Sari Kiuru

Amyloid protein in familial amyloidosis (Finnish type) is homologous to gelsolin, an actin-binding protein

Familial amyloidosis, Finnish type, is clinically characterized by cranial neuropathy and lattice corneal dystrophy. It is an autosomal dominant form of systemic amyloidosis with small deposits of congophilic material occurring in most tissues, particularly in association with blood vessel walls and basement membranes. Amyloid fibrils were extracted from the kidney of patient VUO, and rabbit antiserum raised against the 12 kDa purified amyloid subunit displayed strong immunohistochemical reactivity with the amyloid deposits. The amino terminal sequence of this 12 kDa amyloid protein (ATEVPVSWESFNNGD) showed homology with gelsolin (or actin depolymerizing factor), a 93 kDa plasma protein. The amyloid peptide is a degradation product, starting at position 173, of the gelsolin molecule.

Gelsolin-related spinal and cerebral amyloid angiopathy

Gelsolin‐related amyloidosis (familial amyloidosis, Finnish type) is a rare disorder, reported worldwide in kindreds carrying a G654A or G654T gelsolin gene mutation. Facial palsy, mild peripheral neuropathy, and corneal lattice dystrophy are characteristic, but atrophic bulbar palsy, ataxia of gait, and minor cognitive impairment may occur. In histological and immunohistochemical studies of the central nervous system in 4 patients with a G654A gelsolin mutation, we found widespread spinal, cerebral, and meningeal amyloid angiopathy, with deposition of gelsolin‐related amyloid (AGel). Marked extravascular deposits occurred in the dura, spinal nerve roots, and sensory ganglia. The amyloid deposits were also variably immunoreactive for apolipoprotein E (ApoE), α1‐antichymotrypsin (α1‐ACT), and cystatin C (Cys C). Cerebral perivascular fibrinogen immunoreactivity was occasionally noted. The patients showed posterior column degeneration and diffuse loss of myelin in the centrum semiovale with perivascular accentuation. Postmortem magnetic resonance imaging, performed on 1 patient, showed white matter lesions, colocalizing with the histological abnormalities. Our study shows that deposition of AGel in the spinal and cerebral blood vessel walls, meninges, as well as spinal nerve roots and sensory ganglia is an essential feature of this form of systemic amyloidosis and may contribute to the central nervous system symptoms.Ann Neurol 1999;45:305–311

Autonomic nervous system and cardiac involvement in familial amyloidosis, Finnish type (FAF)

Familial amyloidosis, Finnish type (FAF), is a gelsolin-related inherited systemic amyloidosis. We report autonomic nervous system and cardiac findings in a study of 30 FAF patients (18 females, 12 males aged 27-74 years; mean 53.9 years). Cardiovascular reflex tests showed a significant decrease in heart rate variation in FAF patients compared with healthy controls. Orthostatic hypotension was found in 9 of 28 FAF patients, but only in 3 of 69 controls. Signs of amyloid cardiopathy were rare at clinical examination and in radio-, echocardio- and electrocardiographic examinations. Histological and immunohistochemical studies revealed amyloid deposition and immunoreactivity against the gelsolin-related FAF amyloid subunit in autonomic nervous system structures and in cardiac tissue in 3 autopsied FAF patients. The results show that minor autonomic nervous system dysfunction can be found in FAF, while clinically significant amyloid cardiopathy or autonomic neuropathy is not characteristic of this type of amyloidosis.

Gelsolin variant and β-amyloid co-occur in a case of Alzheimer's with Lewy bodies

Familial amyloidosis, Finnish type (FAF), is an autosomal dominant form of amyloidosis which is related to a point mutation in the gelsolin gene localized on chromosome 9. The mutation corresponds to codon 187 of the secreted form of gelsolin, and is expressed in the amyloid fibril at residue 15. Our original FAF patient was demented, and neuropathological analysis showed Alzheimer type brain lesions associated with both classical and cortical Lewy bodies. Furthermore, antiserum against the gelsolin-derived FAF amyloid reacted strongly with both classical and cortical Lewy bodies of this FAF patient. In preliminary experiments similar results were obtained in cases of Parkinsons disease and diffuse Lewy body disease. These observations may indicate a role for gelsolin in the pathogenesis of Parkinsons disease and related conditions.

Quantification of serum and cerebrospinal fluid gelsolin in familial amyloidosis, Finnish type (AGel)

Familial amyloidosis, Finnish type (FAF) or AGel is an autosomal dominant systemic amyloidosis, characteristic symptoms of which are progressive polyneuropathy and corneal lattice dystrophy. The amyloid in FAF patients consists of peptides of an actin modulating protein, gelsolin, with the substitution ofAsn or of Tyr for Asp187. We developed a novel competitive radioimmunoassay for gelsolin quantification in serum and CSF The serum gelsolin concentration in our patient material was significantly higher (248 μg/ml) than in the controls (179 μg/ ml) (P=0.0012). The serum gelsolin levels inpatients correlated with age (P=0.0001), whereas no age-dependency was observed in the control group. The mean CSF gelsolin concentration in patients below the age of 50 was lower (7.1 μg/ml) than in controls (10.8 μg/ml), but increased with age in the patient group (P=0.014), as did the total CSF protein (P=0.015). Immunoblotting with antibodies to gelsolin revealed one extra fragment of 60 IcDA in the serum and two extr...

CNS abnormalities in patients with familial amyloidosis, Finnish type (FAF)

Thirty-one patients with familial amyloidosis, Finnish (FAF) or Agel amyloidosis were studied for signs of central nervous system (CNS) involvement. Clinical neurological examination, conventional cerebrospinal fluid (CSF) studies and computed tomographic (CT) scanning findings were largely normal. In magnetic resonance imaging (MRI), punctate leukoencephalopathy (p<0.05), mostly frontal, and periventricular (p<0.05) and intrapontine signal hyperintensities (p<0.05) were more common in patients than in age-matched control subjects. In comparison with age-matched control subjects, the patients had prolonged central conduction in somatosensory evoked potentials (SEPs) (p<0.05), prolonged brain stem auditory evoked potentials (BAEPs) (p<0.05), and delayed P100 in pattern reversal visual evoked potentials (PVEPs) (p<0.0001). In addition, FAF patients showed mainly non-verbal abnormalities without dementia in neuropsychological testing. The results suggest minor, previously unrecognized CNS involvement in FAF.

5. Familial amyloidosis, Finnish type (FAF). Clinical, histological and amyloid protein studies

The present study revealed for the first time that this type of systemic amyloidosis leads to generalised nervous system involvement. In addition to frequent clinical and electrophysiological signs of cranial neuropathy, peripheral nerve abnormalities were often evident at physical, electrophysiological and histological examinations. The patients had more commonly signs of autonomic nervous system dysfunction in cardiovascular reflex testing than normal controls. However, the autonomic nervous system dysfunction was mild. In addition, signs of minor CNS involvement were found in these patients. Particularly, signal hyperintensities in magnetic resonance imaging of the white matter and pons and abnormal central responses in somatosensory, visual and brainstem auditory evoked potential examinations were increased compared to normal controls. Abnormalities in neuropsychological tests assessing non-verbal function were common, but dementia was not found. At present, the cause of these findings is unknown as neuropathological studies have not yet been performed for this series.