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Early onset neuropathy in a compound form of CharcotЦMarieЦTooth disease.

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Early Onset Neuropathy in
a Compound Form
of Charcot–Marie–
Tooth Disease
Farid Meggouh, PhD,1 Marianne de Visser, MD, PhD,2
Willem F. M. Arts, MD, PhD,3
Rene I. F. M. De Coo, MD, PhD,3
Ivo N. van Schaik, MD, PhD,2 and
Frank Baas, MD, PhD1,2
A 2-year-old boy presented with early-onset Charcot–
Marie–Tooth disease (CMT). His parents had not been
diagnosed previously with CMT, but on careful examination they showed clinical signs of CMT and reduced
nerve conduction velocities. Genetic analysis identified
the boy as a heterozygote for both a peripheral myelin
protein 22 (PMP22) duplication and a mutation in the
lipopolysaccharide-induced-tumour-necrosis-factor-␣factor (LITAF) gene, whereas each parent only had one
mutated CMT gene. This suggests that LITAF mutations
can severely affect the CMT phenotype caused by a
PMP22 duplication.
Ann Neurol 2005;57:589 –591
Hereditary motor and sensory neuropathy (HMSN),
also known as Charcot–Marie–Tooth disease (CMT),
may result from mutation in a large variety of genes.1
Currently, six genes have been identified for autosomal
dominant demyelinating neuropathies (PMP22, MPZ,
GJB1, LITAF, EGR2, and NEFL). Patients with autosomal dominant inherited demyelinating neuropathies
have reduced nerve conduction velocities (NCVs;
⬍38m/sec), and the usual age of clinical onset is in the
first decade of life.2 We describe a family in which the
proband presented with CMT disease at 2 years old.
Previously, his parents had not been diagnosed as such,
but the mother’s father was known to have CMT.
DNA diagnostics for the presence of a duplication of
the PMP22 gene, the most frequent genetic defect resulting in CMT type 1A (CMT1A), showed that both
From the 1Neurogenetics Laboratory and 2Department of Neurology, Academic Medical Center, Amsterdam; and 3Department of
Pediatric Neurology, Erasmus University Medical Center–Sophia
Children’s Hospital, Rotterdam, the Netherlands.
Received Nov 24, 2004, and in revised form Jan 21, 2005. Accepted for publication Jan 24, 2005.
Published online Mar 28, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20434
Address correspondence to Dr Baas, Neurogenetics Laboratory
AMC, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
E-mail: f.baas@amc.uva.nl
the proband and his father had a PMP22 duplication.
In this article, we present a detailed molecular analysis
of the family.
Patients and Methods
Clinical Information
The proband (I:2) was examined initially at 2.5 years old (by
W.F.M.A.) for evaluation of toe walking. Because of severe
pes equinovarus he had undergone surgery at 2 years old. On
examination, he presented bilateral foot drop, atrophy of the
lower legs, and genua recurvatum indicating weakness of the
thigh muscles. Deep tendon reflexes were diminished at the
arms and absent at the legs. Electrophysiological examination
(ie, electromyogram) was not performed.
Both parents also were suspected to have CMT, because
they both had had Achilles tenotomies and correction of bilateral pes cavis in their teens. Otherwise, they were asymptomatic. On examination, the mother (II:1) had slight bilateral pes cavis, tight Achilles tendons, and slight wasting of
the thenar muscles, but normal strength. Vibration sense was
decreased at the halluces. Reflexes were normal. Electromyogram showed uniformly decreased motor and sensory NCVs.
Motor and sensory median NCVs were 25 and 32m/sec, respectively. Compound muscle action potential (CMAP) and
sensory nerve action potential amplitudes were preserved in
the arms, but the CMAP of the extensor digitorum brevis
muscle was not obtainable, indicating secondary distal axonal
degeneration in the legs.
The father (II:2) had bilateral pes cavis, claw toes, and
slight weakness of the extensor hallucis longus muscles. Vibration sense was decreased at the halluces. Deep tendon reflexes were absent. The electromyogram disclosed uniformly
decreased motor and sensory NCVs. Motor and sensory median NCVs were 22 and 29m/sec, respectively. CMAP amplitudes were preserved in the arms, but sensory nerve action
potential amplitudes were markedly decreased. The CMAP
of the extensor digitorum brevis muscle was not obtainable,
and the CMAP amplitude of the abductor hallucis brevis
muscle was decreased. Family history showed that the mother’s father (III:1) and a paternal aunt also were known to
have CMT, although no DNA analysis had been performed.
The father’s father, his eldest brother, and his youngest sister
had always had bilateral pes cavis. The proband’s brother
(I:1) had no signs of CMT.
Molecular Investigation
For genetic analysis, we obtained peripheral blood from the
parents with their consent, and we performed PMP22 duplication testing. DNA was extracted according to standard
procedures. Quantitative Southern blot analysis with the
probes VAW409 and PMP22 was performed according to
Hensels and colleagues.3
Multiplex ligation-dependent probe amplification (MLPA)
technology also was used to determine the dosage of the
PMP22 gene and neighboring sequences. A series of 8 probes
covering the 1.5MB large CMT1A-associated duplication of
chromosome 17p was tested.4,5 MLPA probes were designed
and manufactured by MRC-Holland (Amsterdam, the Netherlands).
