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A Case of Familial Amyloid Polyneuropathy Homozygous for the Transthyretin Val30Met Gene With Motor-Dominant Sensorimotor Polyneuropathy and Unusual Sural Nerve Pathological Findings
Akira Yoshioka, MD;
Yoko Yamaya, MD;
Shinji Saiki, MD;
Genjiro Hirose, MD;
Kohei Shimazaki, MD;
Masaaki Nakamura, MD;
Yukio Ando, MD
Arch Neurol. 2001;58:1914-1918.
ABSTRACT
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Objective To report a case of familial amyloid
polyneuropathy homozygous for the amyloidogenic transthyretin (ATTR)
Val30Met gene with motor-dominant sensorimotor polyneuropathy
and unusual sural nerve pathological findings.
Methods Mass spectrometry analysis and polymerase chain
reaction–restricting fragment length polymorphism were performed. A
right sural nerve biopsy specimen was obtained for histological
investigation.
Setting Academic medical center.
Results A 56-year-old Japanese man living in a local town
(Nakajima, Japan) in Ishikawa Prefecture, a nonendemic area of type I
familial amyloidotic polyneuropathy, had vitreous amyloidosis,
motor-dominant sensorimotor polyneuropathy, erectile dysfunction, and
urinary incontinence. He had neither orthostatic hypotension nor
indolent diarrhea. Restriction enzyme analysis with EcoT22 I
of amplified DNA and mass spectrometry analysis revealed homozygosity
for ATTR Val30Met. Of 8 family members, 5 were evaluated and
found to be heterozygous for ATTR Val30Met; a family history
found no relative with the similar neurologic disorders. The sural
nerve biopsy specimen showed focal edema and an amyloid deposit in the
subperineural tissue, associated with moderate loss of myelinated and
unmyelinated fibers.
Conclusions In addition to the findings characteristic of
homozygosity for ATTR Val30Met such as vitreous amyloidosis
and relatively less autonomic involvements, this case had the unique
findings of motor-dominant sensorimotor polyneuropathy and unusual
sural nerve biopsy specimen results.
INTRODUCTION
FAMILIAL amyloidotic
polyneuropathy (FAP) type I is an autosomal-dominant disorder
characterized by extracellular amyloid deposit in systemic organs and
by polyneuropathy involving sensory, motor, and autonomic
nerves.1 The cause of FAP type I has been shown to be a
single amino acid substitution of methionine for valine at position 30
of the amyloidogenic transthyretin (ATTR) Val30Met
gene.2 Although many patients with ATTR Val30Met
FAP type I are heterozygous, 13 patients homozygous for ATTR
Val30Met (including 3 asymptomatic carriers) from Sweden,
Turkey, and Japan have been previously identified.3, 4, 5, 6, 7, 8, 9
Characteristics of patients homozygous for ATTR Val30Met FAP
have been reported to have late-onset, ocular manifestation
(vitreous amyloidosis),4 decreased focal depth, and
less autonomic involvement.6, 7, 8 We report a case
of homozygous ATTR Val30Met FAP with motor-dominant
sensorimotor polyneuropathy and unusual sural nerve
biopsy specimen findings.
METHODS
MASS SPECTROMETRY
To screen a mutant TTR in serum, a mass spectrometer (Bruker Reflex;
Bruker Franzen Analytik GmbH, Bremen, Germany) was used. Fifty
microliters of test serum was mixed with 20 µL of an anti-TTR
polyclonal antibody (Dako, Glostrup, Denmark) and assayed as described
previously.12 In the proband's serum sample, peaks of
13 912 dalton that corresponded to ATTR Val30Met were
predominantly observed and no normal TTR peaks were detected (data not
shown).
DNA ANALYSIS
For screening ATTR Val30Met, polymerase chain
reaction–restricting fragment length polymorphism (PCR-RFLP) was
performed: PCR-RFLP showed a normal band of 195 base pair (bp) in a
normal subject (Figure 1A, lane
1), an extra band of 115 and 80 bp associated with ATTR Val30Met
mutation in the proband (Figure 1A, lane 2), and both bands in a
heterozygous patient with FAP ATTR Val30Met
(Figure 1A, lane
3). These results suggest that the proband was a homozygote
with FAP ATTR Val30Met. The PCR-RFLP analysis for 8 family
members revealed 5 heterozygotic ATTR Val30Met gene carriers
(Figure 1B-C).
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Figure 1.
A, Polymerase chain reaction–restricting fragment length polymorphism
(PCR-RFLP) showed a normal band of 195 base pairs (bp) in a normal
subject (lane 1), an extra band of 115 and 80 bp associated with
amyloidogenic transthyretin (ATTR) Val30Met gene mutation in
the proband (lane 2), and both bands in a patient with heterozygote
familial amyloid polyneuropathy ATTR Val30Met (lane
3). M indicates DNA size marker. B, Polymerase chain
reaction–restricting fragment length polymorphism analysis for 8
family members revealed 5 heterozygotic ATTR Val30Met gene
carriers. M indicates DNA size marker; lane 1, normal control; lanes
2-9, family members evaluated; and lane 10, a patient heterozygous for
ATTR Val30Met from a different pedigree. C, Pedigree of
family. The arrow indicates the proband; circle, females; squares,
males; daggers, dead; 6, 3, 2, 9, 4, 5, 7, and 8, all represent persons
who were tested and these numbers correspond to the lane numbers in
Figure 1B.
