Isabel Conceição

Clinical variability in type I familial amyloid polyneuropathy (Val30Met) : Comparison between late-and early-onset cases in portugal

We compared early‐ with late‐onset cases in 86 patients with familial amyloidotic polyneuropathy type I (FAP). Among these patients, 43 presented before age 50 (early‐onset) and 43 after this age (late‐onset). Sex and geographical distribution were similar, although a family history of the disorder was more frequent in early‐onset cases. In late‐onset disease, autonomic dysfunction was less frequent, but organ involvement and severe neuropathic pain were more frequent. Neurophysiological measurements were similar. FAP is a cause of neuropathy in elderly patients, in particular in those presenting with neuropathic pain. Muscle Nerve, 2006

A new method for reproducible coil positioning in transcranial magnetic stimulation mapping

A new method is presented for mapping the motor cortex by transcranial magnetic stimulation in which the position of the stimulation coil on the scalp is measured using a 3D digitizer. The reproducibility of the method was tested by mapping 3 times the left abductor digiti minimi of 6 right-handed subjects and calculating the position of the centre of gravity (CoG), the area and volume of the individual maps. For individual maps, the coordinates of the CoG were found to be reproducible within +/-3 mm and the map areas and normalized volumes to within +/-20%, when the induced current flows anteriorly. Six more subjects were mapped to estimate interindividual variability of the position of the CoG. The methods ability to differentiate the cortical representation of two close muscles was successfully tested by mapping the flexor carpi radialis and the biceps brachii in another subject. Coordinates are given in a Cartesian frame of reference defined by the two tragi and the nasion. This feature will facilitate the comparison of results and their superposition on MR images.

Repetitive nerve stimulation in myasthenia gravis—relative sensitivity of different muscles

OBJECTIVE To correlate repetitive nerve stimulation (RNS) decrement in different muscles with the predominant clinical presentation in myasthenia gravis (MG), and to study single fibre EMG (SFEMG) sensitivity in ocular MG. METHODS Sixty-nine, untreated, consecutive patients suspected for MG were observed prospectively for a minimum of 6 months. Those who improved on medical treatment were diagnosed as MG. The others, in whom the neurophysiological studies were normal and that did not improve on medical treatment served as a control group, from which normative data for RNS and SFEMG was obtained. The MG patients were further classified in 3 subgroups according to the predominant clinical presentation: group I (ocular); group b (bulbar); and group a (axial). We performed RNS in nasalis, trapezius, anconeus, and abductor digiti minimi. All patients with ocular MG underwent jitter determination of the orbicularis oculi muscle. RESULTS Thirty-seven patients were diagnosed as MG (group I, 15; group b, 13; group a, 9). In group I, RNS was abnormal in 33% of the patients. RNS studies disclosed at least one abnormal muscle response in every patient in groups a and b. Trapezius was significantly more sensitive in group a, and anconeus and nasalis in group b (P < 0.01). Jitter was abnormal in all patients in group I, and the most sensitive parameter was an increased number of unstable pairs, 100%. CONCLUSIONS Based on these observations, we recommend that a shoulder muscle, as the trapezius, should be studied first in the limb-axial presentation of MG, and the anconeus-nasalis muscles in predominant bulbar MG. In ocular MG, RNS is not sensitive and jitter should be performed in facial muscles. SIGNIFICANCE This paper shows the unequal sensitivity of several muscles to RNS in different forms of MG.

Reduced myocardial 123-iodine metaiodobenzylguanidine uptake: a prognostic marker in familial amyloid polyneuropathy.

