Vanessa D. Marques

Expanding the phenotypes of the Pro56Ser VAPB mutation: Proximal SMA with dysautonomia

The phenotype of 16 members of a family affected by a late‐onset, dominant, progressive, motor and autonomic disorder is described. The VAPB (Pro56Ser) mutation was detected in Brazilian families with different phenotypes of motor neuron disorders. In this family, proximal and axial muscle weakness and atrophy, associated with abdominal protrusion, defined the motor phenotype. Death occurred in 10–15 years due to respiratory insufficiency. Tone and tendon reflexes were decreased and a distal tremor was common. Sensation was preserved. Autonomic abnormalities were also present, including choking, chronic intestinal constipation, sexual dysfunction, and sudomotor abnormalities, and on nerve morphology there was involvement of unmyelinated fibers. Electromyography disclosed ongoing denervation and reinnervation. Isolated dysfunction of motor and autonomic neurons is unusual among the spinal muscular atrophies. On this basis, this condition seems to represent a new category of disease. Muscle Nerve, 2006

Cross-cultural Adaptation, Reliability, and Validity of the BICAMS in Brazil

Objective: To investigate the reliability and validity of a Brazilian-Portuguese adaptation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Method: A Brazilian sample of 58 multiple sclerosis (MS) patients and 58 healthy controls (HC) were administered the Brazilian-Portuguese BICAMS test battery, comprising the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test Second Edition (CVLT2), and the Brief Visuospatial Memory Test Revised (BVMTR). Mean differences between groups on BICAMS tests were assessed using analysis of covariance (ANCOVA), controlling for age, gender, education, anxiety, and depression. Test–retest data were obtained from 49 of the MS patients, two weeks after the initial assessment. Results: The MS patient group scored significantly lower on all BICAMS tests (CVLT2 F1,110 = 28.99, p < .001; BVMTR F1,110 = 7.77, p < .01; SDMT F1,110 = 21.09, p < .001). Mixed-factor ANCOVAs tested differences in learning curves across trials for CVLT2 and BVMTR. HCs had significantly steeper learning curves on both CVLT2 (F1,111 = 10.82, p < .01) and BVMTR (F1,110 = 7.816, p < .01). These findings support diagnostic validity of the Brazilian-Portuguese adaptation. Test–retest reliability was satisfactory for SDMT, CVLT2, and BVMTR (.86, .84, and .77, respectively). Conclusion: The results suggest that this Brazilian version of the BICAMS will be a valid and reliable measure once complete normative data become available.

Coexistence of two chronic neuropathies in a young child: Charcot-Marie-Tooth disease type 1A and chronic inflammatory demyelinating polyneuropathy.

We report an 18‐month‐old Charcot–Marie–Tooth type 1A (CMT1A) patient who developed a rapid‐onset neuropathy, with proximal and distal weakness, and non‐uniform nerve conduction studies. The neuropathy responded well to immunomodulation, confirming the coexistence of an inherited and an inflammatory neuropathy. Unexpected clinical and/or electrophysiological manifestations in CMT1A patients should alert clinicians to concomitant inflammatory neuropathy. In addition, this association raises reflections about disease mechanism in CMT1A. Muscle Nerve, 2010

Immunological correlates of favorable long-term clinical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation

High dose immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) induces prolonged clinical remission in multiple sclerosis (MS) patients. However, how patient immune profiles are associated with clinical outcomes has not yet been completely elucidated. In this study, 37 MS patients were assessed for neurological outcomes, thymic function and long-term immune reconstitution after AHSCT. Patients were followed for a mean (SD) of 68.5 (13.9) months post-transplantation and were retrospectively clustered into progression- and non-progression groups, based on Expanded Disease Status Scale (EDSS) outcomes at last visit. After AHSCT, both patient groups presented increased regulatory T-cell subset counts, early expansion of central- and effector-memory CD8(+)T-cells and late thymic reactivation. However, the non-progression group presented early expansion of PD-1(+)CD8(+)T-cells and of PD-1-expressing CD19(+) B-cells. Here, we suggest that along with increased numbers of regulatory T-cell subsets, PD-1 inhibitory signaling is one possible immunoregulatory mechanism by which AHSCT restores immune tolerance in MS patients.

Influence of nationality on the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)

Abstract Objective: In answer to the call for improved accessibility of neuropsychological services to the international community, the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS; MS) was validated in multiple, non-English-speaking countries. It was created to monitor processing speed and learning in MS patients, including abbreviated versions of the Symbol Digit Modalities Test, California Verbal Learning Test, 2nd Edition, and the Brief Visuospatial Memory Test, Revised. The objective of the present study was to examine whether participant nationality impacts performance above and beyond common demographic correlates. Method: We combined published data-sets from Argentina, Brazil, Czech Republic, Iran, and the U.S.A. resulting in a database of 1,097 healthy adults, before examining the data via multiple regression. Results: Nationality significantly predicted performance on all three BICAMS tests after controlling for age and years of education. Interactions among the core predictor variables were non-significant. Conclusion: We demonstrated that nationality significantly influences BICAMS performance and established the importance of the inclusion of a nationality variable when international norms for the BICAMS are constructed.

