Brain, Vol. 122, No. 10, 1951-1962,
October 1999
© 1999 Oxford University Press
Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan
Clinicopathological and genetic features
1 Department of Neurology, Nagoya University School of Medicine, Nagoya, 2 Department of Medicine (Neurology), Shinshu University School of Medicine, Matsumoto, 3 First Department of Internal Medicine, Kumamoto University School of Medicine, Kumamoto, 4 Third Department of Internal Medicine, Miyazaki Medical College, Miyazaki, 5 Department of Neurology, Nagano Red Cross Hospital, Nagano, Okazaki Municipal Hospital, 6 Okazaki, 7 Third Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima and 8 Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan
Correspondence to:
Gen Sobue, MD, Department of Neurology, Nagoya University School of Medicine, Tsurumai, Nagoya, 466-8550 Japan E-mail: sobueg{at}tsuru.med.nagoya-u.ac.jp
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Abstract |
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Clinicopathological and genetic features were assessed on 35 Japanese families affected by late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy, FAP TTR Met30) whose siblings were unrelated to endemic Japanese foci. In these patients (50 years or older), the most common initial symptom was paraesthesias in the legs. Autonomic symptoms were generally mild and did not seriously affect daily activities. The male-to-female ratio was extremely high (10.7 : 1). A family history was evident in only 11 out of 35 families, and other patients were apparently sporadic. The rate of penetrance was very low. Symptomatic siblings of familial cases showed a late age of onset, male preponderance and clinical features similar to those of the probands. Asymptomatic carriers, predominantly female, were detected relatively late in life. The geographical distribution of these late-onset, FAP TTR Met30 cases was scattered throughout Japan. In three autopsy cases and 20 sural nerve biopsy specimens, neurons in sympathetic and sensory ganglia were relatively preserved. Amyloid deposition was seen in the peripheral nervous system, particularly in the sympathetic ganglia, dorsal root ganglia and proximal nerve trunks such as sciatic nerve. These abnormalities were milder than those seen in typical early-onset FAP TTR Met30, as observed in two Japanese endemic foci of this disease. While axonal degeneration was prominent in myelinated fibres, resulting in severe fibre loss, unmyelinated fibres were relatively preserved. Our cases of late-onset FAP TTR Met30 showed features distinct from those of typical early-onset FAP TTR Met30 that occurred in the two Japanese endemic foci. Factors responsible for clinicopathological differences between these two forms of FAP TTR Met30 need to be identified.
transthyretin Met30-associated familial amyloid polyneuropathy; transthyretin; clinicopathological study; genetic study; late onset
FAP TTR Met30 = transthyretin Met30-associated familial amyloid polyneuropathy
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy, FAP TTR Met30), associated with a mutant transthyretin substituting methionine for valine at position 30 (Met30), is the most common type of genetic familial amyloid polyneuropathy in the Western countries, as well as in Japan (Andrade, 1952
; Araki et al., 1968; Andersson, 1976; Benson and Cohen, 1977; Coutinho et al., 1980; Kito et al., 1980; Ikeda et al., 1987; Nakazato et al., 1992; Drugge et al., 1993; Sousa et al., 1993, 1995; Holmgren et al., 1994; Reilly et al., 1995; Plantê-Bordeneuve et al., 1998). Typical clinical features include a relatively young age of onset (20–40 years), prominent autonomic symptoms that disrupt the activities of the patient's daily life and sensory impairment that is predominantly superficial in type, with relatively preserved deep sensation (Andrade, 1952; Araki et al., 1968; Ando et al., 1992; Alves et al., 1997). In Japan, typical FAP TTR Met30 is endemic in a restricted area of Arao City in Kumamoto Prefecture and Ogawa Village in Nagano Prefecture (Araki et al., 1968; Kito et al., 1980; Ikeda et al., 1987; Nakazato et al., 1992). These endemic FAP TTR Met30 foci in Japan have been compared with the large Portuguese and Swedish foci of FAP TTR Met30 (Andrade, 1952; Andersson, 1976; Benson and Cohen 1977; Coutinho et al., 1980). In contrast, patients with Met30 transthyretin showing a late age of clinical onset (50 years or older), no apparent family history, no kinship with families in the endemic focus and features that mimic chronic sensorimotor neuropathy without pronounced autonomic symptoms, have been reported anecdotally among the Japanese and Portuguese populations (Ikeda et al., 1981, 1992; Libbey et al., 1984; Nitta et al., 1986; Saraiva et al., 1986; Yamada et al., 1987; Kincaid et al., 1989; Fujitake et al., 1991; Matsushima et al., 1992; Aoki et al., 1993; Tashima et al., 1995). However, details of the clinical and pathological features of these patients have not been fully described. Although liver transplantation is currently the most effective curative treatment for symptomatic patients with FAP TTR Met30 (Holmgren et al., 1991, 1993; Ando et al., 1995; Bergethon et al., 1996; Ikeda et al., 1997a, b; Parrilla et al., 1997; Suhr et al., 1997; Pomfret et al., 1998), factors affecting the age of onset and clinical features of polyneuropathy among FAP TTR Met30 patients with the same transthyretin mutation need to be determined to refine therapeutic approaches to FAP TTR Met30. In the present study, we analysed the clinicopathological and genetic features of late-onset FAP TTR Met30 patients in 35 families in Japan, particularly those unrelated to the endemic areas of Japan, and compared them with those of early-onset FAP TTR Met30 patients in endemic areas.
