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Ile68Leu transthyretin-related amyloidosis (ATTR) is known as a mainly or exclusively cardiogenic variant. We hypothesized that an accurate specialized neurological evaluation could reveal a consistent frequency of mixed phenotypes.Forty-six consecutive subjects with transthyretin (TTR) Ile68Leu (p.Ile88Leu) mutation (29 patients and 17 unaffected carriers) underwent an in-depth cardiac and neurologic evaluation at a single center.All 29 patients showed cardiac involvement. In 20 (69%) cases, it was associated with neurological abnormalities (i.e. a mixed phenotype): 10 (35% of the total) had signs and symptoms of neuropathy, 5 (17%) had abnormalities at the neurologic specialist examination but without symptoms, and 5 (17%) had abnormal nerve conduction study only. None of the asymptomatic carriers showed neurological abnormalities or cardiac involvement. The Neuropathy Impairment Score was5 in seven patients at baseline, and became5 in six more patients during follow-up. The probability of experiencing a major adverse cardiac event (MACE) during follow-up was higher in the mixed than cardiologic phenotype (At least two-thirds of patients with Ile68Leu ATTR and amyloidotic cardiomyopathy show an associated - definite or probable - neurologic impairment of variable degree if accurately evaluated in a neurologic setting. This proportion can rise during follow-up. The mixed phenotype carries a worse prognosis compared to the exclusively cardiologic one. These observations show that more patients could be eligible for treatment with gene silencers than currently indicated and highlight the need for an in-depth and continuous multidisciplinary evaluation of Ile68Leu ATTR patients.

Background Diagnostic delay of hereditary transthyretin amyloidosis (ATTRv, v for variant) prevents timely treatment and, therefore, concurs to the mortality of the disease. The aim of the present study was to explore with nerve ultrasound (US) possible red flags for early diagnosis in ATTRv patients with carpal tunnel syndrome (CTS) and/or polyneuropathy and in pre-symptomatic carriers. Methods Patients and pre-symptomatic carriers with a TTR gene mutation were enrolled from seven Italian centers. Severity of CTS was assessed with neurophysiology and clinical evaluation. Median nerve cross-section area (CSA) was measured with US in ATTRv carriers with CTS (TTR-CTS). One thousand one hundred ninety-six idiopathic CTS were used as controls. Nerve US was also performed in several nerve trunks (median, ulnar, radial, brachial plexi, tibial, peroneal, sciatic, sural) in ATTRv patients with polyneuropathy and in pre-symptomatic carriers. Results Sixty-two subjects (34 men, 28 women, mean age 59.8 years ± 12) with TTR gene mutation were recruited. With regard to CTS, while in idiopathic CTS there was a direct correlation between CTS severity and median nerve CSA (r = 0.55, p r = − 0.473). ATTRv patients with polyneuropathy showed larger CSA than pre-symptomatic carriers in several nerve sites, more pronounced at brachial plexi (p Conclusions The present study identifies nerve morphological US patterns that may help in the early diagnosis (morpho-functional dissociation of median nerve in CTS) and monitoring of pre-symptomatic TTR carriers (larger nerve CSA at proximal nerve sites, especially at brachial plexi).

Axonal polyneuropathy is the main feature of hereditary transthyretin amyloidosis (ATTRv). Nerve morphological abnormalities have been reported, but longitudinal changes have never been assessed. We performed a prospective widespread nerve ultrasound evaluation and nerve cross-sectional area (CSA) was compared with baseline data in both ATTRv patients and pre-symptomatic carriers. Thirty-eight subjects were evaluated (mean follow-up 17.1 months), among them 21 had polyneuropathy while 17 were pre-symptomatic carriers. CSA significantly increased at brachial plexus in both groups (p = 0.008 and p = 0.012) pointing to progressive brachial plexus enlargement as a longitudinal biomarker of both disease progression and disease occurrence in pre-symptomatic carriers.

