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Adenosine kinase (ADK) deficiency is a very rare inborn error of methionine and adenosine metabolism. It is characterized by developmental delay, hypotonia, epilepsy, facial dysmorphism, failure to thrive, transient liver dysfunction with cholestasis, recurrent hypoglycemia, and cardiac defects. Only 26 cases (16 families) of ADK deficiency have been published since its identification in 2011. Vascular abnormalities in cervical arteries and cerebral stroke have never been reported in this condition. Here, we describe two patients with ADK deficiency and vascular tortuosity leading to stroke in one of them. ADK deficiency is a rare inborn error of methionine metabolism with a complex phenotype that might be associated with cerebrovascular abnormalities and stroke.

Leukodystrophies usually affect children, but in the last several decades, many instances of adult leukodystrophies have been reported in the medical literature. Because the clinical manifestation of these diseases can be nonspecific, MRI can help with establishing a diagnosis. A step-by-step approach to assist in the diagnosis of adult leukodystrophies is proposed in this article. The first step is to identify symmetric white matter involvement, which is more commonly observed in these patients. The next step is to fit the symmetric white matter involvement into one of the proposed patterns. However, a patient may present with more than one pattern of white matter involvement. Thus, the third step is to evaluate for five distinct characteristics-including enhancement, lesions with signal intensity similar to that of cerebrospinal fluid, susceptibility-weighted MRI signal intensity abnormalities, abnormal peaks at MR spectroscopy, and spinal cord involvement-to further narrow the differential diagnosis. ©RSNA, 2019.

Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation. There are also a very large number of genetic causes which due to their relative rarity and sometimes variable and overlapping presentations can be difficult to diagnose. In this review, we provide a structured approach to the diagnosis of inherited disorders of white matter in adults. We describe clinical and radiological clues to aid diagnosis, and we present an overview of both common and rare genetic white matter disorders. We provide advice on testing for acquired causes, on excluding small vessel disease mimics, and detailed advice on metabolic and genetic testing available to the practising neurologist. Common genetic leukoencephalopathies discussed in detail includeCSF1R,AARS2, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and mitochondrial and metabolic disorders.

Background Olfactory dysfunction is a nonmotor symptom of Parkinson disease (PD) associated with reduction in quality of life. There is no evidence on whether improvements in olfaction after subthalamic deep brain stimulation (STN-DBS) may be directly attributable to motor improvement or whether this reflects a direct effect of DBS on olfactory brain areas. The aim of the present study was to evaluate the effect of DBS on olfactory function in PD, as well as to explore the correlation between these changes and changes in motor symptoms and brain metabolism. Methods Thirty-two patients with PD were screened for STN-DBS. Patients were evaluated before and 1 year after surgery. Primary outcome was the change in olfactory function (Sniffin' Sticks odor-identification test [SST]) after surgery among the patients with hyposmia at baseline. Secondary outcomes included the relationship between motor outcomes and olfactory changes and [18F]fluorodeoxyglucose-positron emission tomography analysis between subgroups with improvement versus no improvement of smell. Results STN-DBS improved SST after surgery (preoperative SST, median 7.3 ± 2.4 vs. postoperative SST, median 8.2 ± 2.1; P = 0.045) in a subset of patients among 29 of 32 patients who presented with hyposmia at baseline. The improvement in SST was correlated with DBS response (r = 0.424; P = 0.035). There was also an increase in glucose metabolism in the midbrain, cerebellum, and right frontal lobe in patients with SST improvement (P Conclusions STN-DBS improves odor identification in a subset of patients with PD. Motor improvement together with changes in the brain metabolism may be linked to this improvement.