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Patients and methods |
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Patients in this study were from 35 Japanese families with late-onset FAP TTR Met30, sometimes limited to one individual per family. The patients in this study were seen at the Department of Neurology, Nagoya University School of Medicine and its affiliates from 1989 to 1997, and at three familial amyloid polyneuropathy research centres in Japan [Department of Medicine (Neurology), Shinshu University School of Medicine, First Department of Internal Medicine, Kumamoto University School of Medicine and Third Department of Internal Medicine, Miyazaki Medical College], and in addition those collected from information given in the annual report of regional meeting of the Japanese Society of Neurology for 1981–1997. In the latter case, the clinical and genetic information and biopsy information were collected from either the patients' doctors or the hospitals. Inclusion criteria were polyneuropathy, Met30 transthyretin mutation and onset at age 50 years or older. Patients whose two most recent prior generations of family members were related to families in the two Japanese endemic FAP TTR Met30 foci were excluded. Late-onset was designated as age of onset at age 50 years or older based on previous reports (Ikeda et al., 1987
; Sequeiros et al., 1991; Nakazato et al., 1992).
Routine examinations
All patients underwent neurological examination, nerve conduction studies, CSF examination, routine blood and urine examinations, ECG, cranial MRI and CT, and other radiological studies.
Nerve conduction
The nerve conduction study was performed using standard methods (Kimura, 1989a, b).
Nerve biopsy
The sural nerve biopsy was performed as described previously (Sobue et al., 1990; Hattori et al., 1999): specimens were fixed with 2% glutaraldehyde solution in 0.025% cacodylate buffer (pH 7.4) and processed for semi-thin, ultra-thin or teased-fibre studies. The density of myelinated fibres was assessed directly from toluidine blue-stained transverse semi-thin sections of sural nerve using a computer-assisted image analyser (Luzex FS, Nireco, Tokyo) as described previously (Sobue et al., 1989, 1990; Hattori et al., 1999). Unmyelinated fibre density was assessed using the same system based on electron microscope photographs (magnification x5000) taken randomly of uranyl acetate-stained transverse ultra-thin sections (Sobue et al., 1989; Hattori et al., 1999). Isolated single nerve fibres were also prepared from the specimens by teasing, and the condition of each fibre was evaluated pathologically according to criteria described previously (Sobue et al., 1989, 1997; Dyck et al., 1993) A portion of the biopsy specimen was fixed in 10% buffered formalin solution, embedded in paraffin and observed after haematoxylin and eosin, Klüver–Barrera and Congo red staining. Congo red staining was assessed using a polarizing microscope.
Autonomic involvement
Autonomic involvement was recorded with the items of orthostatic hypotension, syncope, diarrhoea/constipation, urination, sweating and impotence, which were evaluated in most cases by neurological examinations and patient interviews. Orthostatic hypotension was defined as a fall of 30 mmHg in the systolic blood pressure in the standing position from the recumbent position. Recurrent episodes of diarrhoea and constipation, urinary retention or incontinence, apparent hypohidrosis or episodes of excessive sweating and complaints of impotence were defined as a positive for these autonomic symptoms. CVR–R (coefficient of variation ECG R–R interval) examination of heart rate variation, thermographic examination of skin temperature, tilt-table testing for orthostatic hypotension and urodynamic studies also were performed for assessment in some patients.
