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Coexistence of hereditary motor and sensory neuropathy type IA and IGM paraproteinemic neuropathy.

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plays a major role in blood-brain barrier permeability
during an exacerbation of MS. It will be worthwhile to
determine if the reciprocal changes in serum levels of
sICAM-1 from patients with MS and HAM are related
to the pathogenesis of vascular lesions in these diseases.
The present data suggest that quantitative assessment of sICAM-I may be of value in detecting or
evaluating inflammatory diseases.
15. Rothlein R, Mainolfi EA, Czajkowski M , Marlin SD. A form of
circulating ICAM-1 in human serum. J Immunol 1991;147:
3788-3793
16. Tsukada N, Matsuda M, Miyagi K, Yanagisawa N. Soluble CD4
and CD8 in the peripheral blood of patients with multiple sclerosis and HTLV-I-associated myeloparhy. J Neuroimmunol
1991;35:285-293
17. Itoyama Y, Kira J, Fujii N, Goto I, Yamamoto N. Increases in
helper/inducer T cells and activated T cells in HTLV-I associated myelopathy. Ann Neurol 1989;26:257-262
This work was supported by grants from the Intractable Disease
Division, Public Health and Welfare of Japan.
Coexistence of Hereditary
Motor and Sensory
Neuropathy Type Ia and
IgM Paraproteinemic
Neuropathy
The authors would like to thank D r M. Osame (Department of
Neurology, Kagoshima University) and Dr. Y. Itoyama (Department
of Neurology, Kyushu University) for collaborative work, and Miss
A. Kiyosawa for technical assistance.
References
1 Broman T. Blood-brain damage in multiple sclerosis. Supravital
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84-92
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modeled in vitro: control by lymphocyte activation, cytokines,
and antigen. Cell Immunol 1990;127:1-11
4. Hughes CCW, Male DK, h t o s PL. Adhesion of lymphocytes
to cerebral microvascular cells: effects of interferon-y, tumor
necrosis factor and interleukin-1. Immunology 1988;64:67768 1
5. Marlin SD, Staunton DE, Springer TA, Stratowa C, Sommergruber W, Merluzzi VJ. A soluble form of intercellular adhesion
molecule-1 inhibits rhinovirus infection. Nature 1990;344:
70-72
6. Merrill JE, Strom SR, Ellison GW, Myers LW. In vitro study of
mediators of inflammation in multiple sclerosis.J Clin Immunol
1989;9:84-96
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interleukin- 1 production by peripheral blood mononuclear cells
in patients with multiple sclerosis. J Neurol Sci 1991;102:
100-104
8. Tsukada N, Miyagi K, Matsuda M, Yanagisawa N, Yone K.
Tumor necrosis factor and interleukin-1 in the CSF and sera of
patients with multiple sclerosis.J Neurol Sci 1991;102:230-234
9. Sobel RA, Mitchell ME, Fondren G. Inrercellular adhesion molecule-l (ICAM-l) in cellular immune reactions in the human
central nervous system. Am J Pathol 1990;136:1309- 1316
10. Osame M, Matsumoto M, Usuku K, et al. Chronic progressive
myelopathy associated with elevated antibodies to human Tlymphotropic virus type I and adult T-cell leukemia like cells.
Ann Neurol 1987;2 1:117-122
11. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria
for multiple sclerosis: guidelines for research protocols. Ann
Neurol 1983;13:227-23 1
12. Yone K, Hashida S, Tanaka K, Ichikawa Y, Ishikawa E. Specific
and sensitive sandwich enzyme immunoassay for human tumor
necrosis factor-a. Clin Chem Entym Comms 1990;3:1-8
13 Dustin ML, Staunton DE, Springer TA. Supergene families
meet in the immune system. Immunol Today 1988;9:213-215
14 Dustin ML, Rothlein R, Bhan AK, Dinarello CA, Springer TA.
Induction by IL-1 and interferon-y: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-I).