As leucodistrofias e as leucoencefalopatias genéticas constituem um grupo heterogêneo de doenças raras que afetam preferencialmente a substância branca encefálica, sendo mais comuns na infância. Possuem amplo espectro fenotípico, com manifestações clínicas muitas vezes inespecíficas, mais comumente sintomas neuropsiquiátricos e acometimento de tratos longos. Os achados de neuroimagem são igualmente muito heterogêneos, mas tendem a ser consistentes para cada doença individualmente, por vezes permitindo precisa correlação fenotípica-genotípica. O uso crescente das técnicas de sequenciamento de nova geração têm possibilitado a identificação das bases genéticas de muitas destas doenças e a descrição de novas entidades, principalmente na faixa etária pediátrica. Já são mais de 60 genes associados a este grupo de doenças, adicionando complexidade à abordagem destes pacientes. No entanto, ainda se conhece pouco a respeito dos fenótipos e genótipos de pacientes adultos com leucodistrofia ou leucoencefalopatia genética. O objetivo do presente estudo foi descrever aspectos clínicos, neurorradiológicos e genéticos de pacientes adultos com leucodistrofia ou leucoencefalopatia genética. Foi realizado um estudo clínico retrospectivo e parcialmente prospectivo dos pacientes em acompanhamento no nosso serviço de neurogenética. Todas as 31 famílias (38 pacientes) incluídas foram submetidas a avaliação clínica e neurorradiológica. Exames neurofisiológicos foram realizados de acordo com a apresentação clínica. Exames diagnósticos bioquímicos ou genéticos foram solicitados em três etapas sequenciais. Na primeira etapa, após avaliação clínica e de neuroimagem, os pacientes foram submetidos a avaliação bioquímica ou teste genético específico conforme a hipótese diagnóstica. Nesta etapa 13 probandos obtiveram diagnóstico definitivo - sete com adrenoleucodistrofia/adrenomieloneuropatia ligada ao X, três com acidúria L2-hidroxiglutárica, um com leucodistrofia autossômica dominante do adulto, um com doença de Alexander e um com síndrome de Sjögren-Larsson. Na segunda etapa, os pacientes foram submetidos a avaliação por sequenciamento do exoma clínico. Nesta etapa, mais 13 probandos obtiveram diagnóstico: quatro com doença de substância branca evanescente, três com CADASIL, três com leucoencefalopatia difusa hereditária com esferoides, um com leucoencefalopatia com acometimento de tronco encefálico e medula espinhal e elevação de lactato, um com a síndrome de Gordon-Holmes e um com a doença relacionada a PLP1. Na terceira etapa, os probandos sem diagnóstico foram submetidos a avaliação por sequenciamento completo do exoma e mais dois probandos obtiveram diagnóstico. Uma família foi diagnóstica com deficiência intelectual relacionada a PUS3, uma condição extremamente rara que cursa com deficiência intelectual sindrômica, leucoencefalopatia e, em nossas pacientes, nefropatia, que não havia sido previamente descrita. A outra família apresentou um fenótipo totalmente novo associado a FDX2. Os pacientes apresentavam atrofia óptica congênita, miopatia mitocondrial, polineuropatia periférica axonal e leucoencefalopatia reversível. Após as três etapas, 28 dentre 31 probandos (90%) obtiveram diagnóstico definitivo e três probandos continuaram sem diagnóstico definitivo. Concluímos que o quadro clínico e neurorradiológico das leucodistrofias e leucoencefalopatias genéticas em adultos é muito heterogêneo e depende da etiologia subjacente. A avaliação clínica e neurorradiológica minuciosas associadas a avaliação genética não enviesada, seja por sequenciamento do exoma clínico, seja por sequenciamento completo do exoma, foi determinante para o diagnóstico correto na maioria dos pacientes Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of rare disorders that affect predominantly the cerebral white matter. They are more common in children and have a wide phenotypic spectrum with non-specific clinical features dominated by neuropsychiatric manifestations and long-tract symptoms. The neuroimaging findings are highly heterogeneous, but commonly have the same features for the same disorders, allowing precise phenotypic-genotypic correlation. As next-generation sequencing techniques become widely used, the genetic basis of a great number of these disorders has been established, as new disorders have been identified, especially in the pediatric population. At least 60 genes have been associated to these disorders, adding complexity to the diagnostic approach of such patients. However, little is known about the phenotypes and the genotypes of adult patients with leukodystrophies and genetic leukoencephalopathies. The aim of the present study was to describe clinical, neuroradiological and genetic aspects of adult patients with leukodystrophy or genetic leukoencephalopathy. A retrospective and partially prospective clinical study was conducted in our neurogenetics service. All 31 families included (38 patients) were clinically and neuroradiologically evaluated. Neurophysiological studies were performed as needed. Biochemical or genetic diagnostic tests were ordered in three sequential steps. On the first step, based on the clinical and neuroradiological presentations, biochemical or single-gene test were ordered according to the diagnostic hypothesis. On this step, 13 probands had a definitive diagnosis - seven with X-linked adrenoleukodystrophy/ adrenomyeloneuropathy, three with L2-hydroxyglutaric aciduria, one with autosomal dominant adult-onset demyelinating leukodystrophy, one with Alexander disease ando ne with Sjögren-Larsson syndrome. On the second step, patients were evaluated by focused exome sequencing and 13 patients were diagnosed: four with vanishing white matter disease, three with CADASIL, three with hereditary diffuse leukoencephalopathy with spheroids, one with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation, one with Gordon-Holmes syndrome and ne with PLP1-related disorder. On the third step, the probands without diagnosis were evaluated by whole-exome sequencing and two had a definitive diagnosis. One family was diagnosed with PUS3-related intellectual deficiency, an extremely rare condition that causes syndromic intellectual deficiency, leukoencepahlopathy and, in our patients, nephropathy, something that was not previously described in this condition. The other family presented a totally new phenotype associated with FDX2. The patients presented congenital optic atrophy, mitochondrial myopathy, axonal peripheral polyneuropathy and reversible leukoencephalopathy. After the three steps, 28 out of 31 probands (90%) had a definitive diagnosis and three probands, remained undiagnosed. We concluded that the clinical and neuroradiological picture of adult patients with leukodystrophies and genetic leukoencephalopathies are highly heterogeneous and depends on the specific etiology. Careful clinical and neuroradiological evaluations associated with a nonbiased genetic test - focused exome sequencing or whole-exome sequencing -, can define the correct diagnosis in a great proportion of patients