Autopsy patients
For the three patients examined at autopsy, the spinal cord, thoracic sympathetic ganglia, lumbar sensory ganglia, sciatic nerves, tibial nerves and sural nerves were removed within 6 h of death, in addition to muscle specimens and the brain. All specimens were fixed in 10% buffered formalin solution, embedded in paraffin, and sections were observed after haematoxylin and eosin, Klüver–Barrera and Congo red staining. To assess neuronal loss in sympathetic and dorsal root ganglia, residual neurons with obvious nucleoli were counted on five 10-µm thick transverse sections. Sections represented every tenth section in a consecutive series and were stained by the Klüver–Barrera method. Neuronal counts were correlated with the control values as described previously (Sobue et al., 1990). Portions of the sciatic, tibial and sural nerves were fixed with 2% glutaraldehyde in 0.025% cacodylate buffer and processed for assessment of myelinated fibre density as in the sural nerve biopsy specimens (Sobue et al., 1989, 1990). Myelinated fibre loss was determined relative to control values as described previously (Sobue et al., 1989, 1990).
Some specimens fixed with 10% buffered formalin and embedded in paraffin were deparaffinized with xylene and processed for immunohistochemical detection of human transthyretin as described previously (Sobue et al., 1990). Anti-human transthyretin rabbit polyclonal antibody (Dako, Denmark) was used as the first antibody.
Genetic analysis
Genomic DNA was extracted from the patient's leucocytes, and exon 2 of the transthyretin gene was amplified by PCR (polymerase chain reaction) as described previously (Saraiva et al., 1986; Sakaki et al., 1989; Nakazato et al., 1992). After the PCR product was digested with the restriction enzyme NsiI, we determined whether digestion at the new site was shown on agarose gels stained with ethidium bromide. In some families, asymptomatic carriers with a mutant transthyretin gene were diagnosed. Genetic diagnostic testing was performed after informed consent was obtained.
The study was approved by The Research Ethical Committee of the Department of Neurology, Nagoya University School of Medicine.
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Results |
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Clinical features
The clinical features of the probands in the 35 families are summarized in Table 1
. The age of onset was 52–80 years (mean ± SD, 62.7 ± 6.6); subjects included 32 men and three women (male-to-female ratio, 10.7 : 1). Initial symptoms were paraesthesias, usually bilateral in the distal portion of the leg (30 patients), and weakness in distal leg muscles (five patients). Heart failure due to cardiomyopathy occurred in one patient. Autonomic dysfunction was not observed as an initial symptom. The duration of illness from onset to study ranged from 0.5 to 10 years, and neurological assessment was performed during this period. When studied, all patients were ambulatory. Cranial nerve defects including difficulty in swallowing, dysarthria, atrophy and fasciculation of the tongue were only seen in five patients. Muscular weakness and atrophy were noted in the upper and lower limbs from a mild to moderate degree, in a distally accentuated manner. In most patients, muscular wasting was more severe in the lower limbs than in the upper limbs. Somatic sensory impairment was distributed in the pattern of a symmetric polyneuropathy for pain and touch sensation as well as vibration and joint position sense. In most patients, sensory involvement was similar for superficial and deep sensory modalities. Dissociation of sensory impairment between modalities was not prominent, nor did painless burns occur in the areas of impaired sensation. Deep tendon reflexes were diffusely absent in all patients.
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Most patients did not complain of autonomic symptoms in the initial phase. Orthostatic hypotension was present in 18 of the 35 patients, but syncopal attacks occurred in three patients. Mild to moderate alternation of diarrhoea and constipation was noted in 13 patients, and mild to moderate disturbances of urination (mainly hesitancy) were present in 15 patients. Decreased sweating, particularly in the legs, was observed in 19 patients. Sexual impotence was encountered in 17 out of 23 male patients assessed. These autonomic symptoms generally were mild to moderate in severity, and did not substantially affect the quality or level of activity of the patient's daily life, except in three patients (patients 22, 26, 35), who had syncopal attacks.