Mutations in the superoxide dismutase-1 (SOD1) gene occur in some forms of familial amyotrophic lateral sclerosis (ALS). To date about 150 mutations are known to involve this gene. Here we describe a novel missense mutation in exon 5 of the SOD1 gene in an Italian family with two members affected by ALS. Sequencing of the SOD1 gene was performed on 11 members of the family and 75 healthy controls. Electron microscopy was also performed on one ALS patient. We identified a heterozygous mutation in codon 137 leading to substitution of threonine by alanine. Further studies are needed to clarify the role of this alteration in ALS aetiopathogensis; nevertheless, T137A seems to represent a new missense mutation of the SOD1 gene in ALS patients.

131 HA-TTR patients from a single referral centre presented at onset five major clinical syndromes: (1) the typical "Portuguese variant" axonal polyneuropathy with dissociated (syringomyelic like) sensory loss and autonomic dysfunction; (2) bilateral carpal tunnel syndrome; (3) restless leg syndrome with impotence and unexplained loss of weight; (4) pure motor neuropathy without autonomic abnormalities; (5) recurrent small brain or spinal cord ischemia or haemorrhages with leptomeningeal amyloid deposition (and late superficial siderosis of the central nervous system) and vitreous deposits. Some patients in our population presented a "pseudodemyelinating" onset of the somatic neuropathy, as well as atypical motor neuropathy simulating lower motor neuron disease. The five syndromes can overlap in advanced stages of the disease. Genetic screening of HA-TTR could be worthwhile in any idiopathic progressive axonal peripheral neuropathy, as well as in drug resistant demyelinating sensory-motor neuropathy or in pure motor neuropathy, when multi-organ involvement is present.

Unexplained focal neurologic episodes (FNEs) can occur in patients with transthyretin-related familial amyloidotic polyneuropathy (TTR-FAP) after orthotopic liver transplantation (OLT). A patient with Val30Met FAP underwent OLT at age 34 years. Twelve years after transplantation, she presented with recurrent FNEs lasting from 10 minutes to 8 hours each, with nonuniform deficitary clinical features and variably associated with headache. Magnetic resonance imaging showed multiple brain microbleeds and diffuse contrast enhancement of the craniospinal leptomeninges consistent with amyloid deposits. Our observation suggests that microbleeds associated with meningovascular amyloidosis can underlie FNEs in TTR-FAP. Moreover, it confirms that OLT does not halt progression of leptomeningeal and vascular amyloid deposition due to TTR production in the choroid plexuses. Such a progression might compromise the good long-term prognosis of patients with TTR-FAP due to increased risk of intracranial hemorrhages. Pharmacologic therapies targeting brain TTR production may modify this scenario.

We report clinical, neurophysiologic, and genetic features of an Italian series of patients with Lafora disease (LD) to identify distinguishing features of those with a slowly progressive course. Twenty-three patients with LD (17 female; 6 male) were recruited. Mean age (± SD) at the disease onset was 14.5 ± 3.9 years and mean follow-up duration was 13.2 ± 8.0 years. NHLRC1 mutations were detected in 18 patients; EPM2A mutations were identified in 5. Patients who maintained >10 years gait autonomy were labeled as "mild" and were compared with the remaining LD patients with a typical course. Six of 23 patients were mild and presented significantly delay in the age at onset, lower neurologic disability score at 4 years after the onset, less severe seizure phenotype, lower probability of showing both photoparoxysmal response on electroencephalography (EEG) and giant somatosensory evoked potentials, as compared to patients with typical LD. However, in both mild and typical LD patients, EEG showed disorganization of background activity and frequent epileptiform abnormalities. Mild LD patients had NHLRC1 mutations and five of six carried homozygous or compound heterozygous D146N mutation. This mutation was found in none of the patients with typical LD. The occurrence of specific NHLRC1 mutations in patients with mild LD should be taken into account in clinical practice for appropriate management and counseling.