Diagnosis of multiple sclerosis (MS) is often difficult because of the wide range of clinical presentations and the absence of biomarkers or specific test to confirm the disease. The condition can therefore be confounded with other inflammatory or genetic conditions that affect the CNS, like inherited leukoencephalopathies. Among inherited leukoencephalopathies, X-linked adrenoleukodystrophy (X-ALD) figures out as one of the most commom.1,2

Defects in iron–sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis. Defeitos na biogênese do cluster ferro-enxofre [Fe-S] são cada vez mais reconhecidos como causadores de doenças neurológicas. Mutações em vários genes que codificam proteínas envolvidas na montagem da proteína mitocondrial [Fe-S] levam a fenótipos neurológicos complexos. Uma classe de proteínas essenciais na montagem inicial do cluster são as ferredoxinas. FDX2 é expresso de forma ubíqua e é essencial na formação de novo de aglomerados de [2Fe-2S] em humanos. Descrevemos e definimos geneticamente uma nova síndrome neurológica complexa identificada em duas famílias brasileiras, com uma nova mutação homozigótica em FDX2. Os pacientes foram avaliados clinicamente, submetidos a ressonância magnética, estudos de condução nervosa, EMG e biópsia muscular. Para definir a etiologia genética, foi realizada uma combinação de mapeamento de homozigose e sequenciamento de todo o exoma. Identificamos seis pacientes de duas famílias aparentemente não aparentadas com herança autossômica recessiva de um fenótipo neurológico complexo envolvendo atrofia óptica e nistagmo desenvolvendo-se aos 3 anos de idade, seguidos de miopatia e episódios recorrentes de cãibras, mialgia e fraqueza muscular na primeira ou segunda década de vida. A neuropatia axonal sensório-motora levou à fraqueza distal progressiva. A ressonância magnética revelou uma leucoencefalopatia reversível ou parcialmente reversível. A biópsia muscular demonstrou um padrão incomum de succinato desidrogenase regional e deficiência de citocromo c oxidase com acúmulo de ferro. O fenótipo foi mapeado em ambas as famílias para a mesma mutação homozigótica missense em FDX2 (c.431C > T, p.P144L). O efeito deletério da mutação foi validado por reação em cadeia da polimerase de transcrição reversa em tempo real e análise de Western blot, que demonstrou expressão normal de mRNA de FDX2, mas expressão severamente reduzida da proteína FDX2 no tecido muscular. Este estudo descreve um novo fenótipo neurológico complexo com características incomuns de ressonância magnética e biópsia muscular, mapeado conclusivamente para uma mutação em FDX2, que codifica uma ferredoxina mitocondrial ubíqua expressa essencial para a biogênese inicial do cluster [Fe-S].

