandem C2H2-type zinc fingers, that controls
expression of myelin protein genes); CMT1F, related to
mutations in NEFL (neurofilament light chain polypep-
tide), is apparently rare and little is known about its pre-
sentation in children (Houlden and Reilly, 2006). NEFL
mutations are associated with a fairly broad phenotypic
spectrum of AD CMT including early onset forms
(Jordanova et al., 2003) and axonal/intermediate CMT
variants (CMT2E).
Despite possible differences in average forms, in clin-
ical practice it is impossible to distinguish between
CMT1A, CMT1B, CMT1C, CMT1D, and CMT1F. Given
the relative frequencies of these AD forms, it is advis-
able to start with screening for the CMT1A duplication,
followed by the analysis of the MPZ gene and the
PMP22 gene. Performing mutational analysis of the
rarely involved genes LITAF, EGR2, and NEFL is
restricted to research laboratories.
CONGENITAL HYPOMYELINATING NEUROPATHY
AND DEJERINE–SOTTAS DISEASE
Congenital hypomyelinating neuropathy (CHN) corre-
sponds to a severe congenital or very early childhood-
onset neuropathy resulting in pronounced hypotonia
and associated breathing and feeding problems. Electro-
physiology shows severely slowed to absent NCVs. Neu-
ropathology reveals markedly reduced or even absent
myelin, suggesting a developmental problem of the mye-
lin’s formation. CHN is closely related to Dejerine–
Sottas disease (DSN), a severe demyelinating neuropa-
thy with somewhat later onset in childhood but usually
before the age of 5 years (Houlden and Reilly, 2006).
DSN, for some, is strictly defined by findings including
early onset, severely slowed NCVs and high protein con-
tent in the spinal fluid. Others have loosely applied the
DSN designation to any early-onset severe CMT, regard-
less of the underlying pathology and NCV findings.
Whether or not CHN and DSN can be considered as sep-
arate disease entities, molecular genetics has shown that
both are in fact the severe end of the CMT1 (or HMSN1)
disease spectrum. When identified, the most frequent
molecular genetic causes are monoallelic mutations in
MPZ (myelin protein zero), PMP22 or EGR2 (early
growth response 2) (Smit et al., 2008). Occurring de novo
in patients without reproductive fitness, these dominant
mutations usually appear as isolated cases. On the other
hand, several recessive demyelinating CMT (CMT4)
 HEREDITARY MOTOR-SENSORY, MOTOR, AND SENSORY NEUROPATHIES IN CHILDHOOD 1421
tend to be associated with severe early-onset phenotypes
resembling CHN or DSN as well, sometimes occurring in
several sibs (see next section).
AR HEREDITARY MOTOR SENSORY NEUROPATHIES
(CMT4)
Most AR CMT subtypes display an onset in early infancy,
either congenital or at least resulting in delayed motor
milestones (Dubourg et al., 2006). With a few notable
exceptions (Bernard et al., 2006), the majority of recessive
CMT forms are demyelinating and are thus characterized
by slow NCVs. They are grouped together under the cat-
egory CMT4 and are numbered accordingly. Due to the
rarity of these forms it is difficult to make reliable esti-
mates of the relative contribution of the several genes.
These forms are more prominent in countries or ethnic
groups with a high degree of consanguinity. Their relative
frequencies may differ from one population to another
due to the occurrence of founder mutations. Although
a broad overlap exists between the different phenotypes,
certain distinctive characteristics are of importance:
● Mutations in GDAP1 (ganglioside-induced
differentiation-associated protein-1, a regulator of
the mitochondrial network) are known to cause a
wide variety of CMT forms including AR demyelin-
ating CMT but also AR axonal, intermediate forms
and even rare AD forms. The demyelinating form
(CMT4A) has an onset before the age of 3 years,
with a rapidly progressing and severe weakness
often resulting in loss of ambulation. NCVs are in
the range from 25 to 35 m/s (Dubourg et al., 2006).
● SH3TC2 (SH3 domain and tetratricopeptide repeat
domain 2 is a protein that interacts in assembling
protein complexes) is probably the most frequently
mutated gene in early-onset AR CMT patients (per-
sonal data, unpublished). Onset can be in the first
year of life but progression is often slow. Motor
NCVs are clearly slowed, but the range is broad.
A particular finding in several patients is a severe
and early scoliosis, sometimes even preceding man-
ifest distal weakness (Dubourg et al., 2006).
● Among MTMRs (myotubularin-related proteins are
tyrosine phosphatases that are believed to be regula-
tors of membrane dynamics), MTMR2 and
MTMR13 or SBF2 (SET binding factor 2) cause
AR CMT variants. Onset is in childhood but usually
after normal motor milestones have been reached.
There is often a rapid progression resulting in the
loss of ambulation and also in facial, bulbar, and dia-
phragmatic weakness in some patients. On neuropa-
thology, irregular foldings and redundant myelin
loops (or myelin outfoldings) can be seen
(Fig. 146.2). This finding is not exclusive but is
specific enough to orient screening in the direction
of MTMRs (Dubourg et al., 2006). Early-onset glau-
coma has been described as an associated feature in
SBF2 mutation carriers (Azzedine et al., 2003).
● HMSN-Lom (hereditary motor and sensory neurop-
athy Lom type) is caused by mutations in NDRG1
(N-myc downstream regulated gene 1, a member
of the a/b hydrolase superfamily, is a cytoplasmic
protein involved in cell growth and differentiation).
This recessive phenotype is almost exclusively
restricted to Gypsies of Eastern European descent,
the vast majority of patients carrying the same foun-
der mutation. HMSN-Lom has an onset in the first
decade of life and weakness often spreads to the
proximal parts of the limbs. NCVs are in the range
of 10–20 m/s. A suggestive additional finding is
the presence of sensorineural deafness.