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SURAL NERVE FINDINGS
Congo red staining and polarized light analysis of excised sural nerve
showed amyloid deposit in the perineural and endoneural tissues (data
not shown). After the specimen was embedded in epoxy resin
and stained with toluidine blue, it showed focal edema and amyloid
deposits in the subperineural tissue (Figure
2A-B). There was a moderate loss
of myelinated fibers (3773 fibers per square millimeter) and
unmyelinated fibers (14 800 fibers per square
millimeter). Myelinated fibers with thin myelin sheaths,
indicative of remyelinated fibers, were noted. Numbers of both large- and small-diameter myelinated fibers decreased (Figure 2C).
The 2-peak pattern of myelinated fibers was well preserved. Electron
microscopic findings showed amyloid fibrils intermixed with
collagen fibers in the subperineural tissue (Figure
2D).
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Figure 2.
Biopsy findings of sural nerve (A and B). After the specimen
was embedded in epoxy resin and stained with toluidine blue, it showed
focal edema and amyloid deposit in the subperineural tissue as well as
a moderate loss of myelinated fibers (3773 fibers per square
millimeter) and unmyelinated fibers (14 800 fibers per square
millimeter). Myelinated fibers with thin myelin sheaths,
indicative of remyelinated fibers were noted. C, Morphometric analysis
of the sural nerve showed a loss of both large- and small-diameter
myelinated fibers. The 2-peak pattern of myelinated fibers was
preserved. D, Electron microscopic findings showed amyloid fibrils
intermixed with collagen fibers in the subperineural tissue.
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REPORT OF A CASE
A 56-year-old Japanese man living in Nakajima, Ishikawa Prefecture,
believed to be a nonendemic area of FAP in Japan, was admitted to our
service on February 14, 2000, for generalized muscle atrophy. His
deceased parents were second cousins who had lived in the same town.
Both parents died of cerebral infarction—his father at the age of 87
years and his mother at the age of 82 years. A family history disclosed
no relatives with similar neurologic disorders. We did not find any
kinship with residents of Ogawa Village, Nagano Prefecture,
and Arao City, Kumamoto Prefecture, 2 endemic foci of FAP type I in
Japan.10, 11
Our patient had been well until 1989, when he noticed blurred vision.
In 1991, a right vitrectomy was performed. Amyloid was recovered from
the vitreous material. At that time, the patient did not have any
muscle atrophy or sensory disturbances. He noticed erectile dysfunction
and dysuria in 1998. He first noticed muscle atrophy of his upper and
lower extremities in July 1999 and was referred to the hematology group
at our hospital, where a biopsy specimen of his lip disclosed an
amyloid deposit, although a biopsy specimen of his bone marrow revealed
no increase in plasma cells. The patient did not report orthostatic
dizziness or diarrhea. On admission, his blood pressure was 110/76 mm
Hg in the sitting and standing positions, his pulse rate was 68/min and
regular, his body weight was 41 kg, and his height was 161 cm.
Neurologically, his mental status was alert and well oriented to time,
place, and person. Cranial nerves were well preserved, except for the
right eye, which showed a sluggish light reflex and lens opacity.
Significant symmetrical muscle atrophy and weakness of the upper and
lower extremities were noted with distal predominance and marked
fasciculation. Deep tendon reflexes were hypoactive in the upper
extremities and areflexic in the lower extremities. The plantar
response was flexor bilaterally. Pain and vibratory sensations were
slightly decreased below the ankles, but position sense was well
preserved. Findings from examination of the cerebral spinal fluid
showed no abnormalities. Motor conduction velocity was markedly
decreased at the right ulnar nerve (22.4 m/s), the right peroneal nerve
(15.5 m/s), the left peroneal nerve (20.8 m/s), the right posterior
tibial nerve (34.7 m/s), and the left posterior tibial nerve (34.6
m/s). Motor conduction was not evoked at the right median
nerve. No significant conduction block was noted. Conversely, sensory
conduction velocity was well preserved at the left median nerve (48.8
m/s) and the left ulnar nerve (50.4 m/s). Sensory conduction
was not evoked at the right median and ulnar nerves. The F-wave
conduction velocity was decreased at the right ulnar nerve (32.4 m/s)
and the left peroneal nerve (29.8 m/s), but it was preserved at the
left posterior tibial nerve (41.3 m/s). F waves were not
evoked at the median nerves bilaterally, the left ulnar nerve, the
right peroneal nerve, and the right posterior tibial nerve. An
echocardiogram showed no cardiomegaly and a computed tomographic scan
of the abdomen revealed no organomegaly. The patient's muscle atrophy
progressed and his body weight was 36.6 kg in October 2000.