Linkage and DNA analysis, magnetic resonance (MR) imaging, and single-voxel proton MR spectroscopy were obtained in 10 members of an Italian kindred with spinocerebellar ataxia type 1 (SCA1). The size of the basis pontis, cerebellar hemispheres, middle cerebellar peduncles, and medulla oblongata were decreased in 4 members carrying the SCA1 gene, compared with 6 unaffected subjects. Diffuse signal changes in the pons and cerebellum were observed only in the carrier with the longest disease duration and greatest disability. The N-acetylaspartate/creatine ratio and the choline/creatine ratio in the basis pontis were markedly decreased in 2 symptomatic SCA1 carriers and moderately decreased in 2 asymptomatic SCA1 carriers, compared with the unaffected family members and a control group of 10 healthy volunteers. Minor decreases in the N-acetylaspartate/creatine ratio and the normal choline/creatine ratio were observed in the cerebellar hemisphere of the SCA1 carriers. Reduction of the N-acetylaspartate/creatine ratio, demonstrated by MR spectroscopy in the pons, is likely to reflect a loss of neuronal viability and might represent a biochemical marker of SCA1 more sensitive than brainstem and cerebellum atrophy and signal changes shown by MR imaging.

Two unrelated Italian families affected by hereditary amyloidosis are described. Molecular genetic characterization demonstrated different mutations of the transthyretin gene. In all patients belonging to the TTR Ala 49 family the vitreous body, the heart and the peripheral nervous system were massively infiltrated by amyloid matter. In the TTR Pro 36 family vitreous opacities were the long-standing isolated manifestations of the disease. Two different patterns of vitreous deposits can be observed in these two families. The authors' data support the hypothesis that different pathological transthyretin proteins may have different affinity for the connective tissue in the vitreous.

We describe 2 normotensive sisters presenting slowly progressive dementia associated with acute or subacute focal neurological symptoms, unilateral or bilateral motor signs, and dysarthria. Their father, who died in the seventh decade, had a similar clinical picture. Computerized axial tomography (CT) scan of the head showed symmetrical hypodensities in the periventricular white matter and mild to moderate hydrocephalus. In these patients a diagnosis of Binswanger's disease was based on the clinical features supported by white matter changes on CT scan. Our study suggests that genetic factors may play a role in the etiology of Binswanger's disease.

Background and purpose Neurodegeneration in spinocerebellar ataxia type 1(SCA1) and 2(SCA2) is associated with white matter(WM) damage. Voxel-Based Morphometry(VBM), histogram analysis of mean diffusivity(MD) and Tract-Based Spatial Statistics(TBSS) enable an in vivo quantitative analysis of WM volume and structure. We assessed with these 3 techniques the whole brain WM damage in SCA1 and SCA2. Patients and methods Ten patients with SCA1, 10 patients with SCA2 and 10 controls underwent MRI with acquisition of T1-weighted and diffusion tensor images. The results were correlated with severity of clinical deficit. Results VBM showed atrophy of the brainstem and cerebellar WM without significant differences between SCA1 and SCA2. Focal atrophy of the cerebral subcortical WM was also present. Histogram analysis revealed increased MD in the brainstem and cerebellum in patients with SCA1 and SCA2 which in SCA2 was more pronounced and combined with mild increase of the MD in the cerebral hemispheres in SCA2. In SCA1 and SCA2 TBSS revealed decreased fractional anisotropy(FA) in the inferior, middle and superior cerebellar peduncles, pontine transverse fibres, medial and lateral lemnisci, spinothalamic tracts, corticospinal tracts and corpus callosum. The extent of tract changes was greater in SCA2 patients who also showed decreased FA in the short intracerebellar tracts. In both diseases VBM, histogram and TBSS results correlated with clinical severity. Conclusions Brain WM damage featuring a pontocerebeellar atrophy is similar in SCA1 and SCA2 but more pronounced in SCA2. In both diseases it correlates with severity of the clinical deficit.

Restless legs syndrome was the first isolated clinical manifestation in four siblings of a family with familial amyloid polyneuropathy. Clinical and electrophysiological evidence of peripheral neuropathy appeared after a variable time interval. Polysomnography showed abnormal sleep patterns and nocturnal myoclonus in all patients. The restless legs syndrome responded favourably to clonazepam.