● Mutations in FGD4 (FGD1-related F-actin binding
protein is a nucleotide exchange factor specific to
a RhoGTPase that plays a key role in mediating actin
cytoskeleton changes during morphogenesis) can
give rise to an early infancy-onset phenotype result-
ing in delayed motor milestones in some patients.
Slow progression, however, has been reported. Elec-
trophysiology often shows very slow NCVs < 15 m/s,
and myelin outfoldings can be seen on neuropathol-
ogy (Stendel et al., 2007; Fabrizi et al., 2009).
● Mutations in EGR2 can behave both as dominant
(CMT1D, see above) and as recessive traits. In both
instances onset can be congenital with markedly
reduced NCVs in the range of 5–20 m/s. Involve-
ment of cranial nerves has been reported.
● Mutations in PRX (periaxin is a protein mainly
expressed during development that is important in
Schwann elongation) typically result in a CMT with
severely reduced motor NCVs, as low as < 5 m/s.
In some instances myelin outfoldings can be seen
on neuropathology.
AXONAL FORMS (CMT2)
AD CMT2. Dominantly inherited axonal CMT (CMT2) is
estimated to represent about one third of all CMT cases.
From a purely clinical point of view no distinction can be
made from CMT1. Electrophysiological evaluation,
however, allows separation, as motor NCVs are normal
or only mildly slowed (>38 m/s). As for demyelinating
forms, CMT2 is genetically heterogeneous (Zuchner
and Vance, 2006). Most forms have their onset in adult-
hood with some notable exceptions.
Mutations in MFN2 (mitofusin 2 regulates both the
fusion of the mitochondria and the respiratory chain)
are found in up to 20% of CMT2 patients and give rise
to various axonal phenotypes (CMT2A). Severity of
1422 P. LANDRIEU ET AL.
CMT2A is more pronounced than for other CMT2
forms. Age at onset varies widely but can be as early
as 5 years (Verhoeven et al., 2006). MFN2 mutations
can also cause an axonal sensorimotor neuropathy with
pyramidal tract signs, usually with an adult onset (also
called HMSN V). Sometimes patients carrying a
MFN2 mutation develop an acute drop in visual acuity
due to an optic neuritis resulting in optic atrophy. This
syndrome, also known as HMSN VI, can have an onset
in the first decade of life (Z€uchner et al., 2006).
A variant SEOAN syndrome (severe early onset axonal
neuropathy) has been described in young children. It is in
fact a biallelic gene disorder caused by the co-occurrence
of two MFN2 mutations (Nicholson et al., 2008).
KIF1Bbeta is an isoform of KIF1B, a member of the
kinesin superfamily involved in mitochondrion trans-
port. A KIF1B mutation has been described in a single
small AD CMT2 family (Zhao et al., 2001), but its path-
ogenicity is still equivocal.
GARS is a glycyl-tRNA synthetase expressed in
sprouting neurites. GARS mutations have been shown
in several families with axonal CMT2D (Nangle et al.,
2007). RAB7 is a small GTP-ase late endosomal protein.
Mutations of the gene have been shown to be responsible
for CMT2B in a few familial cases in which foot ulcers
were a prominent finding. HSPB1 (or HSP27), a 27 kDa
small heat shock protein, and HSPB8 (HSP22), the
22 kDa small heat shock protein, are responsible for a
subset of purely motor neuropathies (HMN-II, see
below). The same genes are mutated in rare CMT2F
and CMT2L families presenting with an axonal motor
and sensory neuropathy.
AR CMT2. Mutations in GDAP1, as mentioned
before, can cause a wide variety of phenotypes among
which the AR axonal phenotype is probably the most
severe. In terms of mutation frequencies, GDAP1 is
likely to be an important player in ARCMT. The pheno-
type is characterized by early onset of weakness with
rapid progression. Scoliosis and breathing difficulties
due to diaphragmatic paralysis and vocal cord paralysis
are features that orient the genetic screening toward
GDAP1 (Bernard et al., 2006).
One single recessive founder mutation in LMNA
found in Moroccan and Algerian families gives rise to
a severe axonal CMT phenotype with an onset between
6 and 27 years. Lamins A/C, belonging to type V interme-
diate filaments superfamily, are major structural con-
stituents of the nuclear lamina that regulate the
chromatin structure as well as various proteins. This neu-
ropathy forms one of the diverse disorders also called
laminopathies (Bernard et al., 2006).
MED25 is a subunit of the activator-recruited cofac-
tor (ARC), a family of large transcriptional coactivator
complexes. Homozygous mutation has been found in a
large family from Costa Rica affected with axonal CMT
(Leal et al., 2009).
AD INTERMEDIATE FORMS
As mentioned before, “intermediate CMT” refers to
families and individual cases in which NCVs show large
variations and overlap between CMT1 and CMT2. Some
genetic defects are especially candidates for these
phenotypes.
Mutations in DNM2 (dynamin 2 is a fission protein
that participates in endocytic vesicle formation and in
the dynamics of microtubules) usually give rise to an
adult-onset phenotype with intermediate electrophysiol-
ogy. As for all CMT variants, there is considerable var-
iability even within families and onset in early childhood
has been described (Claeys et al., 2009). The phenotype is
a classical CMT but in some families concomitant neu-
tropenia and early onset cataract have been reported.
Mutations in YARS (tyrosyl-tRNA synthetase is
involved in protein synthesis) result in AD intermediate
CMT. This form can start in childhood but so far
only a few mutations have been reported (Jordanova
et al., 2006).
