Clinicopathologic and genetic features of early- and late-onset FAP type I (FAP ATTR Val30Met) in Japan.

Type I (transthyretin Val30Met) familial amyloid polyneuropathy (FAP ATTR Val30Met) has been reported in relation to two endemic foci in Japan. These cases are characterized by a relatively young age at onset, between the second and third decade, high penetrance rate, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction, and atrioventricular nodal block requiring pacemaker implantation. In contrast to these endemic cases, because of advances in DNA diagnosis, late-onset cases of FAP ATTR Val30Met with symptoms appearing at or over 50 years of age are now recognized to occur widely throughout Japan. These cases have a male preponderance, low penetrance rate, no relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms. This type of FAP ATTR Val30Met has been overlooked because its clinical and genetic features differ from those of "typical" early-onset cases. Anticipation of age at onset is known to occur in pedigrees from the two endemic foci in Japan, with age at onset becoming younger in patients of successive generations. On the other hand, age at onset of patients in late-onset families seems to be uniformly late among the patient siblings when family history is present. Pathologic findings of the peripheral nervous system also differ in accordance with differences of clinical features. Loss of dorsal root and sympathetic ganglion neurons was severe in the early-onset cases, whereas it was only mild to moderate in the late-onset cases. Unmyelinated fibers in the biopsied sural nerve specimens of late-onset cases seemed to be relatively well preserved compared to those of previously reported early-onset cases.