Background— Transthyretin familial amyloid polyneuropathy is a hereditary form of amyloidosis characterized by sensorimotor and autonomic neuropathy, cardiac conduction defects, and infiltrative cardiomyopathy. Previous studies have suggested that myocardial sympathetic denervation assessed by 123-iodine metaiodobenzylguanidine (MIBG) imaging occurs early in disease progression. However, its prognostic significance was never evaluated. We aimed to study the long-term prognostic value of myocardial sympathetic denervation detected by MIBG imaging in transthyretin familial amyloid polyneuropathy. Methods and Results— A total of 143 individuals with V30M transthyretin mutation underwent Holter, ambulatory blood pressure monitoring, echocardiography, and MIBG imaging. Time to all-cause death was compared with late heart-to-mediastinum MIBG uptake ratio (H/M; either in relation to the estimated lower limit of normal [1.60] or as a continuous variable) using Cox proportional hazards regression. Multivariable analyses were performed to test the prognostic accuracy of clinical, neurological, and cardiovascular parameters. During a median follow-up of 5.5 years, 32 (22%) patients died. Five-year mortality rate was 42% for late H/M <1.60 and 7% for late H/M ≥1.60 (hazard ratio, 7.19; P <0.001). Late H/M was identified as an independent prognostic predictor. Fifty-three patients were submitted to liver transplantation. In comparison with neurophysiological score–matched controls, transplanted patients had lower long-term mortality (hazard ratio, 0.32; P =0.012). Patients with late H/M<1.60 were at higher risk of unfavorable outcome but seemed to have benefited from liver transplantation. Conclusions— Cardiac sympathetic denervation as assessed by MIBG imaging is a useful prognostic marker in transthyretin familial amyloid polyneuropathy.Background— Transthyretin familial amyloid polyneuropathy is a hereditary form of amyloidosis characterized by sensorimotor and autonomic neuropathy, cardiac conduction defects, and infiltrative cardiomyopathy. Previous studies have suggested that myocardial sympathetic denervation assessed by 123-iodine metaiodobenzylguanidine (MIBG) imaging occurs early in disease progression. However, its prognostic significance was never evaluated. We aimed to study the long-term prognostic value of myocardial sympathetic denervation detected by MIBG imaging in transthyretin familial amyloid polyneuropathy. Methods and Results— A total of 143 individuals with V30M transthyretin mutation underwent Holter, ambulatory blood pressure monitoring, echocardiography, and MIBG imaging. Time to all-cause death was compared with late heart-to-mediastinum MIBG uptake ratio (H/M; either in relation to the estimated lower limit of normal [1.60] or as a continuous variable) using Cox proportional hazards regression. Multivariable analyses were performed to test the prognostic accuracy of clinical, neurological, and cardiovascular parameters. During a median follow-up of 5.5 years, 32 (22%) patients died. Five-year mortality rate was 42% for late H/M <1.60 and 7% for late H/M ≥1.60 (hazard ratio, 7.19; P<0.001). Late H/M was identified as an independent prognostic predictor. Fifty-three patients were submitted to liver transplantation. In comparison with neurophysiological score–matched controls, transplanted patients had lower long-term mortality (hazard ratio, 0.32; P=0.012). Patients with late H/M<1.60 were at higher risk of unfavorable outcome but seemed to have benefited from liver transplantation. Conclusions— Cardiac sympathetic denervation as assessed by MIBG imaging is a useful prognostic marker in transthyretin familial amyloid polyneuropathy.

“Red‐flag” symptom clusters in transthyretin familial amyloid polyneuropathy

Transthyretin familial amyloid polyneuropathy (TTR‐FAP) is a rare, progressive, life‐threatening, hereditary disorder caused by mutations in the transthyretin gene and characterized by extracellular deposition of transthyretin‐derived amyloid fibrils in peripheral and autonomic nerves, heart, and other organs. TTR‐FAP is frequently diagnosed late because the disease is difficult to recognize due to phenotypic heterogeneity. Based on published literature and expert opinion, symptom clusters suggesting TTR‐FAP are reviewed, and practical guidance to facilitate earlier diagnosis is provided. TTR‐FAP should be suspected if progressive peripheral sensory‐motor neuropathy is observed in combination with one or more of the following: family history of a neuropathy, autonomic dysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR‐FAP is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy, large‐ and small‐fiber assessment by nerve conduction studies and autonomic system evaluations, and cardiac testing should be performed.

DOMINANT AND RECESSIVE RYR1 MUTATIONS IN ADULTS WITH CORE LESIONS AND MILD MUSCLE SYMPTOMS

Ryanodine receptor gene (RYR1) mutations have been associated with central core disease (CCD), multiminicore/minicore/multicore disease (MmD), and susceptibility to malignant hyperthermia (MH).