X-LINKED CMT
Mutations in GJB1 (gap junction associated protein B1
forms gap junctions between myelin layers) cause the
non-syndromic CMT1X which represents the second
most common variant of CMT, accounting for around
10% of all patients (Kleopa and Scherer, 2006). CMT1X,
especially in males, can begin in early childhood. Males
are more severely affected but females can develop a
clear phenotype as well, presumably by skewed
X-inactivation. Onset in females is usually later and
symptoms are milder; however, a broad spectrum has
been described ranging from true asymptomatic carriers
to phenotypes as severe as in male patients (Kleopa and
Scherer, 2006). Early involvement of small hand muscles
may be a sign pointing to CMT1X. NCVs can still be nor-
mal in young female mutation carriers, while in young
male children they can fall within the range of CMT2
or “intermediate CMT”. Given the high prevalence of
CMT1X, testing should be considered in any family that
does not reveal a clear father–son transmission (Szigeti
et al., 2006).
IIb Hereditary motor neuropathies
Distal hereditary motor neuropathies (HMN) are esti-
mated to represent around 10% of all inherited neurop-
athies (Irobi et al., 2006). Epidemiological data more
specific for pediatric populations are not available.
HMN cover a spectrum of clinically and genetically
 HEREDITARY MOTOR-SENSORY, MOTOR, AND SENSORY NEUROPATHIES IN CHILDHOOD 1423
heterogeneous diseases characterized by the selective
involvement of motor neurons in the peripheral nervous
system (Dierick et al., 2008). In contrast to proximal spi-
nal muscular atrophies (SMA) (see Ch. 145), distal HMN
initially and predominantly affects the distal limb mus-
cles, suggesting a length-dependent mechanism affect-
ing the longest motor axons first. The disease usually
begins in childhood or adolescence with weakness and
wasting of distal muscles of the anterior tibial and pero-
neal compartments. Later, weakness and atrophy may
expand to the proximal muscles of the lower limbs
and/or to the distal upper limbs. However, in some
patients and families the disease starts or predominates
in the hands. Foot deformities (e.g., pes cavus) are some-
times present. A classification has been proposed in
seven subtypes based on age at onset, mode of inheri-
tance, distribution of muscle weakness, and additional
features (Harding, 1993). Some features that were not
included in the original classification have resulted in
further diversification of the clinical spectrum, includ-
ing pyramidal signs, congenital onset and X-linked
inheritance (Irobi et al., 2006).
So far, eight genes have been identified for distal
HMN, six of which are associated with autosomal dom-
inant (AD) forms. The combined mutation frequencies
for all the known dominant genes in a larger cohort
are relatively low (15%), making the yield of diagnosis
screening poor (Dierick et al., 2008). Only the forms
characterized at the gene level are described here.
HMN II is related to mutations in HSPB8 (12q24.3) or
HSPB1 (7q11-q21). Heat shock proteins block signals
inducing apoptosis and are involved in stabilization of
newly produced proteins and repair of damaged pro-
teins, especially from the cytoskeleton (Evgrafov
et al., 2004; Irobi et al., 2004). The HMN II phenotype
is characterized by a pure motor neuropathy with distal
weakness and muscle atrophy without pyramidal tract
signs and typically with the age of onset in adolescence.
In a recent report, however, the Pro182Leu mutation in
HSPB1 was found in association with an early onset
age (5 years) in two children also displaying mild pyrami-
dal tract signs (Dierick et al., 2008).
Overall the combined mutation frequency for HSPB8
and HSPB1 in a large cohort of HMN patients is only 6%
(Dierick et al., 2008). Interestingly, mutations in these
genes can also result in AD axonal sensorimotor neurop-
athy (CMT2F and CMT2L, respectively).
HMN IV (PLEKHG5, 1p36). HMN IV is a recessive
disorder caused by mutations in PLEKHG5 (pleckstrin
homology domain-containing, family G member 5 gene;
pleckstrin domain is present in a wide range of proteins
involved in intracellular signaling or as constituents of
the cytoskeleton) (Maystadt et al., 2007). A mutation
was identified in one African family with childhood onset
(<10 years), distal but also proximal weakness, and rapid
evolution toward tetraplegia and respiratory insuffi-
ciency. Nothing is known about the mutation frequency
of this gene and the variability of the associated phenotype.
HMN V/Silver syndrome (BSCL2, 11q12-q14). Muta-
tions in BSCL2 (Bernardinelli-Seip congenital lipody-
strophy 2 is an endoplasmic reticulum membrane
protein of unknown function) cause a wide spectrum
of AD disorders ranging from a pure distal motor neu-
ropathy without pyramidal tract signs to spastic paraple-
gia (SPG17) (Windpassinger et al., 2004). Silver
syndrome is one of the well-known phenotypic variants
characterized by spasticity of the legs accompanied by
amyotrophy of the hands and occasionally of the lower
limbs (Irobi et al., 2006).
Onset ages can vary widely between, and even within,
families, but can be as early as 5 years (Dierick et al.,
2008). Only two mutations in a mutational hotspot of
BSCL2 have been described so far. In a recent study,
mutation yield was 7% in a large HMN cohort, rising
to 30% in selected patients with proven AD inheritance
and clear pyramidal tract signs (Dierick et al., 2008),
making the two hotspot mutations good candidates to
screen in such patients.
HMN VI (IGHMBP2, 11q-q14). The phenotype asso-
ciated with mutations in IGHMBP2 (immunoglobulin
m-binding protein 2a) is known as SMARD1 or (distal)
spinal muscular atrophy with respiratory distress
(Grohmann et al., 2001). Age of onset is very early after
birth but usually after a symptom-free interval of several
weeks. Despite the misleading abbreviation SMA, the
weakness has a distal distribution. An important addi-
tional feature is bilateral diaphragmatic paralysis rapidly
leading to respiratory insufficiency, with a poor long-
term prognosis in the majority of patients (Bertini
et al., 1989).
ALS4 (SETX, 9q34). Dominant mutations in SETX
(senataxin is a DNA/RNA helicase) cause a phenotype
with the somewhat misleading name amyotrophic lateral
sclerosis 4 (ALS4) or juvenile ALS (Chen et al., 2004).
