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Congenital hypomyelination neuropathy with arthrogryposis multiplex congenita.

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Neuropathy with
Arthrogryposis Multiplex
Kevin B. Boylan, MD,” Donna M. Ferriero, MD,t
Claudia M. Greco, MD,$ R. Ann Sheldon, BA,t and
Michael Dew, MD§
A term male infant is described with a n isolated disorder
of peripheral myelination. A t necropsy, the great majority of medium-to-large axons were unmyelinated. Electron microscopy showed normal axons and redundant
lamination of basement membrane, suggestive of early
onion bulb pathology. Immunohistochemistry of peripheral nerve showed deficiency of the myelin proteins P2
and Po, myelin basic protein, and myelin-associated glycoprotein. Arrest of peripheral myelination at the promyelin stage appears to be the origin of myelin deficiency.
Boylan IU3, Ferriero DM, Greco CM, Sheldon
RA, Dew M. Congenital hypomyelination
neuropathy with arthrogryposis multiplex
congenita. Ann Neurol 1992;31:337-340
Deficiency or absence of peripheral myelin in newborns [ 1, 21, generally referred t o as congenital hypomyelinating neuropathy, is a rare cause of infantile neuromuscular weakness. Five patients with arthrogryposis
muitiplex congenita with deficient peripheral myelin
have been reported, b u t all differ from o u r patient in
that 3 had associated central nervous system defects or
congenital abnormalities apart from t h e arthrogryposis
[3-51, and 2 had complete [ l ] or virtually complete
[6J absence of peripheral myelin.
Patient Report
The patient’s clinical features have been previously reported
171. Briefly, the infant was delivered at 38 weeks’ gestation,
was ventilator-dependent, had large joint flexion contractures
with diffuse hypotonia, severe generalized weakness, and areflexia. Spinal fluid, karyotype, and neonatal inborn errors of
metabolism tests were normal. Electroencephalography and
brain and spine magnetic resonance images showed normal
patterns for age. Sensory action potentials were unobtainable;
motor conduction velocity was extremely slow at 1 to 2
m/sec (normal, 2 1 m/sec). Electromyography showed fibrillations and positive waves with absent motor unit potentials.
Biopsy of vastus medialis at age 8 days showed variation
in muscle fiber size and type 2 predominance in a pattern
consistent with neurogenic change; neither grouped atrophy
nor hypertrophy were present. Results of sural nerve biopsy
are described. Death occurred at 5 weeks of age following
withdrawal of ventilatory support. Autopsy was performed
within 1 hour of death.
Materials and Methods
Morphometric Analysis
Morphometry was performed on biopsied sural nerve (fixed
in 2.5% glutaraldehyde in 0.1 M cacodylate buffer, p H 7.4)
and compared with published control data [Z, 83. Fiber
counts were performed manually o n nonoverlapping electron
micrographs of transverse sections (final enlargement, x
5,000 for myelinated axons and x 10,000 for unmyelinated
axons). Axons in a one-to-one relationship with Schwann
cells were counted as myelinated type axons even if the
Schwann cell had not actually produced myelin membranes.
Schwann cells with axons in this relationship would normally
be expected to have begun myelination in a term infant f81.
If the Schwann cell cytoplasm contained two or more axons,
the axons were counted as unmyelinated. Axonal diameters
were calculated using the “arithmetic” method of Dyck [9].
Lumbosacral cord and roots from the patient were compared
with control spinal cord from a similar-age infant without
nervous system disease who died of hypoplastic left heart
syndrome. Tissue was incubated overnight at 4°C using one
of the following antibodies: antimyelin basic protein (MBP)
at 1:1,000, anti-P2 at 1:500, anti-Po at 1:500, and antimyelin-associated glycoprotein (MAG) at 1:500. Antibody
was visualized with the avidin-biotin-peroxidase method using the Vectastain ABC Elite kit (Vector Labs, Burlingame,
CA). Diaminobenzidine (Sigma) was used as the chromagen.
From rhe *Deparrmenr of Neurology, Johns Hopkins Universiry,
Balrimorc; rhe tDepdrrmenrs of Neurology and Pediatrics, University of California, and the tDeparrment of Neuropathology, Children’s Hospital, San Francisco, CA; and the $Departments of Psychiarry and Neurology, Dwight Eisenhower Army Medical Cenrer, Fort
Gordon, G A 30905.
Received Mar 6 , 1991, and in revised form Aug 8. Accepred for
publication Sep 14, 1991.