Motor nerve conduction velocity in the median nerves was slowed (range 14–54 m/s; mean ± SD, 40.5 ± 9.7), and the distal latency was prolonged (range 3.1–10 ms; mean ± SD, 5.3 ± 2.2). The amplitude of compound muscle action potentials was significantly but variably diminished (range 0.3–6.5 mV; mean ± SD, 2.2 ± 1.8). In the tibial nerves, compound muscle action potentials were diminished (range 0.04–1.9 mV; mean ± SD, 0.4 ± 0.6) when successfully recorded, and no compound muscle action potentials could be elicited in 11 patients. Slowing of the motor nerve conduction velocity (range 22–43 m/s; mean ± SD, 35.2 ± 5.5) and prolonged distal latency (range 5.4–13.6 ms; mean ± SD, 7.3 ± 2.9) were observed when potentials were recorded. Sensory nerve action potentials were not elicited in the median nerves in 13 patients. Sensory conduction velocity was slowed (range 34–56 m/s; mean ± SD, 44.6 ± 8.4) in the remainder. Sensory nerve action potentials were not elicited in the sural nerves except in three patients, who showed slowing (range 33–48 m/s) and low sensory nerve action potential (range 0.6–2 µV). Denervation potentials were detected widely by needle EMG.
The protein content of the CSF was moderately elevated in 10 patients (47–148 mg/dl). CT, MRI and routine blood and urine test results were essentially normal in most patients. Subsequently, one patient developed metastasis of lung cancer to the cerebellum, which was diagnosed by MRI.
Genetic background and family history
The probands proved to have symptomatic siblings in 11 out of 35 families (Table 2). The other 24 probands did not have siblings with manifestations and appeared to have a sporadic occurrence of the mutation. The ages of onset in symptomatic siblings were late in life, between 51 and 85 years, except in two siblings, who were 30 and 40 years old. An extreme male preponderance (19 : 6) was noted, as among the probands. The initial symptoms in affected siblings were sensory, such as paraesthesias in the lower legs. No dissociation of impairments by sensory modality was apparent in their sensory examinations. Autonomic nervous dysfunction symptoms did not represent a major complaint in symptomatic siblings which was similar to the situation with probands. Thirty-six asymptomatic carriers were detected in 21 families by DNA analysis. Most of the cases of asymptomatic carriers with TTR Met30 were only assessed by bedside neurological examinations and interview. In a few cases, a nerve conduction study was carried out, and the results were normal. These carriers showed a female preponderance (13 : 23), in contrast to the symptomatic siblings and probands; 18 of the 36 carriers were at least 50 years or older. These features of symptomatic siblings, asymptomatic carriers, and probands indicate that late onset, extreme male preponderance, and mild autonomic symptoms are common among patients in a late-onset FAP TTR Met30 family, and female preponderance is the rule among asymptomatic carriers. The 35 families presented in this study were distributed widely across Japan (Fig. 1). Kinship with families in Arao City in Kumamoto Prefecture or in Ogawa Village in Nagano Prefecture, two large FAP TTR Met30 foci in Japan, was assessed for at least the two generations preceding the probands, but no such relationship was evident in any of the 35 families.
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Pathology of the peripheral nervous system
Sural nerve biopsy findings
In the 20 sural nerve biopsy specimens, myelinated fibres were severely diminished (range 79–3466/mm; mean ± SD, 929.9 ± 937.3). Unmyelinated fibre density also was diminished (range 701–16 757/mm; mean ± SD, 7391.8 ± 5165.0), but showed better preservation than myelinated fibres. In teased-fibre preparations, axonal degeneration was predominant (range 11–37%; mean ± SD, 21.9 ± 8.4) and only mild segmental demyelination and remyelination (range 0–19%; mean ± SD, 7.6 ± 6.3) was seen in some patients. The Schwann cell population was increased in number. Amyloid deposits were assessed using the Congo red stain and immunohistochemistry for human transthyretin, and was only detected in 18 patients to a minimal or mild degree in the endoneurium of the sural nerves, either associated or unassociated with the endoneurial capillaries (Fig. 2
). These amyloid deposits were extremely limited, particularly when compared with those at autopsy in proximal peripheral nerve trunks, such as the sciatic nerves (Fig. 2). Amorphous material present in the endoneurium that as not stained by Congo red, was stained by the anti-human transthyretin antibody.
