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Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24.

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Confirmation of a
Hereditary Motor and
Sensory Neuropathy IIC
Locus at Chromosome
Meriel E. McEntagart, MD,1 Sarah L. Reid, MRes,2
Alexandre Irtthum, PhD,2 Jenny B. Douglas, BSc,2
Keith E. D. Eyre, FRACP,3 Michael J. Donaghy, DPhil,4
Neil E. Anderson, FRACP,3 and Nazneen Rahman, PhD2
Hereditary motor and sensory neuropathy type IIC
(HMSN IIC) is an autosomal dominant axonal neuropathy. The cardinal features include distal muscle wasting
and weakness, vocal cord paralysis, and mild sensory impairment. Recently, HMSN IIC locus was mapped to
chromosome 12q23-24. Two families affected by HMSN
IIC were identified and evaluated for linkage to this region. Segregation analysis in both families was consistent
with linkage to chromosome 12q23-24. Combined analysis generated a multipoint LOD score of 2.1 at marker
D12S1583 and refined the HMSN IIC gene interval to
The clinical and molecular findings are discussed.
Ann Neurol 2005;57:293–297
Peroneal muscular atrophy syndrome, or CharcotMarie-Tooth disease (CMT), affects 1 in 2,500 of the
population. Three distinct groups of peroneal muscular
atrophy conditions are currently recognized: a demyelinating form, hereditary motor and sensory neuropathy
type I (HMSN-I or CMT-1); an axonal form, hereditary motor and sensory neuropathy type II (HMSN-II
or CMT-2); and distal hereditary motor neuronopathy
(dHMN, also known as distal spinal muscular atrophy
or spinal CMT). The clinical features of all forms are
broadly similar. Affected individuals present with distal
From the 1Department of Medical Genetics, St. George’s Hospital
Medical School, London; 2Section of Cancer Genetics, Institute of
Cancer Research, Sutton, Surrey, United Kingdom; 3Department of
Neurology, Auckland Hospital, Auckland, New Zealand; and 4University Department of Clinical Neurology, Radcliffe Infirmary, Oxford, United Kingdom.
Received Aug 10, 2004, and in revised form Oct 28. Accepted for
publication Nov 10, 2004.
Published online Jan 26, 2005, in Wiley InterScience
( DOI: 10.1002/ana.20375
Address correspondence to Dr McEntagart, Department of Medical
Genetics, Jenner Wing, St. George’s Hospital Medical School,
Cranmer Terrace, London SW17 0RE, United Kingdom.
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
amyotrophy, diminished or absent deep tendon reflexes, and pes cavus foot deformity. Distal sensory loss
is clinically detectable in some cases.
Hereditary motor and sensory neuropathy type IIC
(HMSN IIC)[MIM 606051] is a distinctive form of
HMSN II because the majority of affected individuals
manifest vocal cord paralysis.1–3 The disorder is characterized by a variable degree of muscle weakness of the
limbs, vocal cords, intercostal muscles and diaphragm,
and often by asymptomatic sensory loss. Onset is usually in the second decade but age at presentation may
range from infancy to the third decade. Nerve conduction velocities (NCVs) are normal, but compound motor and sensory nerve action potential (CMAP and
SNAP) amplitudes are reduced. Lifespan may be limited by respiratory complications. An HMSN IIC predisposition gene was recently mapped to a 5.7Mb region on chromosome 12q23-24 in a single large
pedigree.4 Three other dominantly inherited neuromuscular disorders also have been mapped to the same
region (congenital distal spinal muscular atrophy/
dSMA [MIM 600175], scapuloperoneal hereditary motor neuronopathy/SPHMN [MIM 181405] and distal
hereditary motor neuronopathy type II/dHMN II
[MIM 158590]. Distal muscular atrophy is a feature of
all three disorders; however, SPHMN shows most phenotypic overlap with HMSN IIC because affected individuals manifest vocal cord paralysis in addition to
scapuloperoneal muscle atrophy. SPHMN is distinguished from HMSN IIC by the absence of sensory
nerve involvement.
In this report, we describe the clinical features of a
large family with HMSN IIC and provide further evidence to support the location of an HMSN IIC gene
at 12q23-24 based on molecular studies in this family
and a previously published family affected by HMSN
IIC.3 We have also screened the full coding sequence
of Ataxin 2, a candidate gene within the minimally defined HMSN IIC interval, in both families.