J Immunol 1986;137:245-254
R. Gregory, MRCP," P. K. Thomas, DSc,"?
R. H. M. King, PhD,t P. L. J. Hallam, BScJ
S. Malcolm, PhD,$ R. A. C. Hughes, FRCP,$ and
A. E. Harding, FRCP"
A patient with minimal motor dysfunction dating from
early childhood developed more rapidly progressive distal weakness and positive sensory symptoms due to peripheral neuropathy in the fourth decade of life. DNA
analysis showed the partial duplication of chromosome
17p associated with hereditary motor and sensory neuropathy type Ia. In addition, the patient had an IgM
paraproteinemia and the typical morphological features
of IgM paraproteinemic neuropathy on nerve biospsy.
Gregory R, Thomas PK, King RHM, Hallam PLJ,
Malcolm S, Hughes RAC, Harding AE.
Coexistence of hereditary motor and sensory
neuropathy type Ia and IgM paraproteinemic
neuropathy. Ann Neurol 1993;33:649-652
Charcot-Marie-Tooth disease is clinically and genetically heterogeneous 111. The most common of these
disorders is type Ia hereditary motor and sensory neuropathy (HMSN), an autosomal dominant demyelinating neuropathy that maps to chromosome 17 and is
associated with a duplication of band p 11.2 containing
From the "University Department of Clinical Neurology, Institute
of Neurology, tDepartment of Neurological Science, Royal Free
Hospital School of Medicine, $Molecular Genetics Unit, Institute
of Child Health, and $Department of Neurology, UMDS, Guy's
Hospital, London, UK.
Received Oct 13, 1992, and in revised form Jan 27, 1993. Accepted
for publication Jan 28, 1993.
Address correspondence to Prof Harding, University Department of
Clinical Neurology, Institute of Neurology, Queen Square, London,
W C l N 3BG. UK.
Copyright 0 1993 by the American Neurological Association 649
the gene for peripheral myelin protein-22 [2-61. A
superimposed chronic inflammatory demyelinating
polyneuropathy (CIDP) has been reported in occasional patients with HMSN 171, presumably representing a secondary immunological event. The precise
definition of CIDP is still not fully established, although guidelines for diagnosis have been recommended [8]. Some patients with the features of CIDP
have an associated benign monoclonal paraproteinemia. Whether such patients should be classified as
CIDP is a matter of contention; some authorities accept this for patients with IgG and possibly IgA paraproteins but exclude those with IgM paraproteins [9],
although the clinical manifestations may be remarkably
similar 110, 111. This report describes a patient with
HMSN Ia and the duplication of 17pl1.2 who had, in
addition, an IgM paraproteinemia with deposition of
IgM on myelin sheaths and widely spaced myelin on
electron microscopy, features rhat are shown by patients with IgM paraproteinemic neuropathy. It illustrates the complexity of the relationships between
these various demyelinating neuropathies.
Patient Report
A 47-year-old horticulturist presented with a long-standing
peripheral neuropathy for further assessment. Information
regarding his early development was lacking as he was orphaned at the age of 2 years. His only known surviving relative was his brother who was well. He recalled being called
“bandy legs” as a child, and he never ran well; this was attributed to rickets. Despite this he played cricket to a reasonable
standard until he was 25 years old. At the age of 38 years he
developed a tendency to trip. Six months later he noticed
numbness and paresthesiae in his hands, which spread to his
legs the following year, and decreased manual dexterity. His
gait became progressively unsteady; he could only walk with
a frame and required ankle-foot orthoses. His sensory symptoms worsened and he described burning, throbbing dysesthesiae in both hands. In 1987 he received three 5-day
courses of plasma exchange. The first had produced a transient symptomatic improvement, but subsequent exchanges
had no effect. Two courses of oral prednisolone in a daily
dose of 60 mg for 3 weeks were followed by subjective but
not objective deterioration.