Neurophysiological markers in familial amyloid polyneuropathy patients: Early changes

OBJECTIVE Familial amyloid polyneuropathy-type I (FAP-I) is a hereditary, axonal, sensory-motor and autonomic polyneuropathy, with early involvement of small fibres. Liver transplantation is the only effective therapy in FAP, but should be performed early in the course of the disease. Reliable quantitative methods that could allow the determination of early changes in the peripheral nerve function are essential. Our aim was to find sensitive neurophysiological markers in FAP-I. METHODS Eighty-one FAP-I patients were included in this study. They were divided into two groups (G1, asymptomatic FAP-I mutation carriers; G2, early symptomatic). Seventy-six healthy controls formed a control group (G3). Nerve conduction studies, needle electromyography with motor unit potential analysis of the extensor digitorum brevis, RR interval and sympathetic skin response (SSR) were analyzed. RESULTS The amplitudes of the motor response of the peroneus nerve and of the plantar SSR were significantly lower in G1 compared to G3. No other differences were found between those two groups. With a cut-off point of 0.2mV for plantar SSR, its sensitivity and specificity are 0.53 and 0.95, respectively. The positive predictive value and the negative predictive value are 0.82. CONCLUSIONS SSR response at foot is a useful measurement to detect early dysfunction of peripheral nerve fibres in FAP-I. Its abnormality should be considered a warning sign and lead to a careful clinical assessment. SIGNIFICANCE SSR is a useful neurophysiological marker in FAP-I.

Gelsolin-related familial amyloidosis, Finnish type, in a Portuguese family: clinical and neurophysiological studies.

We report a Portuguese family with familial amyloid polyneuropathy related to gelsolin. There were no known Finnish ancestors, but the same mutation as described in Finnish patients (G654A) was carried. Clinical and neurophysiological investigations were performed in four patients. Corneal lattice dystrophy affected all four patients; an axonal lesion of the facial nerve occurred in three patients; visual tract involvement was documented in one case; and corticospinal and posterior column dysfunction was present in one patient. Polarizing microscopy of skin and muscle samples demonstrated amyloid deposits in two patients; anti‐gelsolin immunohistochemistry was positive for amyloidogenic gelsolin. The Finnish mutation of gelsolin protein (G654A) was detected in five family members. The utility of neurophysiological testing in the evaluation and follow‐up of this type of amyloidosis is discussed. Muscle Nerve 28: 715–721, 2003

Acquired amyloid neuropathy in a Portuguese patient after domino liver transplantation.

Familial amyloid polyneuropathy (FAP) is a progressive neuropathy with autonomic dysfunction. Domino liver transplantation (DLT), in which the liver of an FAP patient is transplanted into another patient, is routinely applied to compensate for the shortage of available organs. We report a patient who developed a clinical picture of FAP 9 years after a DLT from an FAP donor. Electrophysiological, neuropathological, and autonomic tests were administered. The patient presented with typical clinical features of FAP. Electrophysiological investigation confirmed a moderate sensorimotor axonal and autonomic neuropathy. Sural nerve biopsy confirmed the presence of amyloid deposits in the endoneurium. Skin biopsy at the ankle showed reduced intraepidermal nerve fiber density. Our report shows that FAP can develop in a recipient of an FAP liver. This suggests that careful longitudinal study is required to evaluate the risk of FAP polyneuropathy in patients who undergo domino liver transplantation. Muscle Nerve, 2010

The diagnostic accuracy of Sudoscan in transthyretin familial amyloid polyneuropathy

OBJECTIVE Transthyretin familial amyloid polyneuropathy (TTR-FAP) is an axonal sensory-motor and autonomic neuropathy. Reliable quantification of sudomotor function could prove essential in the diagnosis and early treatment management. We aim to assess the diagnostic value of a new sudomotor test (Sudoscan) in TTR-FAP. METHODS One hundred and thirty-three TTR-FAP Val30Met carriers, divided in asymptomatic and symptomatic stage 1, were compared with 37 healthy controls. We analyzed the right sural sensory nerve action potential (SNAP), the plantar sympathetic skin response (SSR) and the electrochemical skin conductance (ESC) measured by Sudoscan in both hands and feet. RESULTS All neurophysiological measures were significantly worse in the symptomatic group. However, feet ESC was the only test distinguishing symptomatic patients with autonomic dysfunction from those without autonomic dysfunction, and both groups from asymptomatic subjects and healthy controls. Feet ESC was a significant independent predictor for the presence of symptoms and autonomic failure, after adjusting for demographic characteristics, sural SNAP and SSR amplitudes (p<0.05). Feet ESC showed 76% sensitivity and 85% specificity for detection of dysautonomia. CONCLUSION Feet ESC is a sensitive test to assess early autonomic dysfunction in TTR-FAP subjects. This investigation should be considered for routine assessment in this population. SIGNIFICANCE Abnormal feet responses on Sudoscan support early diagnosis in TTR-FAP.