Age at onset varies widely but usually falls within the
first decade (Irobi et al., 2006). The phenotype is charac-
terized by progressive distal weakness and atrophy with-
out sensory disturbances and with variable pyramidal
tract signs. There is no involvement of the cranial nerves
or respiratory muscles and survival is normal. Mutation
frequencies for SETX, however, account for less than
2% in a large HMN cohort (Dierick et al., 2008).
IIc Hereditary sensory and autonomic
neuropathies
Hereditary sensory and autonomic neuropathies
(HSAN) probably form the rarest subgroup within the
1424 P. LANDRIEU ET AL.
hereditary neuropathies and are clinically and genetically
heterogenous. A selective degeneration of the sensory
neurons in the peripheral nervous system gives rise to
prominent distal sensory loss which can lead to chronic
ulceration of the feet and hands, osteomyelitis, and
amputations of toes and fingers. Due to the concomitant
degeneration of autonomic nerve fibers in some forms,
features such as anhidrosis, fever, blood pressure fluc-
tuations, and gastrointestinal disturbances can be pre-
sent in some patients (Dyck, 1993). The designation
HSAN suggests an exclusive sensory and autonomic
involvement, but in some forms clear weakness may
be present.
A classification into HSAN types I–V was made
based on age at onset, inheritance pattern, and additional
features. HSAN can be transmitted as an AD or AR trait.
Isolated patients are also known (Dyck, 1993; Auer-
Grumbach et al., 2006). The AD forms (HSAN1) usually
present in the second or third decade of life with marked
sensory, minimal autonomic and variable motor involve-
ment. In contrast, the AR forms usually have an early or
congenital onset and present with striking sensory and
autonomic abnormalities or as almost pure autonomic
disorders (Auer-Grumbach et al., 2006). Additional fea-
tures such as mental retardation can be hallmark fea-
tures of specific subtypes.
Overall the contribution of the known genes to the
genetic spectrum of HSAN is not higher than 20%.
Due to this low screening yield, molecular diagnosis is
not forthcoming. However, several phenotypic charac-
teristics result in strict genotype-phenotype correlations
that can help in orienting the molecular screening
(Rotthier et al., 2009).
HSAN I (SPTLC1, 9q22.2). This dominantly inherited
phenotype is caused by mutations in SPTLC1 (serine pal-
mitoyltransferase long chain subunit 1 is a key enzyme in
sphingolipid synthesis) (Dawkins et al., 2001). It is a sen-
sory neuropathy without marked autonomic features
and variable motor involvement in some patients.
It was only described in adults until recently, when a de
novo mutation was described in a child with a congenital
disease onset characterized by hypotonia, microcephaly,
vocal cord paralysis, and breathing problems (Rotthier
et al., 2009). In the same study, mutation frequency in this
gene was reported to be very low (2% of HSAN).
HSAN II (WNK1/HSN2, 12p13.3). Mutations in
WNK1/HSN2 (protein kinase with-no-lysine(K)-1/hered-
itary sensory neuropathy type 2 is a signaling molecule
involved in regulation of neurite extension) cause
autosomal recessive HSAN type II, an early onset ulcer-
omutilating sensory neuropathy (Lafreniere et al., 2004).
Onset can be congenital or later in childhood and
the phenotype is relatively uniform, with pronounced
distal sensory loss resulting in severe acromutilations
in the absence of manifest dysautonomic features
(Auer-Grumbach et al., 2006; Coen et al., 2006). The
mutation yield of 3% in a larger cohort of HSAN is
too low to warrant routine diagnostics.
HSAN III (IKBKAP, 9q31). Riley–Day syndrome, or
familial dysautonomia, is an AR disorder caused by
mutations in IKBKAP (inhibitor of k-light polypeptide
gene enhancer in B cells, kinase complex associated pro-
tein, a protein that plays a role in transcriptional elonga-
tion and in neuronal migration) (Slaugenhaupt et al.,
2001). This disorder has a high prevalence in individuals
of Ashkenazi or Eastern European Jewish origin. HSAN
III presents as a predominantly autonomic disorder with
congenital onset. Symptoms include disturbances of gas-
trointestinal motility resulting in feeding difficulties and
pneumonia due to aspiration. In addition, patients may
display pronounced blood pressure fluctuations. Signs
of sensory loss are present but mild compared to the
autonomic features (Auer-Grumbach et al., 2006;
Axelrod and Gold-von Simson, 2007).
HSAN III seems to be genetically homogenous, war-
ranting screening in selected patients. Over 99% of
patients are shown to carry the same mutation (Auer-
Grumbach et al., 2006).
HSAN IV (NTRK1, 1q21-22). Congenital insensitivity
to pain with anhidrosis (CIPA) or HSAN IV is an AR dis-
order caused by mutations in NTRK1 (neurotrophic tyro-
sine kinase, receptor type) (Indo et al., 1996). The CIPA
phenotype has characteristic features: recurrent episodic
fevers due to anhidrosis, absence of reaction to painful
stimuli, self-mutilating behavior and mental retardation
(Axelrod and Gold-von Simson, 2007). Nerve conduction
values are usually within the normal range (Shatzky
et al., 2000; Auer-Grumbach et al., 2003; Axelrod and
Gold-von Simson, 2007). Nerve biopsy findings are dom-
inated by almost complete disappearance of unmyelin-
ated fibers.
Evidence so far suggests that CIPA is a genetically
homogeneous disorder making diagnostic screening
worthwhile in selected patients. Mutations in NTRK1
are found in up to 7% of cases in large HSAN cohorts
(Indo, 2001; Rotthier et al., 2009).
HSAN V (NGFB, 1p13.1). The phenotype caused by
mutations in NGFB (nerve growth factor b) is closely
related to CIPA but patients do not display prominent
mental retardation and the disease onset is in childhood.
The only mutation described so far may be a private
mutation since broader screenings have remained nega-
tive (Einarsdottir et al., 2004; Rotthier et al., 2009). In
rare instances, NTRK1 mutations can also give rise to
a HSAN V phenotype (Houlden et al., 2001).