O n examination he had a kyphoscoliosis but no foot deformity. His gait was high stepping and unsteady, with rombergism. He had prominent distal muscle wasting with palpably thickened nerves, symmetrical limb weakness maximal
distally, areflexia, and unobtainable plantar responses. There
was pseudoathetosis of the fingers, with impaired touch and
pain sensation in a glove and stocking and anterior abdominal
distribution. Vibration sense was absent to the iliac crests and
joint position sense impaired at the wrists and ankles. His
vital capacity was 3.1 L lying and standing.
Previous investigations in 1989 had shown evidence of a
demyelinating neuropathy with absent sensory nerve action
potentials, inexcitable distal muscles, and a motor conduction
velocity of 10 m/sec in the proximal ulnar nerve on recording
from the flexor carpi ulnaris. A sural nerve biopsy showed a
650 Annals of Neurology Vol 33 No 6 June 1993
Fig 1. Transverse section through portion of fascicle from rural
nerve biopsy showing prominent hypertrophic changes with multiple onion bulbs surrounding small myelinated nerve fibers. Reduplication of basal lamina is evident around the capillau in
the lower left corner of the fascicle. Semithin Araldite section
stained with tbionin and acridine orange. Bar = 20 pm.
demyelinating neuropathy with prominent hypertrophic
changes (Fig 1). Myelinated fiber density was reduced to
4,382/mm2, compared with the normal range of 7,500 to
10,000 {12). All fibers were < 7 pm in diameter, the size
distribution having a single mode at 3 to 4 pm. There was
no detectable paraprotein on repeated serum electrophoresis.
His serum had a positive complement fixation test against
human sciatic nerve and a positive immunoperoxidase test
against human sciatic nerve myelin, but there was no reactivity to myelin associated glycoprotein (MAG).
Investigations in 1992 included a normal full blood count,
erythrocyte sedimentation rate, biochemical profile, and autoimmune profile. Protein electrophoresis showed an IgM-K
paraprotein of 4.5 gm/L with no evidence of irnmunoparesis
or Bence Jones proteinuria. A skeletal survey and bone marrow examination were normal. D N A analysis using hybridization of Msp I digested genomic D N A to the probe
VAW409R3A { 5 ] showed the submicroscopic duplication of
chromosome 17p associated with HMSN Ia ([3-5], Fig 2).
The histology from the previous biopsy was reviewed, and
Fig 2. Autoradiograph showing fragments dgenomic D N A digested with Msp I and hybridized to probe VAW409R3A
(D17Sl22).Lanes b and c represent n o m l subjects without
the duplication, showing 2.8- and 2.7-kbfragments of equal intensity. Lanes a and d contain D N A from the patient and a
positive control with hereditary motor and sensory neuropathy
la, respective&; in both there is increased density of the 2.8-kb
fragment indicating the presence of the duplication.
electron microscopy confirmed a demyelinating neuropathy
with hypertrophic changes (concentric Schwann cell proliferation) and widely spaced myelin (Fig 3). Immunostaining
showed heavy deposition of IgM on the myelin sheaths. His
serum was weakly positive for anti-MAG, but anti-GM1 ganglioside antibodies were not detected. He has continued to
show further deterioration in his sensory symptoms, experiencing burning paresthesiae distally in his arms and over the
abdomen and, to a lesser extent, his feet. His motor disability
has remained stable.
Discussion
Before the identification of segmental trisomy for chromosome 17p in HMSN Ia, the diagnosis of HMSN
was difficult to confirm in the absence of affected relatives. The partial duplication of 17p is found in at least
90% of families with HMSN type I (P. J. Hallam, S.