Address correspondence to D r Boylan, Deparrmenr of Neurology,
Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL
Premortem Studies
Few fibers in t h e sural nerve biopsy w e r e myelinated
(Fig 1A). Myelination, w h e n present, tended t o be thin
relative to axon diameter, but myelin- membrane lamination was normal, as w e r e associated axons (Fig
lB,C). Small unmyelinated fibers appeared normal. Lysosomal inclusion bodies w e r e n o t present. Redundant
basal laminae surrounding nonmyelinated axons were
c o m m o n (see Fig lB,C). Endoneurial collagen was not
Copyright 0 1992 by the American Neurological Association
F i g I . Sural newe biopsy. (A) One pm-thick section of resin.embedded newe shouis striking diminution of myeiinated fibers.
Schu~anncell nuclei appear increased in number. (Tohidine
blue: x 120 before j292 reduction.) (B) Multiple single. nonmyelinated axons are surrounded by redundant bmal laminae
and occasional extensions of Schwann cell cytoplasm. (Tohidine
blue; x 7.500 before 525% reduction.) (C) A single, nonmyelinated axon, J p n in diameter, surrounded by two Schwann cell
nuclei, u6ich may indicate Schwann cell mitotic ‘tctivity. This
actizitj uJouldbe expected during fetal peripheral nerve development but would be abnormal in a term infant for this s h e
axon. (Toluidine blue; x 7,500 before 52% reduction.) I n B
and C. open arrows indicate redundant basal laminae thought
to remain .from abortive attempts at myelination. and dotted
arrows indicate fibroblast processes, distinguishable fkom
Schuiann cell extensions because of the absence of basal laminae.
Morphometric Data
In surd nerve, 642 axons in a one-to-one relationship
with Schwann cells were counted in a 2.52 x lo-’
mm’ cross-sectional area. Diameters ranged from 1 to
10 pm (Fig 2A). Twenty-six axons with diameters from
3 to 8 pm (4.0%’)were actually myelinated; the remainder were enwrapped with Schwann cell cytoplasm
without elaboration of myelin membranes. The ratios
of axon to fiber diameter (g ratio) [S] for the 26 myelinated axons were mostly higher than those reported
for similar-age control infants (Fig 2C). In a crosssectional area of 5.24 x lo-’ mm’, 988 unmyelinated
s o n s were counted. Diameters ranged from 0.2 to 2.6
pm (Fig 2B). Axon densities for myelinated type (1.94
x lo4 mm’) and unmyelinated axons (1.90 x lo5
mm’) were both normal [2, S}. In each distribution
a subset of axons ( 5 % for myelinated arid 10% for
unmyelinated) were up to 60% larger in diameter than
the upper limit reported for control nerve, and the
proportion of small diameter fibers was increased.
Postmortem Studies
Brain and spinal cord were grossly normal. Motor neurons and dorsal root ganglia were histologically normal
in appearance and number. Resin-embedded cross secdons of cervical and lumbar cord showed decreased
myelinization of dorsal roots. There was a mild decrease in the number of myelinated fibers in ventral
roots at both levels, and only rare, thinly myelinated
fibers in sections of cauda equina. Distal median nerve
showed severely delayed myelination compared with
C7 dorsal and ventral roots (Fig 3).
338 Annals of Neurology Vol 31 No 3
March 1992
0.6 -
0.4 -
0.2 -
F i g 2. Diameter distributions for myelinated (A) and unmyelinated (Bi axons. Percentage of axons is plotted versus axon dimieter. Control data were redrawn (with permission from the authors and pzlbhher) from 181. iC) Twenty-six myelinatrd
axons; g ratio is plotted versus axon diameter. The g ratio
ues should generally be between 0.7 and 0.8 for children unu’er
3 years of age {8}.
Fig 3. C7 sensory root iA) and motor root (B) show slightly diminished myelination for age. Distal median nerve (C) shows a
markedly decreased number of myelinated fibers. Also, axon diameters are decreased. Arrowhead in (B) and ICi shows an
axon associated with t w o Schwann cell nuclei. The small c in
(B) denotes a capillary. Filled arrows indicate unmyelinated
large axons, and open arrows point t o myelinated axons. All
sections are from resin-embedded autopsy tissue. IToluidine blue,
x 480 before 52% reduction.)
Sections through lumbosacral cord revealed a normal
pattern of myelin MBP-like irnmunoreactivity. Transition areas through root entry zones revealed a markedly decreased imrnunostaining of P2, Po, and MBP
in the peripheral nerve root, but only moderate deficiency of MAG (data not shown). The decreased immunostaining of the myelin proteins corresponded to
the loss of myelinated nerve fibers (see Figs 1, 3) with
no selective dropout of any of the myelin proteins
This infant’s neuropathic disorder appeared to represent failure or severe delay of myelination at the promyelin stage. The promyelin stage is the phase of
myelination in which Schwann cells have enwrapped
single axons but have not yet begun myelin formation
{ 101. For axons of all diameters, the g ratios were relatively high; hypomyelination did not appear to be confined to any subset of axons distinguishable by size
criteria. Redundant basal lamina and extensions of
Schwann cell cytoplasm were relatively common in
electron micrographs of sural nerve, which are similar
to changes seen early in onion bulb formation in both
human and animal forms of hereditary hypertrophic
neuropathy [l l}.