HSN and RAB7 (small GPTase late endosomal pro-
tein). RAB7 mutations are responsible for CMT2B,
which is a motor and sensory neuropathy with AD
 HEREDITARY MOTOR-SENSORY, MOTOR, AND SENSORY NEUROPATHIES IN CHILDHOOD 1425
transmission (see above). However, the profound sen-
sory loss and ulceromutilations found in these patients
led to considering this phenotype as a part of the HSAN
spectrum (Rotthier et al., 2009). Age of onset is usually
in adulthood but in some patients first symptoms can be
noted in their teens (Kwon et al., 1995).
III SYNDROMIC NEUROPATHIES
IIIa Neurological syndromes with
postnatal revelation
Two situations, though clinically different, lead to the
same diagnostic approach. In the first situation, fre-
quently included among CMT subcategories (see above),
the peripheral neuropathy appears as the initial, prevail-
ing feature, but becomes secondarily enriched by other
neurological features. The second situation covers a
number of multisystemic neurological disorders in
which the peripheral neuropathy appears as a secondary
feature. Most of the latter syndromes have been
described in adults and are denominated by reference
to the symptom clinically prevalent, such as spinocere-
bellar atrophy þ, spastic paraplegia þ, ophthalmoplegia
þ, etc. Other ways of promoting a syndrome which
avoid having to select a prevalent symptom have been
eponyms, such as Friedreich disease, or acronyms, such
as SANDO (see above). To a large extent, the vagaries of
history explain why the same clinical picture can be
attributed to different syndromes, in function of the
chosen denomination, or why the same gene can be
responsible for apparently different syndromes.
The mode of transmission is a major parameter which
allows separation into two groups:
IIIA1 CLASSICAL FAMILIAL, AUTOSOMAL DOMINANT
SYNDROMES WITH OCCASIONAL ONSET IN CHILDHOOD
In most syndromes, the neuropathy is a distal sensory-
motor axonopathy with normal NCVs. The real occur-
rence of the neuropathy is difficult to assess, as it largely
depends on the electrophysiological criteria used and the
stage of the disease.
In a large group of AD spinocerebellar atrophy, a
peripheral neuropathy, when systematically investi-
gated, can be elicited in up to 70% of adult cases, espe-
cially in the forms related to expansions of nucleotide
triplets (SCA1, 2, 3, 7) (van de Warrenburg et al.,
2004). The age at clinical onset appears as a function
of various factors, such as the nature of the protein,
the length of the polyglutamine expansion, and unknown
familial factors.
In a group of AD spastic paraplegia (>16 entities in
2009; see Ch. 195), the presence of a neuropathy is highly
variable. It is usually not found in the most frequent
form, linked to the Spastin gene (SPG4). A sensory
motor axonopathy is frequently encountered in others,
such as SPG 10 (KIF5 mutations; Goizet et al., 2009),
SPG 11 (KIAA1840) and in a form linked to a 12q23-24
locus (Sch€ule et al., 2009). In other SPG, the peripheral
neuropathy mainly affects the motor neurons, some-
times with a striking predominance in the hands. Some
are linked to the two known mutations in the Seipin/
BSCL2 gene (SPG 17 or Silver syndrome, see above)
(Dierick et al., 2008).
Progressive hearing loss must be checked in any
patient with a peripheral neuropathy. This rare associa-
tion is mainly suggestive of a mitochondrial cytopathy,
such as MIDD (maternally inherited diabetes and
deafness), a syndrome usually encountered beyond ado-
lescence and related to the A3243G mutation of mtDNA.
Hearing loss is mainly encountered in mutations of the
connexin gene family. In a large family with a dominant
mutation in the connexin 31 gene (GJB3), some patients
also exhibited a severe axonal neuropathy with a sensory
predominance, resulting in distal ulcerative complica-
tions (López-Bigas et al., 2001). In the more frequent
neuropathy due to connexin 32 (GJB1) mutations, hear-
ing loss is found in only a minority of cases (Stojkovic
et al., 1999). It is a variable feature found in a few
CMT1A patients but also in CMT subtypes caused by
mutations in PMP22, MPZ, and NDRG1 (Pareyson
et al., 2006).
Optic atrophy is associated with a peripheral axonal
neuropathy in a few disorders with AD or mitochondrial
transmission, including cases with a pediatric onset:
LHON þ syndromes (Leber hereditary optic neuropathy
related to mtDNA mutations), OPA1 þ as well as
MFN2-related CMT2.
IIIA2 SYNDROMES WITH AUTOSOMAL (OR X-LINKED)
RECESSIVE TRANSMISSION, WITH FREQUENT OR USUAL
ONSET IN CHILDHOOD
Friedreich disease (see Ch. 192) is the most frequent dis-
order of this category (estimated prevalence: 1/50 000
people, carrier prevalence 1/110). In addition to the cere-
bellar ataxia, other somatic features are cardiomyopathy,
retinopathy, and pancreatic B cell dysfunction. The
largely prevailing mutation is a biallelic amplification
of the triplet GAA in the first intron of the FXN gene,
which codes for frataxin, an iron-binding protein acting
as a chaperone for various mitochondrial iron-sulfur pro-
teins. During the juvenile period, the presenting feature is
usually ataxia, mostly due to the degeneration of spino-
cerebellar tracts as well as sensory nerves. During the
course of the disease, sensory nerve action potentials
and NCVs become inelicitable. Biopsy of sensory nerves
1426 P. LANDRIEU ET AL.
shows a marked axonal degeneration predominating on
large myelinated fibers.