For mutation detection, we prescreened all samples by de-
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
589
naturing high-performance liquid chromatography on an
Agilent 1100 system (Agilent, Amstelveen, the Netherlands)
equipped with a Helix DNA column (Varian, Middelburg,
the Netherlands). The coding exons of PMP22, MPZ, GJB1,
EGR2, NEFL, and LITAF were amplified by polymerase
chain reaction and analyzed by denaturing high-performance
liquid chromatography. Fragments with abnormal elution
patterns were sequenced with ABI big dye v3.1 chemistry
and analyzed on an ABI 3100 capillary system (AB Systems,
Niewekerk aan de Yssel, Netherlands). (Primers and denaturing high-performance liquid chromatography conditions are
available on request.)
Results
Genetic Analysis
Quantitative Southern blotting showed a duplication of
the PMP22 gene in both the proband (I:2) and his father (II:2). The mother (II:1) carried a normal copy
number of the PMP22 gene as determined by this procedure. To exclude the presence of small duplications or
rare polymorphisms that would interfere with the
PMP22 dosage analysis, we also performed an MLPA
assay for the presence of a CMT1A-associated DNA duplication.
MLPA analysis confirmed the presence of the
1.5MB CMT1A duplication in the proband and his
father, whereas the DNA of the mother was again negative for the presence of the PMP22 duplication. This
analysis excluded the presence of a copy number alteration of the PMP22 gene in the mother of the proband, because this method determines the copy number of all five PMP22 exons and flanking markers.
In view of the presence of a demyelinating neuropathy
in the mother and the early-childhood severe presentation of CMT disease in the proband, we continued our
search for mutations in hereditary motor and sensory
neuropathy type 1 genes. Sequencing analysis of
PMP22, MPZ, GJB1, EGR2, and NEFL disclosed no
alterations in the coding region of these genes. Analysis
of LITAF gene demonstrated two heterozygous sequence
alterations resulting in amino acid substitutions in the
maternal gene. We identified a mutation c.274A⬎G, resulting in an Isoleucine92Valine substitution, and a
c.334G⬎A mutation, resulting in Glycine112Serine
substitution. Segregation studies for these mutations also
showed that the mother’s father (III:1) and the proband
(I:2) both carried the two LITAF mutations (see Fig).
The father of the proband also was a heterozygous carrier of the LITAF c.274A⬎G mutation.
Discussion
The proband has mutations in two different genes,
both known to be responsible for CMT1. The PMP22
duplication is the most common alteration seen in patients with CMT1. The phenotype of the proband,
however, unusually is severe for a PMP22 duplication–
590
Annals of Neurology
Vol 57
No 4
April 2005
induced CMT1. Because both parents had a demyelinating neuropathy, our first hypothesis was that they
would both have the PMP22 duplication and that the
child would be homozygous for the duplications; that
is, the child would carry four copies of the PMP22
gene. However, quantitative Southern blot analysis and
MLPA for PMP22 excluded this possibility; therefore,
we expanded the molecular genetic analysis of the
mother. Two LITAF gene sequence alterations predicted to result in amino acid substitutions were identified. The variation c.274A⬎G, resulting in an
Isoleucine92Valine substitution, was found in both the
father and the mother of the proband. We consider
this sequence alteration a polymorphism because we
detected it at a high frequency in a Dutch control population (allele frequency, 16.2%). The DNA sequence
alteration c.334G⬎A, resulting in a Glycine112Serine
substitution in the LITAF gene, has been reported previously as being associated with CMT1C disease.6,7 In
this pedigree and in the study of Street and colleagues,6
this sequence alteration segregates with a CMT phenotype and is most likely responsible for the demyelinating neuropathy. Although the exact function of the
LITAF gene product is still unknown, several data
strongly suggest a role in protein degradation, through
ubiquitin-mediated lysosomal sorting of proteins.8 It is
well known that PMP22 has difficulties folding correctly, because 80% of newly synthesized PMP22 is degraded.9 Perinuclear formation of protein aggregates in
demyelinating CMT has been shown.10 Therefore, a
Fig. Pedigree of the proband’s family. Diagnosed Charcot–
Marie–Tooth disease cases are marked in black. Genotype of
individuals analyzed is given. For the PMP22 gene: normal ⫽ diploid; dup ⫽ three copies in a diploid genome. The
sequence variants in the LITAF gene are given as the predicted amino acid substitutions.
defect in the function of LITAF, as a sorting tool for
protein degradation, may result in accumulation of
misfolded PMP22 and subsequently lead to demyelination and the resulting peripheral nerve pathological features.
