Lars Steen

Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30).

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder characterized by progressive peripheral and autonomic neuropathy, associated with neural and systemic amyloid deposits. The amyloid fibrils contain a variant transthyretin (TTR) molecule (TTR met30), over 90% of which is produced in the liver. After liver transplantation in two patients with severe symptomatic FAP, only normal TTR was detectable in circulation. The two patients are being monitored at regular intervals, and, although in one patient there was no evidence of reduction in the quantity of amyloid present at 6 months, there had been no further progression of the neuropathy.

Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy

Abstract. Objectives. To describe the evolution of nutritional and neurological complications in a Swedish population of patients with familial amyloidotic polyneuropathy, and to identify prognostic factors and useful tests for monitoring the progress of the disease.

Homozygosity for the transthyretin-met30-gene in two Swedish sibs with familial amyloidotic polyneuropathy

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder. Recent biochemical studies have revealed that amyloid protein in FAP of Japanese, Swedish and Portuguese origin mainly consists of a variant transthyretin (TTR) (formerly called prealbumin) with one amino acid substitution of methionine for valine at position 30. In a 56‐year‐old man with typical polyneuropathy, gastrointestinal problems and vitreous amyloid, we diagnosed homozygosity for the TTR‐met30‐gene using RFLP analysis. In a family study, a sister presented the same homozygous RFLP pattern; however, in a careful clinical investigation we were not able to demonstrate any of the typical symptoms of FAP, nor could we demonstrate amyloid deposits in a biopsy skin specimen. This is the first report of homozygosity for the TTR‐met30‐gene, and it shows that the mutation of the protein involved in amyloid formation may be necessary but is clearly not sufficient for the clinical symptoms.

Diagnosis of familial amyloidotic polyneuropathy in Sweden by RFLP analysis

Genomic DNA from 17 Swedish patients with familial amyloidotic polyneuropathy (FAP), and 50 healthy controls were tested with a cDNA transthyretin probe. In seven of the patients, FAP was not reported in either of their parents. All 50 controls showed restriction fragments of 6.6 kb and 3.2 kb after cleavage with Nsil, while the 17 FAP patients showed RFLP markers of 5.1 and 1.5 kb. These observations indicate the same methionine for valine substitution at position 30 in Swedish patients with FAP as seen in patients with FAP from Japan, Portugal and FAP‐patients of Swedish descent from USA. However, the mean onset of FAP symptoms for the 17 Swedish patients was found to be significantly later than for the patients from Japan, Portugal and USA.

Bile Acid Malabsorption Caused by Gastrointestinal Motility Dysfunction? An Investigation of Gastrointestinal Disturbances in Familial Amyloidosis with Polyneuropathy

Gastrointestinal dysfunction due to autonomous neuropathy is a complication described in various diseases such as diabetes mellitus, multiple sclerosis, and familial amyloidosis with polyneuropathy. We present the results of a prospective investigation of bile acid malabsorption in 17 patients with familial amyloidosis by means of 75Se-labelled homocholic-tauro acid (SeHCAT). The diagnosis was in all cases verified by the DNA test for mutation of transthyretin in position 30. Small-intestinal biopsy specimens were examined for deposits of amyloid, and the presence of gastric retention was evaluated by gastroscopy. In addition, the patients were investigated for bacterial overgrowth by means of the bile acid breath test (BABT). A high frequency of abnormal BABT results (44%) was encountered. However, 65% also had abnormal low SeHCAT values, indicating bile acid malabsorption. Only two patients had abnormal BABT and normal SeHCAT results, indicating bacterial contamination of the small intestine. Bile acid losses increased with the duration of gastrointestinal symptoms. Significantly lower SeHCAT values were encountered in patients with gastric retention, whereas the occurrence of amyloid deposits in small-intestinal biopsy specimens was without effect on SeHCAT retention. Bile acid malabsorption is frequently encountered in familial amyloidosis with polyneuropathy and seems to be more closely associated with gastrointestinal motility dysfunction than with amyloid deposits in the intestinal mucosa.

Impact of gastrointestinal dysfunction on survival after liver transplantation for familial amyloidotic polyneuropathy.