Other AR spinocerebellar ataxias are frequently mul-
tisystemic disorders that include a peripheral nerve com-
ponent. Many of the recently identified forms have been
related to genes involved in repair of single-strand
breaks, the most common DNA damage occurring in
cells. Their clinical denomination depends of the preva-
lent clinical feature. Ataxia and oculomotor apraxia are
prominent findings in AOA1 (aprataxin or APTX gene)
and AOA2 (senataxin or SETX gene) (Koenig, 2003).
The neuropathy is highly variable in precocity and sever-
ity. Its physiopathology is multiple, with a predominance
of sensory-motor axonopathy (Ochsner et al., 2005).
A form in which the neuropathy appears a major feature
has been denominated spinocerebellar ataxia with neu-
ropathy 1 and related to the gene TDP1.
AR spastic paraplegias are frequently complicated
forms, in which the peripheral neuropathy is the most fre-
quent complication (see Ch. 195). It is usually a sensory-
motor axonopathy, like in SPG 11 (gene KIAA1840) and
SPG 15 (gene ZFYVE26 or spastizin).
Hereditary sensory neuropathy with spastic paraplegia
is caused by mutations in CCT5 (cytosolic chaperonin-
containing t-complex peptide-1; Bouhouche et al., 2006).
Mutations seem to be confined to patients displaying the
typical phenotype of an early childhood onset spastic
paraplegia with pronounced distal sensory loss and acro-
mutilations (Rotthier et al., 2009).
Infantile neuroaxonal dystrophy (INAD, Seitelberger
disease) is a progressive encephalopathy with cerebellar
atrophy and accumulation of iron in globus pallidus as
the main RMI features. Peripheral sensory-motor neu-
ropathy can be an early and major feature. Nerve biopsy
shows striking axonal dilatations with accumulation of
mitochondria, vesiculotubular structures and neurofila-
ments. Most cases are due to mutations in PLA2G6,
encoding a calcium-independent group VI phospholi-
pase A2 (Morgan et al., 2006) (see Ch. 194).
CMTX type 5 PRPS1 (phosphoribosyl pyrophosphate
synthetase) is the mutated gene in this X-linked recessive
syndromic disorder characterized by early-onset neurop-
athy (first decade), sensorineural deafness, and optic
atrophy. Electrophysiology in these patients has both
demyelinating and axonal features (Kim et al., 2007).
IIIb Multiorgan syndromes with usually
postnatal revelation
In many syndromes with a protracted onset, the elements
that mostly contribute to the clinical diagnosis are the
extraneurological features, whereas the peripheral neu-
ropathy or other neurological complications will appear
as secondary events. In others, on the contrary, the
neurological features reveal the disease, whereas the
other somatic features will appear later on in childhood.
Thus, the frontier between purely neurological syn-
dromes and multiorgan syndromes is neither absolute
nor permanent. This holds true for all disorders in which
the involved biological function affects any tissue in a
poorly predictable way, like mitochondrial OXPHOS,
DNA repair, N-glycosylation of proteins, centrosome-
mediated translocation of various substrates, and more
generally, any disorder affecting a protein with ubiqui-
tous functions. Moreover, rare cases will present with
a fetal hypotrophy or macrosomia, or even with a true
congenital malformation such as polydactyly, blurring
the frontier with the category of congenital syndromes
with a regular perinatal expression. Table 146.4 shows
a nonexhaustive list of such syndromes.
Giant axonal neuropathy, related to GAN (gigaxonin)
mutations, is one of the most recognizable. In addition to
neuropathy, the phenotype includes variable central ner-
vous system findings such as mental retardation and
ataxia, as well as bone and hair abnormalities. On neuro-
pathological examination, the characteristic giant axons
are due to accumulation of neurofilaments. EMG exam-
ination can reveal an unusual pattern that mixes features
of axonal degeneration, marked variation of NCVs from
one nerve trunk to another, and large dispersion in motor
and sensory potentials, probably reflecting the presence
of irregular demyelination along the dilated axonal seg-
ments (Fig. 146.3). The phenotype, however, is variable
(Tazir et al., 2009).
Muscular dystrophy and peripheral neuropathy.
Since EMG anomalies are more systematically investi-
gated in all muscular disorders resulting from proteins
expressed both in muscle and in nervous system, the
association of the two disorders is a growing chapter.
Merosinopathies and disorders of related sarcolem-
mal complexes. One of the most frequent congenital
muscular dystrophies, type 1A, is due to mutations in
the gene encoding merosin (laminin 2), a protein of
the extracellular matrix (see Ch. 143). A peripheral neu-
ropathy is frequently observed, which results in a pro-
gressive, moderate slowing of motor and sensory
NCVs along the course of the disease. In a few cases
sural nerve biopsies have shown abnormal variation of
myelin sheath and internodal length, without evidence
of segmental demyelination (Deodato et al., 2002; Di
Muzio et al., 2003).
Formation of myelin and internodal segments along
the nerve fibers is driven by complex cascades involving
axonal proteins like periaxin, fences of actin and tubulin
in Schwann cell as well as their connections to the
a-dystroglycan complex, to integrin a6b4 and to pro-
teins of the extracellular matrix. Mutations in proteins
of the a-dystroglycan complex and in enzymes of their
 HEREDITARY MOTOR-SENSORY, MOTOR, AND SENSORY NEUROPATHIES IN CHILDHOOD 1427
Table 146.4
Multiorgan genetic syndromes with usually postnatal revelation, including a peripheral neuropathy

Protein biological
Syndrome/disorder Neuropathy type Other organs Gene(s) function

Bardet–Biedl Sensory motor, Obesity, retinopathy, >11 BBS Centrosome-mediated

syndrome axonal MR, kidney, genes intracell transport
hypogenitalism
Ataxia telangiectasia Sensory motor, axonal Immune disorder, ATM DNA double strand
telangiectasia break repair
Xeroderma Axonal/demyelinating Premature aging, skin, >11 genes Nucleotide excision repair
pigmentosum/ Sensory motor eye, brain, liver
trichothiodystrophy/
Cockayne syndrome
Giant axonal Axonal/demyelinating Kinky hair GAN Cytoskeleton dynamics
neuropathy Intermediate filament Brain
accumulation
AAA syndrome Autonomic Achalasia, alacrimia, AAAS ALADIN:
neuropathy, distal adrenal gland nuclear pore complex
motor neuropathy

dominant and recessive transmission (Selcen et al.,

2004). A peripheral neuropathy is elicitable in about one
third of cases, with a mixture of axonal and Schwann cell
degeneration. The nerve biopsy occasionally shows an
aspect of giant axonal neuropathy (Sabatelli et al., 1992).
