Impact of homozygosity for an amyloidogenic transthyretin mutation on phenotype and long term outcome.

Although amyloidogenic transthyretin (ATTR) mutations are common in several populations, such as black Americans, the small number of diagnosed patients homozygous for TTR amyloid and the short follow up in most studies has until now prevented an analysis of their phenotype. In Sweden, nine homozygous patients from eight families carrying the ATTR mutation Val30Met, which gives rise to fatal neuropathic amyloidosis (FAP), have been identified and have now been followed for up to 15 years. This has enabled an analysis of the phenotype of homozygous patients. Genetic testing and detection of amyloid deposits in the vitreous body or in intestinal or skin biopsies confirmed the diagnosis in all patients. The patients' symptoms were obtained from medical records. For comparison, we used a group of 35 heterozygous non-transplanted patients with FAP (18 men and 17 women), who had been evaluated at the Department of Medicine, Umeå University Hospital before their deaths. Vitreous amyloidosis was the most prevalent symptom in the homozygous group, and in two patients it was the only manifestation of the disease during their lifetime. The age at onset was not different from that of heterozygous patients, and their survival tended not to be shorter but actually longer than for heterozygotes. Homozygosity for the mutation associated with FAP, ATTR Val30Met, does not implicate a more severe phenotype for Swedish patients. The most common symptom was vitreous opacity, which may be the only manifestation of the disease. These findings point to the possibilities of different pathways for amyloid formation, or the presence of hitherto unknown genes operating in amyloid formation.

Discordant penetrance of the trait for familial amyloidotic polyneuropathy in two pairs of monozygotic twins.

BACKGROUND: Familial amyloidotic polyneuropathy (FAP) is caused by mutated transthyretin in which valine at position 30 is substituted by methionine (ATTR Val30Met). FAP is inherited as an autosomal dominant trait with variable penetrance. CASES: Two pairs of DNA confirmed monozygotic twin brothers, 63 and 37 years of age respectively, who are heterozygous for the ATTR Val30Met gene, have been identified in Sweden. In the first twin pair (A), the onset of typical FAP symptoms occurred at the age of 48 for twin A1, whilst his twin brother (A2) is still free from FAP symptoms 13 years later. In the second pair of twins (B), the onset of polyneuropathy occurred at the age of 34 for the proband (B1), whilst his brother (B2) is healthy 3 years after the onset of his brother's disease. DISCUSSION: In the following, a detailed description of the clinical presentation of the Swedish twin pairs is provided together with a discussion of possible environmental factors initiating the onset of the disease.

Influence of load orientation on the posteroanterior stiffness of the lumbar spine.

OBJECTIVE: To compare the posteroanterior (PA) stiffness of the lumbar spine when the load is applied in a vertical direction with the stiffness when the load is applied perpendicular to the spinal curve. DESIGN: The PA stiffness of the lumbar spine was assessed at L1, L3 and L5 on 24 normal subjects using a mechanical spinal mobilization apparatus. The PA stiffness was measured when the load was applied in a vertical direction and when the load was applied perpendicular to the spinal curve at the level being tested. SETTING: A university biomechanics laboratory. DESIGN: A repeated-measures design with pseudorandomization of the order of testing. MAIN OUTCOME MEASURES: Stiffness variable derived from force-displacement curve. RESULTS: The difference in PA stiffness between the two loading conditions was small at all three levels tested. The stiffness of L5 was significantly lower when the load was applied in the vertical direction compared with the application of the load in the perpendicular direction (p = .0001). Altering the angle of inclination of PA load had no statistically significant effect on PA stiffness at L1 and L3. The mean PA stiffness of the lumbar spine increased in a caudal direction (L1 = 10.4 N/mm, L3 = 11.4 N/mm, L5 = 11.6 N/mm). CONCLUSION: The orientation of the PA load had only a small effect on the measured PA stiffness and would be unlikely to be detected during manual examination of the spine. However, changes in the orientation of the PA load may be important when considered in relation to the symptom response.