COMMENT
We found a family in which the proband is homozygous for ATTR
Val30Met and 5 of the 8 family members are heterozygous for
ATTR Val30Met. The patient's parents, now deceased, were
second cousins living in Nakajima, Ishikawa Prefecture, which is a
nonendemic area of FAP type I in Japan. No kinship was found in the
families from endemic areas such as Ogawa Village and Arao City, where
the large foci of FAP ATTR Val30Met exist. Previously,
Yoshinaga et al7 described 3 patients with FAP homozygosity
for ATTR Val30Met living in Kanazawa City, Ishikawa
Prefecture, about 70 km south of Nakajima. We could not find any common
ancestors between the family in that article and the family of our
patient. Further study is needed to determine whether Nakajima might be
another endemic area of FAP type I in Japan.
The patient showed his first clinical symptom, vitreous amyloidosis,
when he was 45 years old. This age of onset is younger than the average
previously reported in homozygous cases of ATTR Val30Met (mean
age ± SD, 57.3 ± 5.4 years; age range,
51-68 years).13 The patient noticed erectile
dysfunction and dysuria at the
age of 54 years and had motor-dominant
sensorimotor polyneuropathy at the age of 55 years.
In addition to the clinical symptoms characteristic of homozygosity for
ATTR Val30Met such as vitreous amyloidosis and less autonomic
involvements (without orthostatic hypotension and diarrhea), the
patient showed motor-dominant sensorimotor polyneuropathy with distally
predominant muscle atrophy and marked fasciculation. Pain and
temperature sensations were mildly involved, but vibratory sensation
was spared. Nerve conduction velocity studies showed a predominant
motor involvement. Patients with FAP type I usually have symptoms of
sensory and autonomic neuropathy in their early courses and motor
neuropathy later.10 Motor-dominant polyneuropathy in
early-stage FAP type I has apparently been reported in only 3
patients.14, 15 A case of primary amyloidosis with early
motor-dominant neuropathy that mimicked lower motor neuron disease has
been reported.16 Muscle weakness is noted in the
patients with amyloid myopathy, which is a well-recognized,
but rare, manifestation of amyloidosis.17 However, it is
the primary amyloidosis that most often has involvement of skeletal
muscle.17
The present case disclosed unusual sural nerve biopsy specimen
findings: focal edema and amyloid deposits in the subperineural tissue,
associated with moderate loss of myelinated and unmyelinated fibers.
The morphometric analysis revealed a relatively preserved 2-peak
pattern of myelinated fibers. The previous studies of sural nerve
biopsy specimens from patients with FAP type I revealed the deposit of
amyloid substances within nerve fasciculus, selective loss of small
myelinated and unmyelinated fibers, and predominant axonal
degeneration.18, 19 We could not see pathological findings
of subperineural edema in the sural nerves of patients with FAP type I
whose cases were previously reported. However, Hanyu et
al20 evaluated 3 autopsy cases of FAP type I and found
endoneural edema with segmental demyelination in the brachial plexus
and sciatic nerves, but not in the sural nerves or spinal roots. These
researchers suggested that the proximal nerve lesions induced by
endoneural edema resulting from amyloid deposits on the vessels might
secondarily damage distal nerves such as sural nerves. Regarding the
sural nerves of patients with homozygous ATTR Val30Met,
Yoshinaga et al13 reported 1 case showing a marked loss of
myelinated and unmyelinated fibers, but they did
not find edema or an amyloid deposit in the subperineural
tissue.
Patients homozygous for the ATTR Val30Met gene do not appear
to suffer from more severe illness.6, 7, 8 Even asymptomatic
homozygous ATTR Val30Met gene carriers have been
described.7, 8 However, most of the neurologic symptoms of
FAP are due to infiltrated deposits of amyloid fibrils in the tissues.
Characterization of the various amyloidogenic TTR mutations has set the
stage for an effort to clarify the mechanisms underlying fibril
formation. Amyloid fibrillogenesis has been considered a multifactorial
process.21 The factors influence fibril formation in FAP,
consist of the intrinsic conformation of the TTR fibril protein, its
concentration, the structual effects of TTR mutation, microenvironments
of the lysosome, proteolytic processing, amyloid cofactors and
tissue-specific determinants.21 Therefore, the clinical
phenotypic heterogeneity of TTR mutations can be explained by these
complicated multifactorial mechanisms.
AUTHOR INFORMATION
Accepted for publication March 30, 2001.
From the Department of Neurology, Kanazawa Medical University, Uchinada
(Drs Yoshioka, Yamaya, Saiki, and Hirose); Department of Internal
Medicine, Hamano Hospital, Nanao City
(Dr Shimazaki); and the
Department of Laboratory Medicine, Kumamoto University School of
Medicine, Kumamoto (Drs Nakamura
and Ando), Japan.
Corresponding author: Akira Yoshioka, MD, Department of Neurology,
Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa
920-0293, Japan (e-mail: a-yos{at}kanazawa-med.ac.jp).
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