Familial amyloid polyneuropathy type IV (Finnish type)--a clinicopathological study

Experimental observations on rat glomerulosa cells inspired a model which postulates that plasmalemmal dihydropyridine receptors are in juxtaposition and interaction with inositol 1,4,5-trisphosphate receptors in subplasmalemmal calciosomes. Activation of dihydropyridine receptors promotes the Ca2+ releasing effect of inositol 1,4,5-trisphosphate. The most important observations compatible with the model are the following: (1) angiotensin II does not influence Ca2+ influx during the peak phase of Ca2+ signal; (2) dihydropyridine drugs modify the initial peak of the Ca2+ signal induced by angiotensin II; (3) inhibitors of the dihydropyridine receptor reduce the initial Ca2+ signal also in the presence of 5 mM Ni2+, an inhibitor of voltage dependent Ca2+ influx; and (4) changes in extracellular K+ concentration within the physiological range also modify the cytoplasmic Ca2+ response to angiotensin II.     

Domino hepatic transplantation using the liver from a patient with familial amyloid polyneuropathy

BACKGROUND: In transplantation, novel methods are required to augment the supply of donor organs. We report the first domino liver transplant in which a patient with familial amyloid polyneuropathy (FAP) received an orthotopic split liver graft, and her explanted liver was donated to another patient. Three successful liver transplants were thus achieved from the one cadaver liver. PATIENTS AND METHODS: A cadaveric donor liver was split and the left lobe was grafted into a child with biliary atresia. The right lobe was transplanted into a woman with FAP associated with the transthyretin Met30 variant. Her own otherwise healthy liver was donated to a patient with cirrhosis and hepatocellular carcinoma. RESULTS: Fifteen months after transplantation, all three recipients are well with normal liver function. The domino recipient developed inferior vena cava stricturing at the level of anastomosis after surgery with resultant ascites, requiring dilatation and LeVeen shunt insertion. Serum amyloid P component scintigraphy showed amyloid regression in the domino donor and to date has not identified any amyloid deposits in the recipient, who also remains free of tumor recurrence. CONCLUSIONS: Domino transplantation using the livers from patients with FAP may be justified for patients whose disease condition precludes a long spell on the waiting list, including those with hepatic malignancies and those for whom palliation rather than long-term cure is the aim.     

Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation

Familial amyloid polyneuropathy (FAP) associated with transthyretin (TTR) mutations is the commonest type of hereditary amyloidosis. Plasma TTR is produced almost exclusively in the liver and orthotopic liver transplantation is the only available treatment, although the clinical outcome varies. Serum amyloid P component (SAP) scintigraphy is a method for identifying and quantitatively monitoring amyloid deposits in vivo, but it has not previously been used to study the outcome of visceral amyloid deposits in FAP following liver transplantation. Whole body scintigraphy following injection of iodine-123 labelled SAP was performed in 17 patients with FAP associated with TTR Met30 and in five asymptomatic gene carriers. Follow-up studies were performed in ten patients, eight of whom had undergone orthotopic liver transplantation 1-5 years beforehand. There was abnormal uptake of 123I-SAP in all FAP patients, including the kidneys in each case, the spleen in five cases and the adrenal glands in three cases. Renal amyloid deposits were also present in three of the asymptomatic carriers. Follow-up studies 1-5 years after liver transplantation showed that there had been substantial regression of the visceral amyloid deposits in two patients and modest improvement in three cases. The amyloid deposits were unchanged in two patients. In conclusion, 123I-SAP scintigraphy identified unsuspected visceral amyloid in each patient with FAP due to TTR Met30. The universal presence of renal amyloid probably underlies the high frequency of renal failure that occurs in FAP following liver transplantation. The variable capacity of patients to mobilise amyloid deposits following liver transplantation may contribute to their long-term clinical outcome.     

Case of familial amyloid polyneuropathy discovered at the development of hematemesis

In a retrospective study we analyzed clinical features and their prognostic significance in 72 patients with onset of multiple sclerosis by the age of 21 years. In juvenile multiple sclerosis disease progression does not depend on age of onset, severity of neurologic involvement, or polysymptomatic or monosymptomatic involvement at presentation.     

