Agessandro Abrahao

Milestones in Friedreich ataxia: more than a century and still learning

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia worldwide. This review highlights the main clinical features, pathophysiological mechanisms, and therapeutic approaches for FRDA patients. The disease is characterized by a combination of neurological involvement (ataxia and neuropathy), cardiomyopathy, skeletal abnormalities, and glucose metabolism disturbances. FRDA is caused by expanded guanine-adenine-adenine (GAA) triplet repeats in the first intron of the frataxin gene (FXN), resulting in reduction of messenger RNA and protein levels of frataxin in different tissues. The molecular and metabolic disturbances, including iron accumulation, lead to pathological changes characterized by spinal cord and dorsal root ganglia atrophy, dentate nucleus atrophy without global cerebellar volume reduction, and hypertrophic cardiomyopathy. DNA analysis is the hallmark for the diagnosis of FRDA. There is no specific treatment to stop the disease progression in FRDA patients. However, a number of drugs are under investigation. Therapeutic approaches intend to improve mitochondrial functioning and to increase FXN expression.

MUNIX: Reproducibility and clinical correlations in Amyotrophic Lateral Sclerosis

OBJECTIVE To study the reproducibility, diagnostic yield to detect denervation, and clinical correlations of the Motor Unit Number Index (MUNIX) in subjects with Amyotrophic Lateral Sclerosis (ALS). METHODS MUNIX evaluation was performed in three muscles twice on the same day to assess reproducibility. Cut-off values for the MUNIX were based on data from 51 healthy subjects (controls) to evaluate the sensitivity of the technique to detect denervation in 30 subjects with ALS. RESULTS The method had good reproducibility. The variability was greater in the ALS group. In 23 ALS subjects (77%), low MUNIX values were detected. Most of the muscles with low MUNIX had also low compound muscle action potential (CMAP) and strength, but these parameters were normal in 9% of muscles. According to ROC curve analysis, MUNIX was generally accurate (AUC=0.9504) for discriminating between healthy individuals and subjects with at least one denervated muscle. CONCLUSIONS MUNIX variability was higher in the ALS group. The method showed good diagnostic performance for the detection of denervation in a sample of patients with ALS. SIGNIFICANCE This study demonstrated that in addition to being a quantitative tool MUNIX can detect denervation in subjects with ALS.

SCA2 presenting as an ataxia-parkinsonism-motor neuron disease syndrome

1. Plouin PF, Perdu J, La Batide-Alanore A, Boutouyrie P, Gimenez-Roqueplo AP, Jeunemaitre X. Fibromuscular dysplasia. Orphanet J Rare Dis 2007;2:28. 2. Slovut DP, Olin JW. Fibromuscular dysplasia. N Engl J Med 2004;350: 1862-1871. 3. Dayes LA, Gardiner N. The neurological implications of fibromuscular dys-plasia. Mt Sinai J Med 2005;72:418-420.4. Stahlfeld KR, Means JR, Didomenico P. Carotid artery fibromuscular dysplasia. Am J Surg 2007;193:71-72.5. Touze E, Oppenheim C, Trystram D, et al. Fibromuscular dysplasia of cervical and intracranial arteries. Int J Stroke 2010;5:296-305.

Neurosarcoidosis: guidance for the general neurologist

Neurosarcoidosis (NS) more commonly occurs in the setting of systemic disease. The diagnosis is based on a clinical history suggestive of NS, presence of noncaseating granulomas, and supportive evidence of sarcoid pathology, laboratory, and imaging studies. NS could involve any part of the nervous system and often demands high doses of steroids for symptom control. It presents low response to isolated steroids administration and frequently requires immunosuppressive agents. In NS, lymphocytes are polarized toward an excessive Th1 response, leading to overproduction of TNF-alpha and INF-gama, as well as lL-2 and IL-15. Infliximab, a chimeric monoclonal antibody that neutralizes the biological activity of TNF-alpha, is a new option in the NS treatment. We revised pathophysiology, clinical manifestations, diagnostic work up, and treatment of NS as guidance for the general neurologist.

One family, one gene and three phenotypes: A novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia

BACKGROUND VCP (valosin-containing protein gene) variants have been associated with peripheral and central neurodegenerative processes, including inclusion body myopathy (IBM), Paget disease of bone (PDB), frontotemporal dementia (FTD), and familial amyotrophic lateral sclerosis (ALS) type 14. The combination of IBM, PDB (IBMPFD1) can presented in one individual. However, the association of IBMPFD1 and ALS in the same family is rare. METHODS We reported three individuals from a Brazilian kindred with intrafamilial phenotype variability. Whole exome sequencing (WES) of the proband was performed and revealed a novel VCP variant. VCP Sanger sequencing was performed in the proband and his family members to confirm WES finding and segregation. We performed a systematic review of the literature regarding the genotypic-phenotypic VCP correlations. RESULTS Each individual presented with either myopathy with rimmed vacuoles, ALS, or FTD. There was no PDB. WES of the proband identified the heterozygous variant c.271A>T (p.Asn91Tyr) in the exon 3 of VCP. Sanger sequencing confirmed the segregation of this variant in an autosomal-dominant pattern. CONCLUSION This study expands the genotypic spectrum of the missense mutations of the VCP gene with a novel p.Asn91Tyr variant found in a Brazilian family presenting with the unusual intrafamiliar association of myopathy with rimmed vacuoles, ALS and FTD.