Clinical and neurophysiological features of the hereditary neuropathy with liability to pressure palsy due to the 17p11.2 deletion

The hereditary neuropathy with liability to pressure palsies (HNPP) is an autossomal dominant disorder manifesting recurrent mononeuropathies. Objective Evaluate its clinical and nerve conduction studies (NCS) characteristics, searching for diagnostic particularities. Method We reviewed the neurological manifestations of 39 and the NCS of 33 patients. Results Family history was absent in 16/39 (41%). The onset complaints were weakness in 24, pain in 6, sensory deficit in 5 and paresthesias in 4. Pain was seen in 3 other patients. The following neuropathy patterns were found: multiple mononeuropathy (26), mononeuropathy (7), chronic sensorimotor polyneuropathy (4), chronic sensory polyneuropathy (1) and unilateral brachial plexopathy (1). NCS showed a sensorimotor neuropathy with focal conduction slowing in 31, two had mononeuropathy and another brachial plexopathy. Conclusion HNPP presentation is variable and may include pain. The most frequent pattern is of an asymmetrical sensory and motor neuropathy with focal slowing at specific topographies on NCS.

Clinical and electrophysiological correlates of TTRala71 amyloid neuropathy

This study was partially supported by the Fundacao de Assistencia ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto (FAEPA). We thank Mrs Sandra E.M. Nemoto for skillful laboratory workReceived 2 February 2009Received in final form 20 June 2009Accepted 8 September 2009

Neurophysiological findings of the late-onset, dominant, proximal spinal muscular atrophies with dysautonomia because of the VAPB PRO56SER mutation.

The vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) Pro56Ser mutation has been identified in Brazilian families showing various motor neuron syndromes. However, the neurophysiological characteristics of these patients have not been detailed, and some questions still need to be solved, such as the possible presence of myotonia and the origin of the abdominal protrusion seen in most patients. The eventual finding of suggestive electrophysiological characteristics would be helpful not only for clinical diagnosis but also to selection of the appropriate DNA test. To clarify these questions we carried out sensory and motor conduction studies, including symphatetic skin response, and needle examination in six genetically proven affected members. The electromyographic findings were those of a slowly progressive motor neuron disorder. Topographically, the abdominal muscles were severely affected, but the facial and laryngeal muscles were preserved or very mildly involved. Sensory conduction studies and sympathetic skin responses were normal. No myotonic discharge was recorded. These findings are indistinguishable from those of other motor neuron disorders, although the predominant involvement of the proximal limbs and of the abdominal muscles may be of some help in the appropriate clinical setting.

The genetic heterogeneity of hereditary transthyretin amyloidosis in a sample of the Brazilian population: Lavigne-Moreira et al

To present the genetic heterogeneity of a sample of the Brazilian population with transthyretin (TTR) mutations. This cohort study was descriptive and retrospective, and enrolled patients with peripheral neuropathy of unknown cause that were found to have a mutation in the TTR gene during the process of etiological investigation, between July 1997 to January 2016. Over the study period, 129 point mutations were identified in 448 tested patients, of whom 128 were of Brazilian origin. The TTR Val30Met mutation was identified in 116 patients (90.6%); while 7 (4.7%) patients had a pathogenic non‐TTR mutation and 7 (4.7%) carried non‐pathogenic mutations (4.7%). The four non‐TTRMet30 pathogenic mutations were TTR Aps38Tyr; TTR Ile107Val; TTR Val71Ala; and TTR Val122Ile. In the non‐pathogenic group, we only found two mutations, including TTR Gly6Ser and TTR Thr119Thr. Our study depicts a scenario of greater genetic heterogeneity among Brazilian hereditary transthyretin amyloidosis (hATTR) patients with familial amyloidotic polyneuropathy (FAP). We expect that this number will grow fast over a short period of time, due to increasing availability of genetic tests, increasing knowledge of the disease and the multivariate origin of our population.

Transthyretin Asp38Tyr: a new mutation associated to a late onset neuropathy

Dear Editor, Transthyretin (TTR) is the most common of the hereditary amyloidosis with familial amyloid polyneuropathy (FAP) its most frequent manifestation, and the TTR Val30Met substitution its most frequent mutation (Ando et al., 2013). Endemic foci of FAP occurs in Portugal, Japan, and Sweden. In Portugal and Japan, it is an early-onset, predominantly a small fiber sensory and autonomic neuropathy with late motor involvement, and family history is usually present, whereas in Sweden the disease manifests later, mainly as a length-dependent sensory and motor neuropathy, without any fiber predominance, and family history is frequently absent (Said and Planté-Bordeneuve, 2012). Brazilian patients usually follow the Portuguese pattern probably because of the Portuguese ancestry (Bittencourt et al., 2005; Saporta et al., 2009). At least 100 mutations in TTR gene have been described (Connors et al., 2003). Although the TTR Val30Met variant largely predominates in the endemic countries, other mutations have been reported (Connors et al., 2003; Ikeda et al., 2003; Suhr et al., 2009). In non-endemic countries, mutation variability is even greater (Cappellari et al., 2011; Adams et al., 2012; Sekijima et al., 2014). Most Brazilian studies report only the TTR Val30Met variant, although at least three other variants causing FAP have been described in Brazil (TTR Val71Ala, TTR Ala19Asp, and TTR Ile107Val) (Marques et al., 2010; Cruz, 2012; Ferreira et al., 2013). We report a novel TTR variant in two Brazilian sisters who developed a late onset neuropathy. The first patient was a woman who noted paresthesias in the hands at age 56. A year later, her feet and shins were also involved, and she continued to progressively worsen. At the age 58, her sensory symptoms