Comparison of amyloid deposition in two lines of transgenic mouse that model familial amyloidotic polyneuropathy, type I

Aortic disease frequently requires extended and multiple resections. Occasionally, resection of the entire aorta may be indicated. At our Institution, from 1982 to 1994, 34 patients were operated upon for extended and total simultaneous aortic replacement. In seven patients, the aorta was replaced from valve to bifurcation; in 27, the aortic valve was included. Operations were performed with circulatory arrest under profound hypothermia. As the first step, the aortic valve and ascending aorta are replaced and the coronary arteries are reconnected, following which the aortic arch is reconstructed. Meanwhile, a second surgical team proceeds to open the thoracoabdominal aorta and tie up the intercostal orifices. If circulatory arrest is likely to exceed 60 minutes, the aortic graft is clamped and upper body perfusion (1000 cc/min) is begun. Finally, the thoracoabdominal aorta is fully replaced. Cardiopulmonary bypass (CPB) with rewarming is resumed only after the operation has been completed. Thirty-four patients survived operation; five died within 1 month for an overall mortality of 14.7%. No mortality occurred in the most recent nine operations. No permanent spinal neurological deficits occurred. Total simultaneous aortic replacement for treatment of extended aortic disease may be reasonable using our approach.     

Liver transplantation in familial amyloid polyneuropathy. Case report and review of the literature

A 59-year old male of German origin noticed exercise-independent cardiac arrhythmia two years before admission. An alanine 47 transthyretin variant of Familial Amyloid Polyneuropathy with hypertrophic cardiomyopathy, peripheral sensory-motor polyneuropathy, I, degree AV heart block was diagnosed. To diminish production and deposition of mutant transthyretin and to prevent disease progression orthotopic liver transplantation was performed. Prior to transplant the patient complained of inappetence. Postoperatively, he received a chemically defined enteral nutrition regime that was discontinued after 30 months until return of appetite and weight gain indicated marked improvement. However, a duodenal biopsy still demonstrated amyloid deposits 24 months after transplantation. Echocardiographic findings remained unchanged. Neurologic examination showed an improvement of sensory-motor polyneuropathy with regression of electromyographic changes. Only traces of variant transthyretin were detectable in plasma samples taken 12 months after the operation. During the 3 year follow-up, no additional symptoms have occurred and progression of amyloidosis was prevented. Currently, orthotopic liver transplantation is the only specific treatment to prevent progression of familial amyloid polyneuropathy.     

Analysis of amyloid deposition in a transgenic mouse model of homozygous familial amyloidotic polyneuropathy

Amyloid fibrils derived from the Japanese, Portuguese, and Swedish types of familial amyloidotic polyneuropathy all consist of a variant transthyretin (TTR) with a substitution of methionine for valine at position 30 (TTR Met 30). In an attempt to establish an animal model of TTR Met-30-associated homozygous familial amyloidotic polyneuropathy and to study the structural and functional properties of human TTR Met 30, we generated a mouse line carrying a null mutation at the endogenous ttr locus (ttr-/-) and the human mutant ttr gene (6.0-hMet 30) as a transgene. In these mice, human TTR Met-30-derived amyloid deposits were first observed in the esophagus and stomach when the mice were 11 months of age. With advancing age, amyloid deposits extended to various other tissues. Because no significant difference was detected in the onset, progression, and tissue distribution of amyloid deposition between the ttr-/- and ttr+/+ transgenic mice expressing 6.0-hMet 30, endogenous normal mouse TTR probably does not affect the deposition of human TTR Met-30-derived amyloid in mice. TTR is a tetramer composed of four identical subunits that binds thyroxine (T4) and plasma retinol-binding protein. The introduction of 6.0-hMet 30 into the ttr-/- mice significantly increased their depressed serum levels of T4 and retinol-binding protein, suggesting that human TTR Met 30 binds T4 and retinol-binding protein in vivo. The T4-binding ability of human TTR Met 30 was confirmed by the analysis of T4-binding proteins in the sera of ttr-/- transgenic mice expressing 6.0-hMet 30. The T4-binding studies also demonstrated the presence of hybrid tetramers between mouse and human TTR subunits in the ttr+/+ transgenic mice expressing 6.0-hMet 30.     