Arg47 is a rare transthyretin-related (TTR) amyloidosis variant that is characterised by polyneuropathy and autonomic failure. We describe an Italian family with this mutation whose members (two women and their father) showed a rapid progression of the peripheral nervous system involvement and died within 5 years of clinical onset. Patients with Arg47 or other aggressive TTR amyloidoses should be considered high priority patients for orthotopic liver transplantation.

Objective: To describe a previously unreported clinical and radiologic presentation of hereditary transthyretin (TTR)-related amyloidosis. Background: Unexplained cerebellar ataxia, pyramidal syndrome, and hearing loss are observed in some patients with TTR-related amyloidoses. Methods: We performed clinical, radiologic, and pathologic examinations of three family members with TTR-related (Ala36Pro) amyloidosis. Results: The patient was a 69-year-old woman with vitreal amyloid deposits, progressive sensorineural deafness, cerebellar ataxia, pyramidal syndrome, and recurrent transient neurologic symptoms. Cranial MRI showed symmetric thin rims of low signal intensity in T2- and T2*-weighted images in the cortex of the sylvian fissures, of the cerebellar hemispheres and vermis, and in the quadrigeminal plate consistent with superficial siderosis of the CNS. Her older daughter had vitreal amyloid deposits, acute Brown-Sequard syndrome at C4, acute sensorineural deafness, and recurrent transient neurologic symptoms. Cranial MRI at age 48 revealed a rim of low signal intensity in T2- and T2*-weighted images in the superior vermis folia and the right sylvian cortex. In addition, two small hemosiderin deposits were seen in the left parietal cortex. Lumbar puncture yielded colorless CSF with increased ferritin content and was followed by fourth ventricle hemorrhage. Cranial MRI 11 months later showed progression of brain hemosiderin deposits. The younger daughter had vitreal deposits, sensorimotor polyneuropathy, and acute sensorineural hearing but no evidence of siderosis on cranial MRI. She died at age 43 years of posterior fossa subarachnoid hemorrhage, and the neuropathologic examination showed amyloid deposition in the leptomeningeal spaces and vessels. Conclusion: Transthyretin-related amyloidosis may cause superficial siderosis of the CNS through subarachnoid bleeding related to meningovascular amyloid deposition.

Cranial MRI showed multiple lesions in white matter that were thought to be consistent with multiple sclerosis in two young adults presenting with symptoms of progressive myelopathy. MRI of the cervicothoracic spine around one and two years after onset showed the myelopathy to be due to mid-thoracic tumours. The tumours (an extradural meningioma and intradural neuroma) were resected with complete resolution of myelopathy in one patient but no recovery in the other. Spinal MRI (or myelography) should be performed in young patients presenting with signs of progressive myelopathy even when cranial MRI shows a picture typical of multiple sclerosis.

We report the biochemical and molecular characterization of two new transthyretin (TTR) variants in two Italian families with hereditary amyloidosis. Both families presented neuropathy and cardiomyopathy but they differ in other clinical features. These TTR variants were previously detected by isoelectric focusing (IEF); one is a neutral TTR variant and the other one is basic. By protein and DNA analysis the neutral variant was found to have a substitution of an alanine for a threonine residue at position 49 (TTR Ala-49) of the polypeptide chain. The basic variant has a glutamine residue replacing glutamate at position 89 (TTR Gln-89). © 1992 Wiley-Liss, Inc.

Light chain amyloidosis and transthyretin (TTR) amyloidosis both have peripheral neuropathy as a prominent neurologic feature.1 We report two patients with amyloidotic peripheral neuropathy and remarkably different abnormal appearance of the tongue. One showed …

We studied 58 patients with partial or generalized epilepsy who had transcranial magnetic stimulation (TMS) of the brain motor regions. Short-term monitoring disclosed that the stimulation did not provoke seizures or EEG changes in any patient. Long-term follow-up disclosed that the epileptic condition was not made worse by TMS. TMS, as currently used for monitoring conduction in central motor pathways, does not induce seizures in drug-treated epileptic patients.

