Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan

Abstract

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.

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

“…Apart from these studies, patient disability has rarely been documented, especially with respect to gait disorders and overall survival, ruling out any direct statistical comparison of times to onset. This may explain discrepancies in the severity of Tyr77 and LateMet30 FAP in previous reports31, 32, 33 and in our series, in which the median times to assisted walking were longer in Tyr77 than in LateMet30 FAP.…”

“…Almost all our patients exhibited autonomic dysfunction, as previously reported. Autonomic symptoms are less severe in LateMet30 FAP, accounting less for disability than tetraparesis or cardiomyopathy, as previously reported 31, 33, 36. These differences could be explained by less abundant amyloid deposits and less severe neuron loss in sympathetic than dorsal root ganglia, as previously suggested by a histopathological study of Japanese LateMet30 FAP 36…”

Upper limb neuropathy such as carpal tunnel syndrome as an initial manifestation of ATTR Val30Met familial amyloid polyneuropathy

“…Even in patients with the same gene mutation of ATTR Val30Met the clinical feature is not uniform: ATTR Val30Met FAP patients originating from endemic foci show an autosomal dominant trait with high penetration, an early age of onset, equal sex distribution, and the presence of dissociated sensory loss and severe autonomic dysfunction. However, this classic feature of FAP is not seen in patients from sporadic kindreds, whose clinical manifestations are characterized by a late age of onset, male predominance and an obscure family history [11,12]. Concerning CTS in FAP, a family of Swiss origin living in Indiana was originally reported to start with this disorder [13] and in some patients with this form of FAP the clinical manifestations were confined to CTS even 20 or more years after onset [14].…”

Estimating the global prevalence of transthyretin familial amyloid polyneuropathy

“…Endemic to Portugal, Sweden, and specific regions of Japan,1 ATTR‐FAP has been reported in 36 countries worldwide,6 with an estimated global prevalence of 5,000–10,000 persons 7, 8. This commonly accepted prevalence range, however, does not appear to have been formally or transparently determined.…”