Malcolm, A. E. Harding, unpublished data). Although
our patient did not seek medical advice until he was
38 years old, it was clear from his early history and
skeletal deformities that a neuropathic process had
been present since childhood. This patient demonstrates how DNA analysis is useful in making a diagnosis of HMSN Ia in apparently sporadic patients, and in
distinguishing this disorder from other chronic demyelinating neuropathies such as CIDP. This distinction
has important implications for therapy and genetic
counseling. Hoogendijk and colleagues C131 demonstrated the presence of the 17p partial duplication in 9
of 10 patients with chronic demyelinating neuropathies
Fig 3 . Electron micrograph .ftransverse section through a small
myelinated newe fiber showing widely spaced myelin (arrows)
with expansion of the intraperiod line. Bar = 0.5 pm.
compatible with HMSN but in whom the parents were
normal clinically, neurophysiologically, and genetically.
Thus, new mutations for this disorder are common.
Positive sensory symptoms are very unusual in
HMSN [11 and strongly suggest an additional process.
Although paraproteinemia was not initially detected in
this patient, the finding of IgM deposition on myelin
and the presence of widely spaced myelin is typical of
IgM paraproteinemic neuropathy 1111. It is possible
that the occurrence of both HMSN Ia and paraproteinemic neuropathy in this patient is a chance association. Although this cannot be excluded with certainty,
onset of paraproteinemic neuropathy at his age is unusual and raises the question as to whether the paraprotein is secondary to the inherited neuropathy. It has
been suggested that patients with HMSN are more
likely to develop CIDP [7}. As mentioned, the clinical
features of CIDP and paraproteinemic neuropathy are
similar, although tremor tends to be more prominent
in neuropathy associated with IgM paraproteinemia
than with IgG or IgA paraproteins [ 10, 111.The occurrence of widely spaced myelin is confined to IgM paraproteinemic neuropathy. A major difference is that
CIDP occurs at all ages, whereas paraproteinemic neuropathy is largely a late life disorder El 11. Until more
Brief Communication: Gregory et al: HMSN la and IgM Paraproteinemia 651
is known as to the underlying disease mechanisms in
CIDP and paraproteinemic neuropathy, it will be difficult to elucidate their interrelationships. In the present patient, it is conceivable that the paraprotein has
arisen as an autoimmune phenomenon secondary to
the exposure of myeiin antigens by the inherited neuropathy. If so, why a monoclonal expansion should
have occurred requires explanation, but this could depend upon genetic factors. It could be speculated that
the 17p duplication contains other genes that modify
the immune response. The existence of this patient
should prompt testing for a paraprotein in others with
HMSN in whom it is suspected that CIDP may have
developed.
Financial support from the Muscular Dystrophy Group of Great
Britain and Northern Ireland and the Medical Research Council is
gratefully acknowledged.
We thank Miss Jane Workman for technical assistance, Dr Peter
Misra for the morphometric observations on the nerve biopsy, and
Dr Norman Gregson for the anti-MAG immunoblots.
Molecular
Genetic
-.
Characterization ot an
X-linked Form of Leigh's
Syndrome
c
P. M. Matthews, MD, DPhil, FRCPC,"t
D. R. Marchington, PhD," M. Squier, MRCP, MRCPath,S
J. Land, MRCPath, PhD,O(I R. M. Brown, MSc,* and
G. K. Brown, BM, PhD"
We report a patient with necrotizing encephalomyelopathy (Leigh's syndrome) associated with a deficiency of
pyruvate dehydrogenase complex activity. The underlying mutation is an A to C transversion in the pyruvate
dehydrogenase complex Ela subunit gene. As the Ela
subunit is encoded on the X chromosome, this observation confirms that some patients with Leigh's syndrome
may potentially exhibit X-linked inheritance.