Palmar spiny keratoderma associated with type IV hyperlipoproteinemia

Long-term hypokinesia is accompanied by changes in the activity of Mg(2+) and 2,4-dinitrophenol (DNP)-stimulated ATPases of rat brain and liver mitochondria. These changes are phasic and especially pronounced at periods characterised by most pronounced metabolic alterations Treatment of animals with GABA and piracetam tends to normalise the enzyme activities.     

Association of keratoconus with granular corneal dystrophy

A 23-year-old woman presented with a history of reduced vision and foreign body sensation in both her eyes. Ocular examination revealed the simultaneous presence of bilateral keratoconus and granular corneal dystrophy. To our knowledge, bilateral concurrent occurrence of keratoconus and typical granular corneal dystrophy has not been reported previously. In such a case, penetrating keratoplasty performed for keratoconus may also carry the risk of recurrence of the granular dystrophy.     

Chronic inflammatory demyelinating polyneuropathy associated with carcinoma

BACKGROUND: Restenosis after carotid endarterectomy is a dynamic process likely influenced by surgical technique as well as by anatomic, hemodynamic, and patient factors. METHODS: To characterize the healing of carotid endarterectomy sites, intraoperative and serial postoperative color duplex scans were performed in 126 patients (136 repairs). Vessel-wall imaging, midstream spectral analysis, and measurements of diameter and cross-sectional area from common carotid artery (CCA) and internal carotid artery (ICA) segments were compared (at 3, 6, 15, and 30 months) and severity of lumen stenosis was determined. RESULTS: After primary closure (n = 15), patch angioplasty (n = 121), or intraoperative revision based on duplex scanning (n = 5), 12 repairs had mild residual flow abnormalities and 1 repair had a moderate flow abnormality. Mean ICA bulb diameter was greater in patched repairs (0.81 cm, range 0.6 to 1.1 cm) than primary closed repairs (0.7 cm, range 0.45 to 0.8 cm). No ICA occluded during follow-up (mean 24 months), and three repairs, two in the ICA and one in the CCA, demonstrated 50% to 75% diameter reduction at 9 months. Lumen cross-sectional area of vein-patched repairs increased 0.6 cm2 to 0.76 cm2 (P < 0.01) in the ICA and 0.69 cm2 to 1.1 cm2 (P < 0.01) in the CCA segments by 3 months compared with intraoperative measurement. Four patients with progressive dilatation of the patch segment to a mean of 1.77 cm2 developed asymptomatic posterior wall mural thrombus. Postoperative blood flow velocities measured through the repair were similar to intraoperative values. Minor intraoperative hemodynamic abnormalities were not associated with the development of restenosis, and changes in repair site anatomy occurred within 3 months with little change thereafter. CONCLUSIONS: We have found intraoperative scanning useful for detection of anatomic defects and associated turbulence, lesions that should be immediately corrected. Surgical technique that achieves normal intraoperative carotid flow hemodynamics and B-mode ultrasonic vessel wall appearance should predict an endarterectomized segment free of significant residual plaques and neointimal hyperplasia. Tailoring of the vein patches to achieve lumen diameters < 1 cm is recommended because of the dilataton likely to develop after surgery that may lead to vessel wall mural thrombus.     

Infantile familial cardiomyopathy due to mitochondrial complex I and IV associated deficiency

Two brothers, aged 27 and 20 months, born from consanguineous healthy parents, presented with cardiomyopathy, lactic acidosis and carnitine abnormalities in serum and muscle, without clinical evidence of muscle involvement. The histochemical reaction for cytochrome c oxidase (COX) activity was negative in all muscle fibres, although the holoenzyme and subunits were present at a normal level, as shown by immunocytochemistry. The COX activity was, respectively, 5 and 25% of control values, in muscle biopsies. Partial deficiency of complex IV was confirmed in fresh isolated muscle mitochondria from patient 2 and was associated with a defect of complex I. Patient 1 died at age 3 yr 6 months. Partial improvement of cardiomyopathy in patient 2 was obtained under carnitine therapy, but seizures occurred and CT scan and magnetic resonance imaging (MRI) revealed thalamic hypodensity. Thus, the disorder appears to be progressive despite the clinical stabilization of the cardiomyopathy. This further demonstrates the complexity and clinical heterogeneity of combined respiratory chain complex deficiencies.     