Unusual movement disorders in spinocerebellar ataxias.

Spinocerebellar ataxias (SCA) are a group of neurodegenerative diseases that may affect the cerebellum and its connections. Although the clinical spectrum of SCA is mostly characterized by progressive cerebellar ataxia, phenotypic variability has often been reported. Moreover, a wide range of non-ataxia features can be observed during disease progression. Among non-ataxia features, several types of movement disorders may be found in SCA, and are not uncommon [1]. Almost all types of movement disorders can be detected in patients with SCA, and may be related to basal ganglia involvement. Up to this moment, 36 subtypes of SCA are known. The most common related movement disorders with SCA subtype are: myoclonus in SCA2 and SCA14; dystonia in SCA2, SCA3 and SCA17; eyelid dystonia in SCA3; chorea in SCA3 and SCA17; parkinsonism in SCA2, SCA3 and SCA17; akathisia in SCA3; action tremor SCA12 and SCA27; palatal tremor in SCA20 [1–4]. Thus, the observed movement disorder, when present in combination with cerebellar ataxia, could point to the underlying SCA. Conversely, some patients with SCA may present with complex and unusual movement disorders. Herein, we describe four patients presenting with unusual movement disorders in three different subtypes of SCA. We also comment on phenomenology and underlying pathophysiology involved.

Gradenigo's Syndrome: Beyond the Classical Triad of Diplopia, Facial Pain and Otorrhea.

We report a case of a non-Hodgkin’s lymphoma in a young woman presenting with an abdominal mass and an unusual instance of cranial nerve palsies mimicking Gradenigo’s syndrome. This condition is characterized by a triad of otorrhea, facial pain and diplopia, related to otitis media in the pre-antibiotic era. Incomplete and atypical clinical features of Gradenigo’s syndrome have been described and noninfectious causes may mimic this condition. Careful clinical history and physical examination, including neuroimaging, are necessary to make a differential diagnosis.

Why averaging multiple MUNIX measures in the longitudinal assessment of patients with ALS

OBJECTIVE To assess the impact of averaging multiple MUNIX trials on the follow-up of patients with amyotrophic lateral sclerosis (ALS). METHODS We determined the percent relative change (%RC) of MUNIX, in healthy subjects and patients with ALS, by subtracting the MUNIX value in the second visit from the first. Both the mean of a set of three MUNIX (mean-MUNIX) and the first MUNIX sample (single-MUNIX) were evaluated. Then, we studied the sensitivity to detect relative changes over time and the statistical dispersion of the %RC from these two parameters. RESULTS We found that the mean-MUNIX %RC has lower mean coefficient of variation than the single-MUNIX %RC in all muscles. The mean-MUNIX also resulted in more ALS patients with significant %RC, i.e., outside reference limits. CONCLUSION The mean-MUNIX resulted in less dispersed values of %RC in patients with ALS and thus, increased the precision of the technique. The mean-MUNIX resulted also in an increase in the sensitivity to track changes over time in these patients. SIGNIFICANCE The mean-MUNIX should be considered in any ALS follow-up study as a more reliable approach and as a way of potentially reducing the sample size needed for the study.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): typical clinical and neuroimaging features in a Brazilian family

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder characterized by late-infantile onset spastic ataxia and other neurological features. ARSACS has a high prevalence in northeastern Quebec, Canada. Several ARSACS cases have been reported outside Canada in recent decades. This is the first report of typical clinical and neuroimaging features in a Brazilian family with probable diagnosis of ARSACS.

When should we test patients with familial ataxias for SCA31? A misdiagnosed condition outside Japan?

The autosomal dominant spinocerebellar ataxias (SCAs) are a highly heterogeneous group of genetic diseases characterized by progressive gait ataxia and variable degrees of extracerebellar symptoms and signs. SCAs comprise a large number of unusual genetic disorders, and may be considered a diagnostic challenge. Genetics has a significant role to play in the etiology, and up to now, approximately 40 SCA subtypes have been described, and at least 32 different loci were identified [1]. As the knowledge of clinical and genetic features of SCAs is growing, the “What type of SCA should this patient tested for?” question becomes important before ordering a SCA diagnostic panel. Although wholeexome sequencing is a promising approach to search simultaneously for a large number of genetic conditions, it is usually ineffective to identify some SCA subtypes, since their mutations may lie in a noncoding genomic region or consist of large repeat expansions. Spinocerebellar ataxia type 31 (SCA31), a late-onset cerebellar ataxia with or without hearing loss, is one of the most common inherited ataxia in Japan. To date, only two cases of SCA31 were described in other countries [2,3] and large European [4] and Taiwanese [5] population studies showed no SCA31 cases. Thus, SCA31 could be a misdiagnosed condition outside Japan. In this article, we aimed to describe a Brazilian family with SCA31 and to provide clinical clues in order to request a specific genetic testing for this unusual SCA subtype outside Japan.