Subjects and Methods
Family Data
Permission for the study was obtained from the Bro Taf
Health Authority local research ethics committee. Two pedigrees affected by HMSN IIC (A5 and D3) (Fig) were analyzed, and informed consent was obtained. Family A5 originates from New Zealand. The clinical details of Family D3
have been published previously.3
DNA was extracted from
blood by standard techniques. Twelve known chromosome
12q markers encompassing the HMSN IIC locus were identified using the University of California–Santa Cruz Human
Genome Project Working Draft sequence July 03 (http:// The order and distance between these
Annals of Neurology
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February 2005
markers are from centromeric to telomeric, D12S78
(1.3Mb), D12S317 (0.6Mb), D12S1683 (0.9Mb),
D12S1331 (2.2Mb), D12S105 (0.5Mb), D12S1583
(0.2Mb), D12S1645 (0.03Mb), D12S1339 (1.6Mb),
D12S1343 (0.6Mb), D12S1344 (1Mb), D12S1340
(2.7Mb), and D12S79. The microsatellite markers were radiolabeled and polymerase chain reaction–amplified and the
products were electrophoresed through 4% denaturing polyacrylamide gels before exposure to x-ray film.
HMSN IIC was modeled as an autosomal dominant trait with full penetrance and a disease allele
frequency of 0.0001. Two-point logarithm of odds (LOD)
scores were calculated using the MLINK program of
FASTLINK (version 4.1P). Multipoint LOD scores were calculated using GENEHUNTER (version 2.1_r5).
ATAXIN 2 MUTATION ANALYSIS. Primers amplifying all 25
ATX2 exons and intron–exon boundaries were designed using Primer 3 software. All exons were amplified in DNA
from a selection of affected individuals. Mutation screening
was performed using the BigDye Terminator Cycle Sequencing Kit and a 3100 automated sequencer (ABI Perkin Elmer,
Boston, MA).
Family A5
The clinical details and the electrophysiology findings
of Family A5 are summarized in Tables 1 and 2, respectively. The proband III:2 presented with sloping
shoulders at birth and developed bilateral foot drop in
childhood and a hoarse voice in adolescence. At 55
years, he required a wheelchair and assistance in all activities in daily living because of progressive impairment of manual dexterity and gait. He required bi-level
positive airway pressure (biPAP) at 66 years for hypercapnic respiratory failure and obstructive sleep apnoea.
He had severe distal amyotrophy and wasting of the
trapezii and shoulder girdle muscles. There was mild
weakness of the lower limb proximal muscles. Tendon
reflexes were absent and there was no plantar response.
Quantitative sensory testing showed abnormal touch,
pressure, and vibration sensation in the legs with normal thermal cooling discrimination. Laryngoscopy
showed bilateral vocal cord paralysis. Five further
symptomatic relatives were examined (see Table 1). All
had evidence of distal amyotrophy and hyporeflexia in
varying combinations with distal sensory impairment,
vocal cord involvement, and a shoulder deformity similar to that seen in the proband. Subject III-3 also required biPAP for respiratory failure. Electrophysiology
studies in III-2, III-3, and IV-3 showed evidence of an
axonal motor and sensory polyneuropathy.
Family D3
All individuals had neurological and electrophysiological examinations. The proband II:1 presented at 43
Fig. Haplotype analysis at the HMSN IIC locus on chromosome 12q23-24 in pedigrees A5 and D3
McEntagart et al: Locus for HMSN IIC
Table 1. Clinical Features in Family A5
Age at onset (yr)
Age at last assessment (yr)
Hoarse voice
Neck flexion
Proximal UL
Distal UL
Proximal LL
Distal LL
Sensory loss
Round shoulders
Respiratory failure
Weakness 0 ⫽ absent; ⫹ ⫽ mild or moderate; ⫹⫹ ⫽ severe (grade 0 or 1 MRC weakness for limb muscles).
UL ⫽ upper limb; LL ⫽ lower limb.
years with a 4-year history of diminished manual dexterity, difficulty walking, and a 2-year history of dysphonia. He had distal amyotrophy, pes cavus foot deformity, a left lateral rectus palsy, and a left vocal cord
paralysis. Generalized areflexia and loss of vibration
sense was detected in the legs of his mother I:2 and
older sister II:4. Both were asymptomatic, but distal
muscle weakness was elicited on examination. All three
showed evidence of an axonal polyneuropathy on electrophysiology testing.