In conclusion, molecular genetic analysis allowed the
identification of a compound phenotype in a severe case
of CMT1. The cooccurrence of both PMP22 duplication and a LITAF mutation resulted in a more severe
phenotype. Additional screening for CMT gene mutations can be done for two reasons: either a CMT-like
phenotype exists in the other parent, or the severity of
the phenotype falls outside the known phenotypic variations. In our patient, both reasons are valid. If the diagnosis of CMT1 had not been made in the mother of
the proband, we might not have continued our search
for CMT1 mutations. This underscores that phenotypic
variations of CMT1 disease can be attributed to mutations in other genes. In view of the plethora of genes
involved in CMT disease, many modifier genes for
CMT might exist in the population. Careful neurological and genetic examination of patients and their relatives will probably show similar compound CMT cases.
Commonality of TRIM32
Mutation in Causing
Sarcotubular Myopathy
and LGMD2H
Benedikt G. H. Schoser, MD,1 Patrick Frosk,2
Andrew G. Engel, MD,3 Ursula Klutzny,1
Hanns Lochmüller, MD,1
and Klaus Wrogemann, MD, PhD2
Sarcotubular myopathy (OMIM 268950) is a rare autosomal recessive myopathy first described in two Hutterite
brothers from South Dakota and in two non-Hutterite
brothers from Germany. We report that sarcotubular myopathy (STM) is caused by mutation in TRIM32, the
gene encoding the tripartite motif-containing protein 32.
TRIM32 was found to be the gene mutated in limb girdle
muscular dystrophy type 2H (LGMD2H [OMIM
254110]), a disorder that has been confined to the Hutterite population. The TRIM32 mutation found in the
STM patients is identical to the causative mutation for
LGMD2H (D487N), Haplotype analysis shows that the
disease chromosomes share common ancestry.
Ann Neurol 2005;57:591–595
References
1. Young P, Suter U. The causes of Charcot-Marie-Tooth disease.
Cell Mol Life Sci 2003;60:2547–2560.
2. Dyck PJ, Lambert EH. Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. II. Neurologic,
genetic and electrophysiologic findings in various neuronal degenerations. Arch Neurol 1968;18:619 – 625.
3. Hensels GW, Janssen EA, Hoogendijk JE, et al. Quantitative
measurement of duplicated DNA as a diagnostic test for
Charcot-Marie-Tooth disease type 1a. Clin Chem 1993;39:
1845–1849.
4. Slater HR, Bruno DL, Ren H, et al. Rapid, high throughput
prenatal detection of aneuploidy using a novel quantitative
method (MLPA). J Med Genet 2003;40:907–912.
5. Slater H, Bruno D, Ren H, et al. Improved testing for
CMT1A and HNPP using multiplex ligation-dependent
probe amplification (MLPA) with rapid DNA preparations:
comparison with the interphase FISH method. Hum Mutat
2004;24:164 –171.
6. Street VA, Bennett CL, Goldy JD, et al. Mutation of a putative
protein degradation gene LITAF/SIMPLE in Charcot-MarieTooth disease 1C. Neurology 2003;60:22–26.
7. Bennet CL, Shirk AJ, Huynh HM, et al. SIMPLE mutation in
demyelinating neuropathy and distribution in sciatic nerve. Ann
Neurol 2004;55:713–720.
8. Bonifacino JS, Traub LM. Signals for sorting of transmembraneproteins to endosomes and lysosomes. Annu Rev Biochem
2003;72:395– 447.
9. Pareek S, Notterpek L, Snipes GJ, et al. Neurons promote the
translocation of peripheral myelin protein 22 into myelin.
J Neurosci 1997;17:7754 –7762.
10. Ryan MC, Shooter EM, Notterpek L. Aggresome formation in
neuropathy models based on peripheral myelin protein 22 mutations. Neurobiol Dis 2002;10:109 –118.
In 1973, Jerusalem and coworkers1 described sarcotubular myopathy (STM) as a congenital disorder in two
Hutterite brothers aged 11 and 15 years. Both boys
had mild-to-moderate symmetrical proximal muscle
weakness and wasting, and they experienced minor difficulties on strenuous activity (Cases 1 and 2, respectively, in Jerusalem and colleagues1). The disorder was
thought to be autosomal recessive in nature because the
parents of the two boys were asymptomatic, as well as
consanguineous. STM was distinguished from other
myopathies by its unique structural features.1,2 The
second report of STM was of two brothers aged 33 and
35 years from a small village in southern Germany
From the 1Department of Neurology, Friedrich-Baur Institute,
Ludwig-Maximilians University, Munich, Germany; 2Departments
of Biochemistry and Medical Genetics and Pediatrics and Child
Health, University of Manitoba, Winnipeg, Canada; and 3Department of Neurology, Neuromuscular Research Laboratory, Mayo
Clinic, Rochester, MN.
Received Oct 5, 2004, and in revised form Jan 25, 2005. Accepted
for publication Jan 27, 2005.
Published online Mar 28, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20441
Address correspondence to Dr Schoser, Friedrich-Baur Institute,
Department of Neurology, Ludwig-Maximilians University Munich,
Ziemssenstrasse 1a, 80336 Munich, Germany.
E-mail: bschoser@med.uni-muenchen.de
Schoser et al: STM Is Caused by TRIM32 Mutation
591
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