Laminopathies (see above) are responsible for vari-
ous phenotypes including Emery–Dreifuss muscular
dystrophy, lipodystrophy, restrictive dermopathy, pre-
mature aging syndromes and axonal neuropathy. Some
cases can exhibit both myopathic and neuropathic find-
ings (Benedetti et al., 2005).

IIIc Congenital neuropathies with

Fig. 146.3. Single fiber from giant axonal neuropathy, iso-
lated by teasing technique. Some internodal segments keep a
relatively normal myelination (top), whereas others exhibit
more or less complete demyelination, especially in the most
dilated axonal portions. (bottom, arrows) (bar ¼ 100 mm).
O-glycosylation are responsible for a category of
syndromes that include muscular dystrophy, brain and
ocular malformations, and CNS dysmyelination
(Walker–Warburg syndrome, Fukuyama congenital
muscular dystrophy, muscle-eye-brain syndrome; see
Ch. 143). Peripheral nerve dysmyelination, which has
been shown in animal models of these a-dystroglycano-
pathies, remains to investigate in the human syndromes.
Myofibrillar myopathies (MFMs) are related to disin-
tegration of Z-disks and then of myofibrils, followed by
ectopic accumulation of multiple proteins. Mutations
have been found in various genes (alphaB-crystallin,
desmin, myotilin, Zasp, filamin-C, Bag3), both with
presentation in the perinatal/early
infancy period
When the diagnosis of polyneuropathy is made in the
neonatal period, or is suggested in late gestation by
abnormal ultrasound findings, it usually implicates spe-
cial features, which are not exclusive: (1) the polyneuro-
pathy is severe, thus vital functions are frequently
threatened in the first days of life; (2) the fetal onset
of motor disturbances can result in joint and skeleton
deformations (arthrogryposis), that will raise serious
orthopedic difficulties; (3) syndromic forms are fre-
quent, thus malformative elements must be looked for
by multidirectional investigations; (4) given the particu-
lar sociological status of the newborn, special ethical
considerations are put forward in the most severe cases.
For the physician facing a baby with a diffuse motor
insufficiency together with other elements suggestive of
a neuromuscular disease, the most relevant parameters are:
1428 P. LANDRIEU ET AL.
● autonomy of vital functions (ventilation, sucking/ mutations in the genes involved in other CMT1 forms,
swallowing) whereas homozygosity or compound heterozygosity
● evidence of an associated encephalopathy for usually dominant CMT1 mutations remain the excep-
● evidence of dysautonomic features tion (see supra).
● presence of orthopedic complications (arthrogrypo- Early-onset axonal neuropathy is a heterogeneous
sis, luxations, bone hypoplasia) phenotype, with clinical onset in early infancy for some
● evidence of associated malformations. cases (Ouvrier et al., 1981). Most forms are sporadic and
unresolved at the molecular level. A growing number of
Whether or not a specific clinical score will totalize the cases, however, have been related to homozygous or
grade of severity for each item, three schematic situa- compound heterozygous mutations in a gene involved
tions can be encountered: in a classical form of AD axonal neuropathy, such as
Grade 1: the baby has autonomy for all vital functions, MFN2 (see supra).
motor activity is not severely deficient, and no malfor- Disorders originally described as motor neuron dis-
mative context is evident. The first imperative is to rule ease are in fact sensory-motor neuropathies, in which
out a general disease, liable to secondary worsening if the sensory component is easily unrecognized behind
the opportunity for an appropriate treatment is missed. the severe motor presentation. One example is the neu-
Once this has been done using the appropriate clinical ropathy called SMARD1 or HMN type VI (see above)
and metabolic investigations, a diagnostic approach will (Fig. 146.4). In the same way, detailed pathological stud-
be embarked on taking all the time necessary, depending ies of the peripheral nerve remain to be performed in
on the parental choices. many other motor neuron disorders with a perinatal
Grade 2: the neonate presents with no sign of vital dis- expression. This is the case with lethal congenital con-
tress but with one or several preoccupying findings: tractures syndromes (LCCS 1, 2, 3), recently ascribed
severe motor deficiency, poor social contact, minor mal- to genes involved in mRNA processing and generation
formations, limited arthrogryposis, dysautonomic fea- of precursors of Schwann cells (Narkis et al., 2007;
tures. A complete neurological and genetic work-up is Nousiainen et al., 2008).
usually demanded and will be done in an ordered way.
Grade 3: the neonate presents with a severe malfor- EARLY SYNDROMES WITH A MARKED NEUROLOGICAL
mative context and/or with no autonomy of vital func- EXPRESSION
tions. Some forms are regularly lethal in the fetal or The possible association with an encephalopathy is a cen-
neonatal period, whereas others will survive beyond tral preoccupation in any neonate with a neuromuscular
the neonatal period with major handicaps. Ethical discus- disorder. Several cases have been reported associating a
sions will be initiated within a reasonable period of time, congenital axonal neuropathy and an encephalopathy.
usually less than 2 weeks, that aim towards reaching as Nerve biopsy is usually poorly specific, showing only a
accurate a diagnosis as possible as soon as possible, if reduction of large diameter fibers. Central nervous
necessary by using invasive procedures (neuromuscular
biopsy). In case of death occurring without a clear diag-
nosis, an autopsy should be proposed, including brain,
spinal cord, peripheral nerve and muscle, as well as stor-
ing of DNA and fibroblast culture.