Matthews PM, Marchington DR, Squier M, Land J,
Brown RM, Brown GK. Molecular genetic
characterization of an X-linked form of Leigh's
syndrome. Ann Neurol 1993;33:652-655
References
1. Harding AE, Thomas PK. The clinical features of hereditary
motor and sensory neuropathy type I and 11. Brain 1980;103:
259-280
2. Vance JM, Nicholson GA, Yamaoka LH, et al. Linkage of Charcot-Marie-Tooth neuropathy type l a to chromosome 17. Exp
Neurol 1989;104:186- 189
3. Raeymakers P, Timmerman V, Nelis E, et al. Duplication in
chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy
type la (CMT la). Neuromusc Disord 1991;1:93-98
4. Lupski JR, Montes de Oca-Luna R, Slaugenhaupt S, et al. DNA
duplication associated with Charcot-Marie-Tooth disease type
IA. Cell 1991;66:219-232
5. Hallam PJ, Harding AE, Berciano J, et al. Gene mapping and
mutation detection in hereditary motor and sensory neuropathy
type I (Charcot-Marie-Tooth disease type 1). Ann Neurol
1992;31:570-572
6. Patel PI, Roa BB, Welcher AA, et al. The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-MarieTooth disease type 1A. Nature Genet 1992;1:159-165
7. Dyck PJ, Low PA, Bartelson JD, et al. Prednisone responsive
hereditary motor and sensory neuropathy. Mayo Clin Proc
1982;57:239-246
8. Cornblath DR, Asbury AK, Albers JW, et al. Research criteria
for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology 1991;71:617-6 18
9. Kelly JJ, Kyle RA, Latov N. Polyneuropathies associated with
plasma cell dyscrasias. Boston: Marcinus Nijhoff, 1987
10. Gosselin S, Kyle R, Dyck PJ. Neuropathies associated with
monoclonal gammopathies of undetermined significance. Ann
Neurol 1991;30:54-61
11. Yeung Kl3, Thomas PK, Kmg RHM, et al. The clinical spectrum
of peripheral neuropathies associated with benign monoclonal
IgM, IgG, and 1A paraproteinemia. Comparative clinical, immunological and nerve biopsy findings. J Neurol 1991;238:
383-391
12. Jacobs JM, Love S. Qualitative and quantitative morphology of
human sural nerve at different ages. Brain 1985;108:897-924
13. Hoogendijk JE, Hensels GW, Gabreels-Festen AAWM, et al.
De-novo mutation in hereditary motor and sensory neuropathy
type I. Lancet 1992;339:1081-1082
Subacute necrotizing encephalomyelopathy, or Leigh's
syndrome 111, is clinically and causally heterogeneous
L2f. Pathological features of bilaterally symmetrical foci
of gliosis and necrosis (particularly in the diencephalon
and brainstem) with an associated capillary proliferation characterize the syndrome. Biochemical studies
have defined associations most commonly with deficiencies of cytochrome oxidase and the pyruvate dehydrogenase complex (PDHC) (including abnormalities
of both catalytic and regulatory subunits) (reviewed by
Van Coster and colleagues 131).
The pattern of inheritance of Leigh's syndrome is
generally considered to be autosomal recessive [2f, but
there is indirect evidence that some forms may be Xlinked 141. The absence of many large kindreds in the
patient reports and the lack of specific, molecular genetic diagnoses preclude definite assessment of inheritance patterns. Here we report a patient with acute
infantile Leigh's syndrome associated with PDHC deficiency in which the underlying mutation has been
From the *Genetics Laboratory, Department of Biochemistry, and
tDepartment of Clinical Neurology, University of Oxford, $Department of Neuropathology, Radcliffe Infirmary, and §Department of
Clinical Biochemistry, John Radcliffe Hospital, Oxford, UK.
Received Oct 13, 1992, and in revised form Jan 21, 1993. Accepted
for publication Jan 27, 1993.
//Currentaddress: Department of Chemical Pathology, The National
Hospital for Nervous Diseases, Queen Square, London, UK.
Address correspondence to D r Brown, Genetics Laboratory, Department of Biochemistry, South Parks Road, Oxford, OX1 3QU, UK.
652 Copyright 0 1993 by the American Neurological Association
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