Amyloidotic polyneuropathy in a jewish family. evidence for the genetic heterogeneity of the lower limb familial amyloidotic neuropathies

Joseph Gafni, Beno Fischel, Renata Reif, Michael Yaron, Mordechai Pras

Research output: Contribution to journalArticlepeer-review


The first instance of familial amyloidotic polyneuropathy affecting a Jewish family is reported. Vitreous opacities were its presenting feature in the father at age 30 and the son at 25. Severe autonomic dysfunction and progressive peripheral neuropathy affecting initially the lower extremities soon followed. Death, suicidal in the son, occurred after seven and four years of illness. Their amyloid contained three proteins- an entire variant monomer of prealbumin, glycine replacing threonine as residue 49, and both products of its cleavage at the point of substitution.Lower limb familial amyloidotic polyneuropathy has been recorded in many families in Portugal, Sweden and Japan and occasionally in families of various ethnic stocks. This ethnic, diversity prompts consideration of genetic heterogeneity. Differentiation on a genetic basis is forestalled since all pedigrees are compatible with autosomal dominant transmission and clinical data are marred by observer variance, even regarding vitreous opacities. Nothwithstanding, an isolated British family is unique in the frequent occurrence of intractable peptic ulceration, cataracts, deafness and renal disease not attributable to amyloidosis and a striking predominance of males afflicted. Biochemically, monomeric prealbumin has been demonstrated by electrophoretic and immunologic techniques as the single protein constituent of amyloid isolated from Portuguese, Japanese and Swedish patients. The variant prealbumin of Japanese amyloid is characterised by methionine replacing valine as residue 30 and is identical to that found in plasma (but not as yet in amyloid) of affected Swedes.These limited data suggest that: (a) derivation of their amyloids from prealbumin is the biochemical common denominator of lower limb familial amyloidotic neuropathies regardless of the ethnic derivation of the afflicted; (b) to the extent that ethnic diversity reflects genetic heterogeneity, this will be demonstrable in the amyloid (and hopefully in the plasma) of the afflicted as entity-specific variant prealbumin monomers distinguished by different single amino acid substitutions; (c) on clinical and biochemical grounds, lower limp familial amyloidotic neuropathies include at least three genetic entities.In the upper limb and facial forms of familial amyloidotic polyneuropathy first recorded in Swiss and Finns respectively, the differences in their patterns of neurological disease and ocular lesions could be the result of their amyloids deriving from proteins other than prealbu.

Original languageEnglish
Pages (from-to)33-44
Number of pages12
JournalQJM - Monthly Journal of the Association of Physicians
Issue number1
StatePublished - Apr 1985
Externally publishedYes


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