Differing haemodynamic and catecholamine responses to exercise in three groups with peripheralautonomic dysfunction: insulin-dependent diabetes mellitus, familial amyloid polyneuropathy and pure autonomic failure

BACKGROUND: The nosological status of postpartum psychoses has remained controversial because of their often 'atypical' symptomatology. A polydiagnostic approach may further clarify this issue. METHODS: In a retrospective study, we applied the ICD-10 and Leonhard's classification to 39 patients with severe postpartum psychiatric disorders. The patients were personally reexamined on average 12.5 years (6-26 years) after the onset of the illness. RESULTS: An acute onset and a polymorphous psychotic symptomatology with rapid changes characterized the majority of our cases. Unipolar depressive disorders (28%) and acute polymorphous psychotic disorders (21%) represented the largest proportions within the ICD-10-classification. Applying Leonhard's classification, over half the patients (54%) suffered from a cycloid psychosis. Among cycloid psychoses, motility psychoses clearly predominated. Schizophrenias occurred rarely (10%) according to both classifications. LIMITATIONS: Due to the unknown prevalence of the various diagnoses among women of child-bearing age, it is impossible to statistically infer a specific association between childbirth and a distinct diagnosis from our data. CONCLUSIONS: Our findings suggest that cycloid psychoses, in particular motility psychoses, account for the majority of postpartum psychoses, and do not support the hypothesis of a nosological independence of postpartum psychoses.     

Reflex sympathetic dystrophy syndrome associated with phenobarbital

Reflex sympathetic dystrophy syndrome (RSDS) is clinically characterized by pain and edema of one or more extremities, trophic skin changes and vasomotor instability. Although the pathogenesis is unknown, it could be caused by an abnormal reflex of the sympathetic nervous system. Different studies haven't yet confirmed the classical division in three clinical phases (warm, of vasomotor instability and cold). Barbiturates are the precipitating event in 10-30% of cases. We describe the clinical features of a patient with RSDS associated with phenobarbital who needed corticosteroid treatment. The Technetium diphosphate bone scan (Tc 99m DPD) is very useful because there is an increased radionuclide uptake in the involved areas during the early phases of the disease and precedes in some weeks the radiologic signs. The Magnetic Resonance Imaging (MRI) may be useful because of the early signs it shows. The patient may develop contractures and atrophy of the involved extremities in spite of the indispensable withdrawal of the drug.     

Improved orthostatic tolerance in familial amyloidotic polyneuropathy with unnatural noradrenaline precursor L-threo-3,4-dihydroxyphenylserine

Disabling orthostatic hypotension, due to insufficiency of the autonomic nervous system, is a common complication of type I familial amyloidotic polyneuropathy (FAP). We investigated whether oral treatment with L-threo-3,4-dihydroxyphenylserine (L-threo-Dops), a noradrenaline precursor, might be of therapeutical benefit. In twenty untreated FAP patients, aged 33 to 44 years, who, because of severe orthostatic hypotension, were bedridden or constrained to a sitting life, supine and erect blood pressure (BP), plasma noradrenaline and tilting time, defined as the interval (s) between the beginning of a 60 degrees head-up tilt and the occurrence of orthostatic symptoms (dizziness, blurred vision or near syncope) were determined before and at repeated intervals during oral treatment with L-threo-Dops, 100 mg bid, for 6 months. Before treatment supine mean BP was 80 (76-85) mmHg (mean and 95% CI), supine plasma noradrenaline was low, 59 (41-77) pg/ml and tilting time ranged from 38 to 118 s. In response to tilt, mean BP immediately fell by 36 (31-41) mmHg, whereas plasma noradrenaline increased by only 11 (0-21) pg/ml (p = 0.05). After 3 to 5 days of treatment with L-threo-Dops all patients experienced marked improvement of their orthostatic tolerance as reflected by their ability to walk freely around. This effect sustained throughout the six months of treatment. Plasma noradrenaline increased moderately by 37 (11-63) pg/ml (p = 0.02) and supine mean BP increased by 8.6 (5.8-12.4) mmHg (p < 0.001) during chronic treatment. Supine or nocturnal hypertension did not develop, the fall in mean BP in response to tilt diminished by 12.5 (6.5-17.3) mmHg (p < 0.001) and tilting time became longer than 600 s in all patients. Because of its efficacy, its sustained duration of action and the lack of side effects, L-threo-Dops is advocated to improve orthostatic tolerance in patients with autonomic insufficiency due to FAP.