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Autopsy findings
Spinal motor neurons were well preserved in number, but most showed central chromatolysis. Myelinated fibre loss in the dorsal columns of the spinal cord was seen particularly in the fasciculus gracilis, but was minimal in all three patients. Multiple nodular proliferations of Schwann cells resembling Schwannoma were observed in the ventral sulcus or in the central grey matter of the thoracic spinal cord in two patients. Neuronal loss was evident in the dorsal root ganglia and in the sympathetic ganglia, but was only mild to moderate (Table 3
; Fig. 2
). Residual nodules of Nageotte were seen frequently, particularly in dorsal root ganglia. Mild to moderate amyloid deposits were noted in dorsal root ganglia and sympathetic ganglia (Table 3; Fig. 2). Myelinated fibre loss was mild in the segmental nerves and was only minimal in the ventral and dorsal spinal roots, but was prominent in the sciatic, tibial and sural nerves (Table 3). Myelinated fibre loss with distal accentuation was seen in peripheral nerve trunks and clusters of myelinated fibres of nerve sprouts were present throughout these trunks. The Schwann cell population was increased, and cytoplasmic process formation was prominent. Amyloid deposits were prominent in the endoneurium of proximal nerve trunks such as the sciatic and tibial nerves, but they were minimal or few in the spinal nerve roots and sural nerves (Table 3; Fig. 2). They were frequently associated with endoneurial capillaries. Amorphous material that was not stained by Congo red but was immunoreactive for human transthyretin were present in the endoneurium throughout the nerve trunks. Cellular infiltrates were not observed.
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The central nervous system was essentially intact except that a small cell carcinoma of the lung had metastasized to the cerebellum in one patient.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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The clinical features of late-onset FAP TTR Met30, which had clinical onset at age 50 or later and was unrelated to endemic foci in Japan, included a marked male preponderance, sensorimotor complaints in the legs as an initial symptom, essentially parallel involvement of superficial and deep sensation without sensory dissociation, mild autonomic dysfunction not interfering with activities of daily living of most patients, and little family history of symptomatic siblings. These features resemble those of chronic, sporadic somatic sensorimotor neuropathy of late onset. Before availability of molecular diagnosis, these patients frequently were misdiagnosed with chronic inflammatory demyelinating polyradiculoneuropathy or polyneuropathy of undetermined cause (Ando et al., 1993
). Corticosteroid therapy had been administered to some patients in the present series under a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy. The late-onset patients resided in many parts of Japan, as opposed to the two major foci of early-onset FAP TTR Met30 in Arao City and Ogawa Village. Moreover, the ancestors of the siblings were not related to FAP TTR Met30 families in these two Japanese endemic foci. The clinical features of late-onset FAP TTR Met30 differ strikingly from those of early-onset FAP TTR Met30, which occurs in one of the endemic foci (Table 4). Early-onset FAP TTR Met30 generally manifests by a superficial loss of pain sensation leading to painless burns or skin ulcers, early autonomic dysfunction such as alternating diarrhoea and constipation or syncopal attacks due to orthostatic hypotension or A–V (atrioventricular) conduction block (Andrade, 1952; Araki et al., 1968; Ikeda et al., 1987; Sobue et al., 1990; Ando et al., 1992; Alves et al., 1997). All of these symptoms critically disturb the quality and activities of patients' daily lives (Andrade, 1952; Araki et al., 1968; Coutinho et al., 1980; Ikeda et al., 1987; Sobue et al., 1990).
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The penetrance rate of early-onset FAP TTR Met30 is very high, representing an essentially completely penetrant autosomal dominant trait. Male preponderance in early-onset FAP TTR Met30 in endemic foci (up to 1.7 : 1) is much less striking than in late-onset FAP TTR Met30 (10.7 : 1 in proband cases). In contrast, the sex ratio in asymptomatic carriers detected late in life in late-onset FAP TTR Met30 families showed an extreme female preponderance. Some non-genetic factors specific to females, such as hormonal milieu, might suppress clinical onset of FAP TTR Met30 more effectively in the late-onset form.