A rostral-caudal gradient in spinal root myelination
is normal {12), but the degree of myelin deficiency in
the roots, and especially in median and sural nerve, was
quite abnormal. In addition, Figure 2 shows a marked
difference in axon diameters between the spinal roots
(which seemed normal) and the distal median nerve.
We found no published infant control data on this
point, but in adults axon diameters in distal peripheral
nerve are not substantially less than in corresponding
spinal roots {9}. Similar to these observations in median nerve, a relative excess of smaller diameter axons
was present in surd nerve (see Fig 2A,B). An increased
proportion of smaller diameter axons therefore seems
likely to have been a generalized condition.
MAG is expressed by Schwann cells during the promyelin stage before full expression of Po, P2, and MBP
[13}. There was no selective dropout of any of these
proteins, so it seems unlikely that deficiency of any
one protein led to diffuse peripheral hypomyelination.
The moderate deficiency of MAG with severe dehciency of the remaining proteins supports the suggestion that hypomyelination resulted from developmental arrest at the promyelin stage, particularly given
the presence of relatively normal myelination of some
Presented in part at the 42nd Annual Meeting of the American
Academy of Neuroiogy, Miami Beach, FL, April 1990.
The opinions or assertions contained herein are the private views of
the authors and are not to be construed as official or as reflecting
the views of the Army or the Department of Defense.
We would like to thank Dr John Whitaker for the generous gift of
anti-MBP; Dr Richard Quarles for the generous gift of anti-MAG;
and D r Bruce Trapp for the generous gift of anti-Po and anti-P2. We
also thank D r John Griffin and Dr Yuen So for helpful discussions
regarding the manuscript.
1. Charnas L, Trapp B, Griffin J. Congenital absence of peripheral
myelin: abnormal Schwann cell development causes lethal
arthrogryposis multiplex congenita. Neurology 1988; 38:
2. Ouvrier R, McLeod JG, Pollard J, eds. Pevipherd neuroputhjj 292
rhildbood. New York: Raven, 1990:13-20
3. Hakamada S, Kumagai T, Hara K, et al. Congenital hypomyelinating neuropathy in a newborn. Neuropediatrics 1983;14:
4. Pleasure JR, Shuman S, Rorke LB. Congenital absence of peripheral nervous system (PNS) myelin presenting as arthrogryposis multiplex congenita (Part 11). Pediatr Res 1986;20:
5. Seitz RJ, Wechsler W, Mosny DS, Lenard HG. Hypomyelination neuropathy in a female newborn presenting as arthrogryposis multiplex congenita. Neuropediatrics 1986;17:
6. Palix C, Coignet J. Un cas de polyneuropathie peripherique
neonatale par myelination. Pediatrie 1978;33:201-207
7. Boylan K, Dew M, Greco C, Ferriero D. Hypomyelination neuropathy: a rare form of neonatal neuromuscular weakness. Neurology 1990;40:409A
8. Jacobs JM, Love S. Qualitative and quantitative morphology of
human sural nerve at different ages. Brain 1985;108:837-924
9. Dyck PJ. Parhologic alterations of the peripheral nervous system
in humans: In: Dyck PJ, Thomas PK, Lamberr EH, Bunge R,
eds. Peviphevuf Neuroputhjj. Philadelphia: W.B. Saunders,
Brief Communication: Boylan et al: Congenital Hypomyelination Neuropathy
10. Friede RL, Samorajski T. Myelin formation in the sciatic: nerve
of the rat. A quantitative electron microscopic and radioauto-
graphic study. J Neuropathol Exp Neurol 1968;27:546--570
11. Low PA. The evolution of “onion bulbs” in the hereditary hy-
pertrophic neuropathy of the trembler mouse. Neuropathol
Appl Neurobiol 1977;3:81-92
12. Dobosz-Niebrol I, Fidzianska A, RafalowskaJ, Sawicka E. Correlative biochemical and morphological studies of myelination
in human ontogenesis. 11. Myelination of the nerve roots. Acta
Neuropathol 1980;49:153-158
13. Willison HJ, Ilyas AL. OShannessy DJ, et al. Myelin-associated
glycoprotein and related glycoconjugates in developing cat peripheral nerve: a correlative biochemical and morphometric
study. J Neurochern 1987;49:1853-1862
Familial Amyloidotic
Polyneuropathy: Report
of Patients Heterozygous
for the Transthyretin
Tatsufumi Murakami, MD,” Shigehiro Yi, MD,”
Kenji Yamamoto, MDJ Shoichi Maruyama, MD,t
and Shukuro Araki. MD”
We studied 2 patients from aJapanese family with familial amyloidotic polyneuropathy (FAP). Their clinical
features are similar to type 1 FAP, and the proband’s
rectal tissue contained amyloid that stained with antihuman transthyretin (TTR) antiserum. Direct DNA
sequencing of the proband’s T T R gene revealed a
guanine-for-adenine substitution in the second base of
codon 42, producing a glycine for glutamate substitution in the plasma protein.