Summary Six children with tactile-evoked spikes in the EEG, also defined as extreme somatosensory evoked potentials (ESEPs), underwent an SEPs study in order to define the characteristics of such evoked potentials. Short-latency SEPs showed normal mean latency and amplitude values. Mid- or long- latency SEPs of abnormally high amplitude were recorded after stimulation of one or more extremities. Such extreme responses which showed the same reactivity proper to normal long-latency SEPs could be considered to correspond to the evoked spikes in the EEG.

As part of an epidemiological study that aims to characterize chemically the mutation(s) in transthyretin (TTR) related to familial amyloidotic polyneuropathy (FAP) of different ethnic origins, studies were carried out on TTR from two FAP kindreds of Italian origin. Two different criteria were employed in the characterization of TTR from these kindreds: (1) immunoblotting of cyanogen bromide fragments for screening of TTR(Met30) and (2) isoelectric focusing. TTR(Met30) was not detected but other substitutions were demonstrated using isoelectric focusing techniques. One of the variants found is a basic TTR variant. The substitutions occurring in the variant TTRs of these two kindreds are not known and are presently under study.

MRI showed impingement of the vertebral artery on the left lateral medulla in two patients with arterial hypertension, exaggerated startle reflexes (hyperekplexia), and progressive spastic paresis. One patient underwent microvascular decompression with normalization of arterial hypertension, disappearance of hyperekplexia, and improvement of spastic paresis. The combination of arterial hypertension, hyperekplexia, and progressive spastic paresis should arouse suspicion of neurovascular compression of the lateral medulla.

To investigate whether proton magnetic resonance (MR) spectroscopy is a useful complement to MR imaging in patients with degenerative ataxia.Brain MR imaging and single-voxel proton MR spectroscopy of the right cerebellar hemisphere and pons were performed in 30 patients with sporadic (n = 16) or inherited (n = 14) degenerative ataxia and in 20 healthy control subjects. Several indexes of brainstem and cerebellar atrophy were measured on MR images, as well as the N-acetylaspartate/creatine (NAA/Cr), choline/Cr (Cho/Cr), and myo-inositol/Cr (mI/Cr) ratios in the MR spectra. Differences between patients and subjects were evaluated with the Kruskal-Wallis and Mann-Whitney tests, whereas correlation of clinical, MR imaging, and spectroscopic data was assessed with nonparametric Spearman rank correlation.Measurements of brainstem and cerebellar atrophy obtained from MR images revealed patients had olivopontocerebellar atrophy (OPCA) (n = 11), spinal atrophy (SA) (n = 8), or corticocerebellar atrophy (CCA) (n = 4). Seven patients did not fulfill the criteria for any group and were considered undefined. In patients with OPCA, the pontine and cerebellar NAA/Cr and Cho/Cr ratios were significantly decreased when compared with those of the control subjects. Pontine and cerebellar NAA/Cr ratios were also significantly reduced in patients with SA and CCA. Five patients with undefined ataxia had a substantial decrease of pontine or cerebellar NAA/Cr ratio when compared with that of the control subjects. In patients with OPCA, the pontine NAA/Cr ratio (but not the atrophy measurements) showed a correlation (P =.04) with disability.MR spectroscopy is a useful complement to MR imaging in patients with degenerative ataxia.

The gene for one form of autosomal dominant spinal cerebellar ataxia (SCA1), is mapped by linkage to chromosome 6p, very close to the microsatellite locus D6S89. Eight large Italian kindreds segregating SCA1, as defined by very close linkage to D6S89, were genotyped with five microsatellite markers linked closely to D6S89, all mapping within a 6 cM interval on 6p. Multipoint linkage analysis and haplotypes from recombinants map SCA1 between two of these markers, D6S274 and D6S259, 5-6 cM apart. A single rare four marker haplotype within this interval shows linkage disequilibrium with the disease locus in southern Italy and is transmitted with SCA1 in five kindreds originating from this area.

A 60-year-old patient had a 3-year history of recurrent memory disturbances. The video electroencephalographic (EEG) recording of one attack showed that the amnesic state, which clinically resembled transient global amnesia, was characterized by a normal EEG tracing followed by electroclinical complex partial seizures. We suggest that "epileptic" transient global amnesia is postictal in nature.