ISOLATED NEONATAL POLYNEUROPATHY

In an akinetic but alert newborn, once the early forms of
spinal muscular atrophies, congenital myopathies,
and myasthenic syndromes (see Chs 138, 150, 151) have
been ruled out, a polyneuropathic origin is rare but
heterogeneous.
Early forms of hypomyelinating neuropathies usually
show themselves with hypotonia in early infancy rather
than real difficulties in the neonatal period. Many will
Fig. 146.4. Severe axonal reduction in the superficial (sen-
exhibit a severe handicap, though a stable course and a sory) branch of the lateral popliteal nerve in a 4-month-old
favorable mental outcome are frequent (Levy et al., baby with a typical phenotype related to a SMARD1 mutation
1997; Phillips et al., 1999). The CMT1A duplication has (original magnification  200) Sensory NCVs were unobtain-
not been reported as the causal mutation in severe neo- able in the sural nerve, 30 m/s in the median nerve. (Unpub-
natal forms. Rare cases have been related to uniallelic lished case; courtesy of C. Lacroix.)
 HEREDITARY MOTOR-SENSORY, MOTOR, AND SENSORY NEUROPATHIES IN CHILDHOOD 1429
system manifestations and MRI study are also poorly
specific, including microcephaly, hypoplasia of corpus
callosum, seizures, and developmental delay. In one
case, absence or marked decrease of microtubule-
associated proteins was shown by western blot in cortex
samples (Chau et al., 2008), a finding probably second-
ary to a disorder of the cytoskeleton’s organization.
Association with a Hirchsprung or pseudo-
Hirchsprung disease together with congenital deafness
is very suggestive of mutations in SOX10, a transcription
factor including a homeobox domain. In the example
shown Figure 146.1, NCVs were clearly in the range of
a dysmyelinating neuropathy, whereas the pathological
findings included both developmental anomalies (micro-
fasciculation of the nerve trunks) and severe hypomye-
lination of myelinated fibers (Pingault et al., 2000).
Association with a partial gonadal dysgenesis has
been described in a male patient carrying a homozygous
missense in exon 1 of the desert hedgehog (DHH) gene.
Sural nerve pathology revealed extensive minifascicular
organization of the endoneurium and a decreased den-
sity of myelinated fibers (Umehara et al., 2000).
Association with a congenital cataract directs investi-
gations toward a few recognizable entities:
● Deficiency of Hyccin, a membrane protein involved
in myelination of both the central and the peripheral
nervous system, is responsible for a picture of neona-
tal hypotonia followed by the progressive appearance
of spasticity, cerebellar ataxia, and mental retarda-
tion. MRI shows a diffuse supratentorial hypomye-
lination. The peripheral neuropathy is characterized
by slowed NCVs and, on sural nerve biopsy, by a
reduction in myelinated fiber density and in thickness
of myelin sheath (Biancheri et al., 2007).
● Marinesco syndrome is an autosomal recessive
disorder characterized by cerebellar atrophy, cata-
racts, developmental delay, dysmorphism, and
Table 146.5
Multiorgan genetic syndromes with a peripheral nervous system PNS component and usual presentation in neonatal
period/early infancy period.
Syndrome Neuropathic findings
ARC syndrome Arthrogryposis
CEDNIK syndrome Poorly defined
Trichomegaly-chorioretinopathy Motor–sensory
(Oliver–McFarlane syndrome) axonopathy
St€
uve–Wiedemann Dysautonomia
MICRO syndrome Motor neuropathy
Noonan/ Axonal motor- sensory
Cardiofaciocutaneous neuropathy
syndrome
neuromuscular degeneration. The neuropathy,
mainly a sensory-motor axonopathy (Zimmer
et al., 1992), is clinically blurred by the presence of
a muscular dystrophy. The causative gene, SIL1, is
a nucleotide exchange factor for the Hsp70 chaper-
one BiP, a key regulator of the endoplasmic reticu-
lum functions (Senderek et al., 2005).
● Congenital cataract-facial dysmorphism-neuropa-
thy (CCFDN) is a rare AR syndrome, specific to
patients of Vlax Roma ethnicity, that resembles
the Marinesco–Sj€ogren syndrome. Peripheral neu-
ropathy is dominated by hypomyelination of nerve
fibers. A myopathic component is responsible for
a risk of postinfectious rhabdomyolysis. A unique
ancestral mutation is found in the CTDP1 gene,
encoding a phosphatase specific for the phosphory-
lated serine residues of the carboxy-terminal domain
of the largest subunit of RNA polymerase (Varon
et al., 2003).
Congenital deafness must be looked for in any neo-
nate or infant exhibiting a peripheral neuropathy,
whether or not other neurological or extraneurological
anomaly is present. Until now, this association has not
been reported in mutations of the connexin gene family,
but principally in multisystemic metabolic diseases (per-
oxisome, mitochondrion disorders) and in SOX10
mutants (see above).
CONGENITAL SYNDROMES WITH PERIPHERAL
NEUROPATHY AS A MARGINAL FEATURE
The peripheral nerve has not been thoroughly studied in
most congenital syndromes affecting many organs,
including the nervous system, in a severe way.
Table 146.5 gives a (not exhaustive) list of examples.
The expression of the peripheral neuropathy is very var-
iable, both in precocity and in severity.
Main organs involved Gene Protein function
Skin, liver, kidney, VPS33B Vesicle fusion
brain
Brain, skin SNAP29 Vesicle fusion
Retinae, hair, brain ?
Skeleton, brain LIFR Embryonic
differentiation
Brain, eye, face RAB3GAP Exocytose
Skin, heart, face RAS/MAPK Cell cycle
pathway
1430 P. LANDRIEU ET AL.
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