The peripheral nerve pathology of the two onset-defined forms of FAP TTR Met30 includes both similarities and differences. In late-onset FAP TTR Met30, neuronal loss in sensory and sympathetic ganglia occurred, as well as a length-dependent, distally accentuated axonal loss. Amyloid deposition was prominent in proximal nerve trunks and mild in the sural nerves and spinal nerve roots. The spatial distribution pattern of neuronal and fibre loss as well as amyloid deposition in the peripheral nervous system in late-onset FAP TTR Met30 closely resembled that in early-onset FAP TTR Met30 (Said et al., 1984; Hanyu et al., 1989; Sobue et al., 1990; Takahashi et al., 1991, 1997), but the pathology differed in severity between these two conditions. Sensory and sympathetic neuronal loss was mild in dorsal root ganglia and sympathetic ganglia, and the amount of amyloid deposition in these ganglia was also rather small in late-onset compared with early-onset FAP TTR Met30, as documented in our previous study and in other reports (Hofer et al., 1975; Yamada et al., 1984; Ikeda et al., 1987; Hanyu et al., 1989; Sobue et al., 1990; Takahashi et al., 1991). Myelinated fibre loss involving distal portions of long axons such as those of sural nerves was as severe in late- as in early-onset FAP TTR Met30 (Ikeda et al., 1987; Hanyu et al., 1989; Sobue et al., 1990; Takahashi et al., 1991), but in the late-onset form, unmyelinated fibre loss was milder than myelinated fibre loss, even in the sural nerves. Thus, although the process of amyloid deposition and subsequent axonal and neuronal loss is indistiguishable between the early-onset and late-onset FAP TTR Met30 groups, the pathological extent of severe involvement is less in late- than early-onset FAP TTR Met30. This difference correlates well with the differences in the severity of clinical symptoms particularly of autonomic symptoms, which are milder in late-onset FAP TTR Met30. Takahashi and colleagues have reported that in autopsy cases with late-onset FAP TTR Met30, amyloid deposition was marked in the heart, kidney and thyroid, but was slight to moderate in the peripheral nervous system, including autonomic pathways (Takahashi et al., 1997), in agreement with our present pathological findings.
The question arises as to whether differences in pathological involvement between early- and late-onset FAP TTR Met30 result from a difference in the mechanism underlying amyloid deposition or simply from a difference in the duration of the disease process; all three of our patients with late-onset FAP TTR Met30 studied at autopsy had a relatively short disease duration from onset (4–10 years). This issue should be addressed further by assessing the findings according to the disease duration in further selected autopsy cases. However, relatively mild pathological and clinical involvement in late-onset FAP TTR Met30, even at the autopsy stage, may support the view that late-onset FAP TTR Met30 is clinicopathologically distinguishable from early-onset FAP TTR Met30 and should be considered as a distinct clinicopathological condition.
Another important issue is the identification of factors determining the contrasting clinicopathological manifestations among the FAP TTR Met30 cases with the same Met30 transthyretin mutation. Symptomatic siblings in our late-onset FAP TTR Met30 families generally had late onset of symptoms resembling those in the probands. Furthermore, most asymptomatic carriers in their families were identified late in life. Such familial clustering of relatively old symptomatic siblings and asymptomatic carriers in a late-onset family suggests the presence of a haplotype background differing between the late-onset and early-onset FAP TTR Met30 families and capable of influencing gene expression or tissue deposition of mutant transthyretin. FAP TTR Met30 patients with Met30 in Swedish endemic foci have been reported to have a relatively late onset and relatively mild clinical manifestations, as well as a low rate of penetrance (Andersson, 1976; Benson and Cohen, 1977; Drugge, 1993; Sousa et al., 1993); their clinical features are also dissimilar to those of Japanese early-onset FAP TTR Met30 patients in endemic foci (Araki et al., 1968; Ikeda et al., 1987). On the other hand, age of onset and phenotype of patients in an endemic area in Portugal with Met30 are similar to those of early-onset FAP TTR Met30 patients in Japan (Andrade, 1952; Coutinho et al., 1980; Sousa et al., 1995). These phenotypic similarities and dissimilarities of FAP TTR Met30 cases involving the same transthyretin mutation in different ethnic populations also appear to reflect different genetic backgrounds. Interestingly, Portuguese FAP TTR Met30 patients whose parents are both unaffected show a tendency toward a later onset and a somewhat atypical geographical distribution, suggesting that the FAP gene may have a lower expression in certain families (Coelho et al., 1994). For elucidation of the genetic background of these phenotypic differences, the late- and early-onset FAP TTR Met30 families with similar ethnic backgrounds in the Japanese population would be an effective model for haplotype analysis.
