Amyloidosis, Finnish Type

A number sign (#) is used with this entry because the Finnish type of amyloidosis is caused by mutation in the gelsolin gene (GSN; 137350).

See also corneal lattice dystrophy due to local amyloid deposition (122200), which occurs as an isolated dominant.

Description

The Finnish type of systemic amyloidosis is characterized clinically by a unique constellation of features including corneal lattice dystrophy, and cranial neuropathy, bulbar signs, and skin changes. Some patients may develop peripheral neuropathy and renal failure. The disorder is usually inherited in an autosomal dominant pattern; however, homozygotes with a more severe phenotype have also been reported (Meretoja, 1973).

Clinical Features

In a massive investigation in Finland, Meretoja (1973) identified 207 affected persons. Two patients, whose parents were affected and who were more severely affected than the others, were thought to represent homozygosity. A few of the patients developed nephrotic syndrome and renal failure and some had cardiac involvement. Amyloid involvement was rather widespread at autopsy. Meretoja et al. (1978) collected 307 patients in Finland.

Three Czechoslovakian sisters with bulbar palsy, 'cutis hyperelastica,' and lattice dystrophy of the cornea, reported by Klaus et al. (1959), may have had this disorder. Cases were reported from the United States by Sack et al. (1981), Purcell et al. (1983), Darras et al. (1986), and Starck et al. (1991); from Holland by Winkelman et al. (1971); and from Denmark by Boysen et al. (1979).

One of the patients reported by Sack et al. (1981) had onset of facial paralysis, which began as inability to control a drooping lower lip, at the age of about 56; the lip became strikingly protuberant and everted with exposure of the lower gingival mucosa. Five years after onset he could not wrinkle his forehead and there was an intermittent twitch of the right side of the lower lip. The extraocular muscles were affected only minimally and there was no ptosis. A striking feature was laxity of the skin, which raised the question of cutis laxa. Slit-lamp examination showed a lattice type of corneal opacity bilaterally. The mother had the identical disorder beginning at about the same stage of life. The proband had bulbar manifestations.

Kiuru (1992) reported the clinical findings of 30 patients. Signs of cranial neuropathy especially affecting the facial nerve were found in all, and peripheral polyneuropathy mainly affecting vibration and touch senses was demonstrated in 26 patients. Kiuru et al. (1994) studied the autonomic nervous system and heart in 30 patients. Minor autonomic nervous system dysfunction was found in most patients, but clinically significant autonomic dysfunction or cardiopathy was not characteristic.

Molecular Genetics

Maury et al. (1990) studied amyloid fibrils isolated from the kidney of a patient with the Finnish form. The amino acid sequence determined for part of the protein was identical to that deduced for plasma gelsolin in the region of amino acids 235-269. Using PCR and allele-specific oligonucleotide hybridization analysis of genomic DNA in patients with this disorder, Maury et al. (1990) identified a 654G-A transition in the GSN gene, resulting in an asp187-to-asn substitution (137350.0001), in all 5 unrelated patients studied, but not in 45 unrelated control subjects.

Haltia et al. (1990) likewise showed that the amyloid in this disorder is antigenically and structurally related to gelsolin. The same mutation in gelsolin (asp187-to-asn) has been found in all Finnish families studied to date (Maury et al., 1990; Paunio et al., 1992; de la Chapelle et al., 1992; Haltia et al., 1992; Sipila and Aula (2002)); furthermore, it was found also in the affected son of the proband of the Scottish-American family reported by Sack et al. (1981); see de la Chapelle et al. (1992).

Maury (1993) reported the findings in 2 sisters who were homozygous for the asp187-to-asn mutation in gelsolin. In both, the disease was unusually severe, manifesting with nephrotic syndrome and end-stage renal failure. Immunohistochemical studies of the kidneys demonstrated heavy glomerular deposits of gelsolin-derived amyloid. Immunostaining also demonstrated gelsolin in the tubular epithelium, where it was Congo-red negative.

Akiya et al. (1996) reported a Japanese brother and half-sister with lattice corneal dystrophy as part of the Finnish type amyloidosis. They referred to the Finnish-type as FAP type IV. The patients were 70 and 68 years old, respectively.