Murakami T, Yi S, Yamamoto K, Maruyama S,
Araki S. Familial amyloidotic polyneuropathy:
report of patients hererozygous for the
transthyretin Gly”” gene.
Ann Neurol 1992;31.340-342
Familial amyloidotic polyneuropathy (FAP) is an autosomal, dominantly inherited disorder characterized
by the extracellular deposition of fibrillar amyloid pro-
tein and peripheral nerve involvement. The amyloid
proteins of most types of FAP have been identified
as variant types of transthyretin (?TR). The amyloid
deposits derived from patients with FAP who are of
Portuguese, Japanese, and Swedish origin were found
to consist of a variant I T R with a single amino acid
substitution of methionine for valine in position 30 of
normal TTR El-31. Moreover, a number of FAP family groups throughout the world have genetic variants
of ‘ITR E4- 101. Recently, Ueno and colleagues { 1 1,
121 identified three different variants of TTR (Glui2
to Gly, Ser5’ to Arg, and Tyrl’* to Cys) in Japanese
patients with FAP by a combination of genomic amplification followed by cloning and sequencing. We studied 2 Japanese patients whose eldest brother was
reported to have the variant GIu4’ to Gly and characterized this family with FAP.
Patient Reports
The proband (111-3 in Fig 1) is a 38-year-old man whcise
symptoms began at age 34 with chronic diarrhea followed
several years later by orthostatic hypotension, as well as scnsory disturbance and weakness in the lower extremities. H e
was admitted to a hospital in 1989, and amyloid was detected
in a sural nerve biopsy specimen. Later that year, he was
admitted to Tokyo Women’s Medical College Hospital. Clinical neurological examination revealed signs of polyneuropathy and bilateral Argyll Robertson pupils. His visual acuity
was 0.7 in the right eye and 0.9 in the left. N o vitreous
opacities were detected by ophthalmoscopic and slit-lamp
The elder brother is a 41-year-old man (111-2 in Fig I )
whose symptoms began at age 39 with muscle weakness in his
lower extremities. In early 1980, he was admitted to Takeda
Hospital in Kyoto, where clinical neurological examination
revealed muscle weakness in the upper and lower extremities, sensory disturbance in the lower extremities, and orthostatic hypotension. His chest radiograph showed cardiac
enlargement, and his echocardiogram showed diffuse hypertrophy and hypokinesis. No vitreous opacities were seen.
Family history revealed that the proband’s mother (11-l),
uncle (11-5), and maternal grandmother (1-2) had similar
symptoms. The maternal grandmother was in Toyama Prefecture in Japan. His mother had died at age 57, and his uncle
at age 48. Medical records were not available for review. The
proband’s eldest brother (111-1) was reported to be 42 year!;
old with symptoms of lower limb neuropathy and chronic:
diarrhea. He was heterozygous for the ‘ITR Gly“’ gene 111.
From the *First Department of Internal Medicine, Kurnamoto University Medical School, Kumamoto; and the ?Department of Neurology, Neurological Institute, Tokyo Women’s Medical College,
Received Jun 28, 1991, and in revised form Aug 19 and Sep 9.
Accepted for publicarion Sep 14, 1991.
Address correspondence to Dr Murakami, the First Department of
Internal Medicine, Kumamoto University Medical School, 1-1- I
Honjo, Kumamoro 860, Japan.
A rectal biopsy specimen from the proband (111-3) was exam.ined histologically. Congo red stain, treatment with potassium permanganate (KMnO,,) by Wright’s staining method,
and polarization microscopy were performed. For immunohistochemistry, the avidin-biotin complex method was
employed, using antihuman TTR antiserum (Behrinperkc:,
Marburg, Germany). Sections of kidney from a patient in
Japan with FAP type 1 were also examined as control specimens.
Copyright 0 1092 by the American Neurological Association
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arthrogryposis, hypomyelination, neuropathy, congenital, multiple
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