Leukoencephalopathies are a diverse group of white matter disorders that can be difficult to diagnose. Using focused and whole-exome sequencing, Lynch et al. expand the known clinical and mutational spectrum of genetic leukoencephalopathy in adulthood, and describe the frequency and clinical and radiological phenotype of the most commonly mutated genes., Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults.

Mutations in PUS3 , which encodes a highly conserved enzyme responsible for posttranscriptional modification of tRNA, have been shown in a single family to be a cause of nonsyndromic intellectual disability (ID).1 In this study, we used whole-exome sequencing (WES) to identify biallelic mutations in PUS3 associated with syndromic ID with dysmorphic features, white matter disease (WMD), and renal abnormalities in a nonconsanguineous family from Brazil. The authors thank the patients and their family for participating in this study.

Neurosyphilis, formerly a frequent cause of dementia, is now a rare condition in developed countries. However, syphilis remains common in many developing countries, where adequate diagnosis and treatment of early syphilis may be lacking, increasing the chances of neurosyphilis and prevalence of syphilitic dementia. Objectives: To present cases of syphilitic dementia seen in a cognitive and behavioral neurology unit in Brazil, emphasizing their first symptoms and the challenges they posed in diagnosis. Methods: At our unit of the Hospital das Clínicas of the University of São Paulo, all patients are submitted to blood treponemal tests. When the test is positive, a lumbar puncture is performed. We retrospectivelly reviewed all cases of neurosyphilis seen in our unit from January 1991 to November 2009. Results: Nine cases of neurosyphilis (0.77% of the 1160 cases in our files) were identified over the period. Patients with neurosyphilis were all men, had a mean age of 47.8 (±13.0) years (median of 43 years), and presented with various neuropsychiatric syndromes and elusive diagnoses. The median time from onset of symptoms to diagnosis was 24 months and only one patient made a full recovery after treatment. Conclusions: Neurosyphilis is not frequent but remains present, causing several types of neuropsychiatric syndromes. As it is very simple to rule out neurosyphilis by performing a blood treponemal test, this test should be performed in all patients with neuropsychiatric symptoms, particularly in regions of the world where syphilis is still a commonly occurring disease. Resumo Neurossífilis, anteriormente uma causa freqüente de demência, é atualmente rara nos países desenvolvidos. A sífilis é ainda uma doença comum em muitos países em desenvolvimento, onde o diagnóstico e tratamento da sífilis precoce podem não ser adequados, o que aumenta a possibilidade de ocorrência de neurossífilis e de demência. Objetivos: apresentar casos de demência sifilítica atendidos em uma unidade de neurologia cognitiva e do comportamento no Brasil, enfatizando os primeiros sintomas e os desafios que impuseram ao diagnóstico. Métodos: Em nossa unidade do Hospital das Clínicas da Universidade de São Paulo, todos os pacientes são submetidos a teste treponêmico no sangue. Quando o teste é positivo, é realizada punção lombar. Avaliamos retrospectivamente todos os casos de neurossífilis atendidos em nossa unidade de janeiro de 1991 a novembro de 2009. Resultados: Nove casos de neurossífilis (0,77% dos 1.160 casos de nossos arquivos) foram identificados neste período. Os pacientes com neurossífilis eram todos homens, com idade média de 47,8 (±13,0) anos (mediana de 43 anos), e apresentaram-se com vários tipos de síndromes neuropsiquiátricas, de difícil diagnóstico. O tempo médio entre o início dos sintomas e o diagnóstico foi de 24 meses e apenas um paciente teve recuperação completa após o tratamento. Conclusões: Neurossífilis não é frequente, mas ainda está presente causando vários tipos de síndromes neuropsiquiátricas. Como é muito simples excluir o diagnóstico de neurossífilis mediante teste treponêmico no sangue, este teste deve ser realizado em todo paciente com sintomas neuropsiquiátricos, particularmente nas regiões do mundo onde a sífilis é ainda uma doença comum.