Another possible explanation for these phenotypic differences involves environmental factors. Discordant phenotypic expression of FAP TTR Met30 in monozygotic twins supports this view (Holmgren et al., 1997). Transgenic mice carrying the human mutant transthyretin gene express the phenotype of amyloid deposition in non-neural organs (Yi et al., 1991; Araki et al., 1994; Kohno et al., 1997) but not in peripheral nerves (Yi et al., 1991; Araki et al., 1994). In these transgenic mice, amyloid deposition was observed in different organs at different times in the course of the experimental disorder, despite a consistently high plasma level of mutant transthyretin (Yi et al., 1991; Takaoka et al., 1997). These results suggest that environmental factors unrelated to the mutant gene are involved in the distribution and timing of amyloid deposition in each organ. When these transgenic mice are maintained under germ-free conditions, amyloid deposition is significantly inhibited, suggesting that external environmental conditions can influence phenotypic expression. A feminized environment in terms of gonadal factors may also influence phenotypic expression, particularly in late-onset FAP TTR Met30, as mentioned above. Proteins binding to transthyretin such as T4 (thyroxine) (Kohno et al., 1997) or retinol-binding protein (Kohno et al., 1997), as well as oxidative stress in tissues (Ando et al., 1997), may modify amyloid deposition. Recently, post-translational modification of the transthyretin protein has been suggested as a factor in determining tissue amyloid deposition (Suhr et al., 1998), specifically the ratio of the free form to the cysteineylated form of transthyretin in plasma (Ando et al., 1998). Many environmental and genetic factors could also influence these binding protein expression levels. The factors differentiating phenotypic expression among ethnic Portuguese, Swedish and Japanese populations could be at least partly environmental. Elucidation of factors influencing age of onset and phenotype is important in devising an optimally effective therapeutic approach for FAP TTR Met30 capable of ameliorating symptoms or delaying onset.
As we found in the present study, the wide geographical distribution of cases and the difficulty of correct diagnosis without genetic testing suggest that late-onset FAP TTR Met30 is more prevalent in Japan and elsewhere than is generally believed. The early-onset form is considered to be the prototype of FAP TTR Met30. However, although further studies should be performed with respect to haplotype and environmental factors, one might speculate that late-onset FAP TTR Met30 with low penetrance may have been the original form of this Met30 transthyretin mutation. Unknown genetic or environmental factors might have induced an early-onset form with a high penetrance rate in two large endemic foci in Japan. Anticipation of the age of onset observed in the FAP TTR Met30 families in two endemic foci in Japan (Tashima et al., 1995; Yamamoto et al., 1998) would relate to this speculation.
In summary, a distinctive type of FAP TTR Met30 with a late onset exists in Japan. This form is a clinicopathologically mild, somatic sensorimotor neuropathy. Often occurring sporadically, it has a wide distribution throughout Japan that is unrelated to the two endemic foci. A genetic difference is likely to separate the late-onset group from early-onset families, but environmental factors should also be considered.
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Acknowledgments |
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We wish to thank Drs J. Fujitake, MD (Department of Neurology, Kyoto City Hospital, Kyoto); K. Matsushima, MD (Department of Neurology, Tokai University School of Medicine, Kanagawa); T. Mitomi, MD (Department of Internal Medicine, Kitasato University School of Medicine, Kanagawa); M. Tateyama, MD (Department of Neurology, Tohoku University School of Medicine, Miyagi); K. Ichikawa, MD (Department of Neurology, Hyogo Prefectural Hospital, Hyogo); H. Tanaka, MD (Department of Neurology, Neurological Institute, Kyushu University, Fukuoka); K. Matsumoto, MD (Department of Internal Medicine, Konan Hospital, Hyogo); H. Aii, MD (Department of Neurology, Hamamatsu Rosai Hospital, Shizuoka); K. Saito, MD (Department of Neurology, Okazaki Municipal Hospital, Aichi); M. Hashizume, MD, Y. Suzuki, MD, M. Sugiura, MD (Department of Neurology, Anjô Kôsei Hospital, Aichi); I. Aiba, MD (Department of Neurology, Higashi Nagoya National Hospital, Aichi); T. Umemura, MD, T. Sakakibara, MD (Department of Neurology, Chubu Rousai Hospital, Aichi); and E. Mukai, MD (Department of Neurology, Nagoya National Hospital, Aichi) for the provision of clinical and sural nerve biopsy data. This study was supported by grants from the Ministry of Health and Welfare of Japan, and a COE (Center of Excellence) grant of the Ministry of Education, Science, Sports and Culture of Japan.
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Received December 15, 1998. Revised April 2, 1999. Accepted May 10, 1999.
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