MICROSATELLITE, LINKAGE, AND ATX2 ANALYSIS. Microsatellite analysis of 12 markers spanning the 5.7Mb
HMSN IIC region between D12S105 and D12S13304
was performed in Families A5 and D3 (see Fig). A distinct haplotype segregating with the disease was seen in
each family. Combined analysis of both families generated a multipoint LOD score of 2.1 at marker
D12S1583. This is the maximum LOD score that
Table 2. Nerve Conduction Studies in Members of Family A5 Affected by HMSN IIC
ID (age)
Motor Velocity,
(m/sec) (range)
III-2 (47 yr)
41 (49–70)
0.35 (4–18)
3 (50–180)
III-3 (54 yr)
54 (49–71)
1.9 (6–16)
Absent (⬎15)
Tibial l
Tibial r
Peroneal l⫹r
36 (41–48)
0.13 (4–19)
Absent (2–12)
Absent (6–25)
IV-3 (36 yr)
l ⫽ left, r ⫽ right, ⫹ ⫽ widespread.
Annals of Neurology
Vol 57
No 2
February 2005
Absent (6–25)
5 (20–60)
Absent (6–47 ␮V)
Fibrillations⫹. Few distal motor
units detected. Large polyphasic
motor units in proximal, paraspinal, and facial muscles.
Fibrillation⫹. Large polyphasic motor units.
Distal denervation
could be generated from two families of this size.
These data are supportive of an HMSN IIC gene at
chromosome 12q23-24. The combined recombination
data refines the HMSN IIC predisposition gene interval to 3.9Mb, between D12S105 and D12S1340. This
region contains 66 known genes including ATX2. No
mutations were found in ATX2 in either family.
HMSN IIC is characterized by distal muscle wasting
and weakness, vocal cord paralysis, and mild sensory
impairment.1–3 We present a new family, A5, with the
classic clinical and electrophysiology features of HMSN
IIC. In earlier descriptions of HMSN IIC, the age of
onset and severity of symptoms has varied greatly,1,2
and this variability was also observed in Family A5.
Two less common clinical features of HMSN IIC are
highlighted by the findings in Family A5. First, identification of respiratory failure in two family members
(III-2 and III-3) confirms this as an important complication of HMSN IIC. Second, the presence of shoulder
deformity in at least four of the seven affected individuals (III-2, IV-3, IV-6, and II-2), suggests that this
may be a variable clinical feature of HMSN IIC that
has not been documented previously.
A predisposition gene for HMSN IIC was recently
mapped to chromosome 12q23-24 in a single large
pedigree by Klein and colleagues.4 The microsatellite
results in Families A5 and D3 are consistent with linkage to this locus. The combined mapping data reduces
the HMSN IIC critical interval to 3.9Mb. Ataxin 2 is
within this interval. Triplet-repeat expansions of this
gene cause spinocerebellar ataxia type 2 (SCA2) [MIM
183090]. Ataxin 2 is a reasonable candidate for HMSN
IIC because peripheral neuropathy, distal amyotrophy,
and vocal cord paralysis are recognized features of some
SCAs.5–7 Klein and colleagues excluded a pathological
expansion and a point mutation of the triplet repeat of
Ataxin 2 in their family.4 We screened the entire coding region of Ataxin 2 for disease causing mutations in
both families. No sequence change was identified suggesting that Ataxin 2 is highly unlikely to be the gene
Apart from HMSN IIC, the predisposition loci for
three further neuromuscular disorders are located at
chromosome 12q23-24. They are SPHMN, congenital
dSMA, and dHMN II.4,8 –10 All three disorders present
with distal amyotrophy and are classified as motor neuronopathies. Vocal cord paralysis is also a feature of
SPHMN. dHMN II is caused by mutations in
HSP22.11 The causative genes for SPHMN and congenital dSMA are unknown. The critical intervals for
SPHMN, congenital dSMA, and HMSN IIC overlap,
whereas the critical interval for dHMN II is slightly
telomeric and distinct. Analysis of the haplotypes in
Families D3 and A5 show that the dHMN II locus is
clearly excluded as the disease locus in Family D3.
However, in Family A5 it is possible that the linked
haplotype extends distally to include this locus. It
seems more likely that the disease in Family A5 is
caused by mutations of the HMSN IIC gene given the
phenotype and the fact that two of three HMSN IIC
families4 are clearly unlinked to the dHMN II locus.
Although clinically distinct, it is possible that congenital dSMA, SPHMN, and HMSN IIC result from mutations in the same gene.4 Isolation of these genes will
further our understanding of the pathogenesis of peroneal muscular atrophy syndrome associated with vocal
cord paralysis.
We are grateful to the families for their kind cooperation with the
study. We also thank Dr Simcock for clinical information on affected members of Family A5.
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McEntagart et al: Locus for HMSN IIC
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