Department of Neurology and Institute of Radiology, Medical School, University of Sao Paulo, Sao Paulo SP, Brazil. A 19-year-old previously healthy boy was admitted with a ten-day history of rapidly progressive urinary retention, constipation, ascending hypoesthesia up to the thoracic level and gait instability. On physical examination, he presented fever, tetraparesis, brisk reflexes, multidirectional nystagmus, right-side Horner’s syndrome. CSF: 225 cells/mm (15% neutrophils), protein 142 mg/dl, glucose 46 mg/dl. MRI: Fig 1. Acute demyelinating encephalomyelitis was diagnosed and the patient was treated with high doses of corticosteroids for five days. Despite CSF improvement after corticosteroid treatment, clear signs of clinical worsening were observed. Anti-CMV (IgG and IgM) antibodies were detected in the CSF, and this justified empirical treatment with ganciclovir, starting one week after the corticosteroids. In one month, the patient was able to stand and walk with canes. MRI showed complete recovery (Fig 2).

O presente estudo realizou análise retrospectiva e parcialmente prospectiva de pacientes com diagnóstico de paraplegia espástica hereditária que são acompanhados no ambulatório de Neurogenética (NCL6500) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Apresenta como objetivo principal descrever os aspectos clínicos, genéticos, laboratoriais, de neuroimagem e eletrofisiológicos destes pacientes e como objetivo secundário visa identificar características no exame clínico, nos estudos laboratoriais e eletrofisiológicos e nas diferentes técnicas de neuroimagem, além de dados epidemiológicos, que contribuam para a definição etiológica, além de relacionar achados clínicos e laboratoriais com possíveis padrões genéticos. Os pacientes incluídos foram avaliados clinicamente por meio da versão brasileira da escala SPRS (Spastic Paraplegia Rating Scale) e também com avaliação cognitiva através do mini-exame do estado mental (quando aplicável) e submetidos a estudo de ressonância magnética de encéfalo e eletrofisológicos (quando aplicáveis), além da realização da investigação genética com técnicas diversas, inclusive por meio do sequenciamento completo do exoma. Entre os 70 sujeitos incluídos na pesquisa, o estudo genético foi conclusivo em 39 . Nos casos confirmados foi realizada a descrição clínica e sociodemográficas detalhada e realizado comparação entre os resultados por meio de análise estatística descritiva. Foi realizada ainda análise estatística inferencial que revelou relação entre achado de neuroimagem de corpo caloso afilado com gravidade da escala SPRS. Conclui-se por este estudo que a apresentação demográfica dos pacientes com paraplegia espástica hereditária é fenotípica e geneticamente variável, sendo o padrão autossômico recessivo o mais encontrado nesta amostra, com destaque para SPG11. Identificamos ainda casos habitualmente não classificados entre as paraplegias espásticas hereditárias, tais como a deficiência de arginase ou que representam uma expansão fenotípica, como a forma autossômica recessiva de paraplegia espástica associada a SQSTM1 The present study performed a retrospective and partially prospective analysis of all patients diagnosed with hereditary spastic paraplegia followed in the Neurogenetics Outpatient Service (NCL6500) at Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo. Its main objective is to describe the clinical, genetic, laboratorial, neuroimaging and electrophysiological aspects of these patients and as a secondary objective it aims to identify characteristics in the clinical examination, laboratorial and electrophysiological studies and in the different neurological imaging techniques, in addition to epidemiological data that contribute for the etiological definition, as well to relate clinical and laboratory findings with possible genetic patterns. Included patients were clinically evaluated using the SPRS (Spastic Paraplegia Rating Scale) Brazilian version and a cognitive assessment through the mini mental state exam (when applicable). Additionally brain magnetic resonance imaging and whenever applicable, electrophysiological studies were done. Different techniques for genetic analysis were performed, including whole exome sequencing. Of the 70 patients included in the survey, a conclusive genetic result was achieved in 39. In confirmed cases, a detailed clinical and sociodemographic description was performed and a comparison between the results was carried out through descriptive statistical analysis. Inferential statistical analysis was also carried out, which revealed a relationship between the neuroimaging finding of the thin corpus callosum and the severity of the SPRS scale. This study concludes that the demographic presentation of patients with hereditary spastic paraplegia is phenotypic and genetically variable, with the autosomal recessive pattern being the most common in the sample and the pathogenic variants in the SPG11 gene the most prevalent. We also identified cases not habitually classified as hereditary spastic paraplegia, as arginase deficiency and a phenotypic expansion, as SQSTSM1-related autosomal recessive spastic paraplegia