Liver transplantation is the only effective treatment of familial amyloidotic polyneuropathy type I (FAP). The aim of the present investigation was to identify factors at the time of submission for transplantation that had impact on survival, with special reference to gastrointestinal disturbances. All 28 liver-transplanted FAP patients evaluated at Umeå University Hospital were included in the study. A modified body mass index was used to assess nutritional status. Intestinal examinations were performed to diagnose bile acid malabsorption, gastric retention, and bacterial contamination of the small bowel. A significantly improved survival rate was found for patients in a good nutritional state (P=0.002). Peripheral neurological symptoms were unrelated to survival, whereas increased mortality was found for patients with bile acid malabsorption (P<0.05). Bacterial contamination and gastric retention were common complications of the disease. In conclusion, malabsorption and malnutrition have a profound impact on the outcome of liver transplantation for familial amyloidotic polyneuropathy.

World-wide survey of liver transplantation in patients with familial amyloidotic polyneuropathy

The First International Workshop on liver transplantation in patients with familial amyloid polyneuropathy (FAP) was held at Huddinge Hospital in Stockholm, Sweden, September 10–11, 1993. Information was presented on 64 liver transplant recipients treated at 15 centers in 10 countries. Twenty-two patients had a follow-up time of more than 12 months, the longest follow-up was 41 months. Fifty-three patients had survived the procedure, while 11 had died within 8 months after the operation. The 1 and 2 year actuarial patient survival rate was 67 per cent. In most of the 22 patients surviving more than 1 year, the neurological symptoms had stabilized and the beneficial effect was most apparent as regards symptoms from the autonomic nervous system. There was consensus among the participants at the Workshop that liver transplantation for FAP is a worthwhile procedure and that such transplantation activities should continue. Transplantation should preferably be performed before the symptoms become severe and whi...

Homozygosity for the transthyretin-Met30-gene in seven individuals with familial amyloidosis with polyneuropathy detected by restriction enzyme analysis of amplified genomic DNA sequences

Holmgren G, Bergström S, Drugge U, Lundgren E, Nording‐Sikström C, Sandgren O, Steen L. Homozygosity for the transthyretin‐Met30‐gene in seven individuals with familial amyloidosis with polyneuropathy detected by restriction enzyme analysis of amplified genomic DNA sequences. Clin Genet 1992:41:39–41.

Familial amyloidosis with polyneuropathy – Type 1 A NEUROPHYSIOLOGICAL STUDY OF PERIPHERAL NERVE FUNCTION

Twenty‐four consecutive patients with familial amyloidosis with polyneuropathy (type 1), who were at different stages of the disease were investigated. The purpose was to report the electrophysiological features and to compare them with those found in other generalized neuropathies; 12 cases were familiar and 12 cases were sporadic. The diagnosis was confirmed by examining the occurrence of amyloid substance in rectal or skin biopsies or both. Single fiber EMG with fiber density determination showed signs of collateral innervation, prominent in advanced cases, and a disturbance of neuromuscular function similar to that of progressive spinal motorneurone diseases. Action potentials from afferent fibers were not obtained in 91 % of the nerves in the lower and 49 % of the nerves in the upper extremities. When sensory or motor action potentials were obtained, the conduction velocities were normal or slightly subnormal. The neurophysiological findings indicate a symmetrical axonal degeneration, starting in the legs.

Alteration in molecular structure which results in disease: the Met-30 variant of human plasma transthyretin

The structure of a variant transthyretin has been determined by X-ray crystallography at 2.3 A resolution in order to investigate those changes which lead to amyloid formation. This variant transthyretin, in which the internal valyl residue at position 30 is replaced by methionyl, is associated with the most common form of familial amyloidotic polyneuropathy (FAP). Comparison to the known structure of the normal transthyretin tetramer shows that the bulkier methionine residue 30 which lies between the nearly orthogonal beta sheets of the dimer, results in the sheets being displaced an average of 0.4 A. The internal structure of the sheets and of the monomer-monomer interface is maintained. Such global changes may affect the metabolic properties and the tendency towards polymerization of the mutant protein. These findings may form a basis for understanding other amyloid-deposition diseases.