Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit.

We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic cerebrospinal fluid (CSF) profiles from 12 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3-glucose, and xylose-α1-3-xylose-α1-3-glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose may originate from glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O-glucosylation. Since many proteins are O-glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake.

The clinical and biochemical hallmarks generally associated with GLUT1DS may be caused by defects in genes other than SLC2A1.

Glucose transporter 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder caused by haploinsufficiency of the GLUT1 glucose transporter (encoded by SLC2A1) leading to defective glucose transport across the blood-brain barrier. This work describes the genetic analysis of 56 patients with clinical or biochemical GLUT1DS hallmarks. 55.4% of these patients had a pathogenic variant of SLC2A1, and 23.2% had a variant in one of 13 different genes. No pathogenic variant was identified for the remaining patients. Expression analysis of SLC2A1 indicated a reduction in SLC2A1 mRNA in patients with pathogenic variants of this gene, as well as in one patient with a pathogenic variant in SLC9A6, and in three for whom no candidate variant was identified. Thus, the clinical and biochemical hallmarks generally associated with GLUT1DS may be caused by defects in genes other than SLC2A1.

Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias.

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.

Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases.

BACKGROUND: Variants in POLG are one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition. METHODS: A multinational, retrospective study using data from 155 patients with POLG variants recruited from seven European countries. RESULTS: We describe the spectrum of clinical features associated with POLG variants in the largest known cohort of patients. While clinical features clearly form a continuum, stratifying patients simply according to age of onset-onset prior to age 12 years; onset between 12 and 40 years and onset after the age of 40 years, permitted us to identify clear phenotypic and prognostic differences. Prior to 12 years of age, liver involvement (87%), seizures (84%), and feeding difficulties (84%) were the major features. For those with onset between 12 and 40 years, ataxia (90%), peripheral neuropathy (84%), and seizures (71%) predominated, while for those with onset over 40 years, ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) were the major clinical features. The earlier the onset the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis. CONCLUSION: Based on our data, we propose a simplified POLG disease classification, which can be used to guide diagnostic investigations and predict disease course.

Status epilepticus in POLG disease: a large multinational study.

We aimed to provide a detailed phenotypic description of status epilepticus (SE) in a large cohort of patients with POLG disease and identify prognostic biomarkers to improve the management of this life-threatening condition. In a multinational, retrospective study with data on patients with POLG disease from seven European countries, we identified those who had SE. The age of SE onset, accompanying clinical, laboratory, imaging and genetic findings were analysed. One hundred and ninety-five patients with genetically confirmed POLG disease were recruited, of whom 67% (130/194) had epilepsy. SE was identified in 77% (97/126), with a median age of SE onset of 7 years. SE was the presenting symptom of the disease in 43% (40/93) of those with SE, while 57% (53/93) developed SE during the disease course. Convulsive SE was reported in 97% (91/94) followed by epilepsia partialis continua in 67% (56/84). Liver impairment 78% (74/95), ataxia 69% (60/87), stroke-like episodes 57% (50/88), were the major comorbidities. In the majority (66%; 57/86) with SE this became refractory or super-refractory. The presence of seizures was associated with significantly higher mortality compared to those without (P ≤ 0.001). The median time from SE debut to death was 5 months. SE is a major clinical feature of POLG disease in early and juvenile to adult-onset disease and can be the presenting feature or arise as part of a multisystem disease. It is associated with high morbidity and mortality, with the majority of patients with SE going on to develop refractory or super-refractory SE.

The impact of gender, puberty, and pregnancy in patients with POLG disease.

OBJECTIVE: To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. METHODS: Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. RESULTS: We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. INTERPRETATION: Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor.

Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.

OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Muscle Involvement in a Large Cohort of Pediatric Patients with Genetic Diagnosis of Mitochondrial Disease.

Mitochondrial diseases (MD) are a group of genetic and acquired disorders which present significant diagnostic challenges. Here we report the disease characteristics of a large cohort of pediatric MD patients (n = 95) with a definitive genetic diagnosis, giving special emphasis on clinical muscle involvement, biochemical and histopathological features. Of the whole cohort, 51 patients harbored mutations in nuclear DNA (nDNA) genes and 44 patients had mutations in mitochondrial DNA (mtDNA) genes. The nDNA patients were more likely to have a reduction in muscle fiber succinate dehydrogenase (SDH) stains and in SDH-positive blood vessels, while a higher frequency of mtDNA patients had ragged red (RRF) and blue fibers. The presence of positive histopathological features was associated with ophthalmoplegia, myopathic facies, weakness and exercise intolerance. In 17 patients younger than two years of age, RRF and blue fibers were observed only in one case, six cases presented cytochrome c oxidase (COX) reduction/COX-fibers, SDH reduction was observed in five and all except one presented SDH-positive blood vessels. In conclusion, muscle involvement was a frequent finding in our series of MD patients, especially in those harboring mutations in mtDNA genes.

HaNDL syndrome in a 14-year-old girl.

Transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL syndrome) consists of recurrent headaches with focal neurological signs, which can include motor, sensory and aphasic symptoms. Although considered rare, it is becoming increasingly recognised in clinical practice due to the accumulation of case reports. The pathophysiology remains unclear although changes in the neurovascular resemble those found in migraine, which are thought to be triggered by an infectious process. HaNDL can mimic various serious, including life-threatening, diseases, such as stroke and meningoencephalitis, which is why vigorous tests should be sought before this diagnosis of exclusion can be reached. Treatment is symptomatic and the prognosis is excellent. A literature review of the topic is discussed. We report an adolescent girl who presented with recurrent expressive dysphasia and right-sided hypoaesthesia and moderate occipital headaches who was diagnosed with HaNDL syndrome.

Dr. Google: what about the human papillomavirus vaccine?

OBJECTIVES: To assess and analyze the information and recommendations provided by Google Web Search™ (Google) in relation to web searches on the HPV vaccine, indications for females and males and possible adverse effects. RESULTS: In the comprehensive analysis of results, 72.2% of websites offer information favorable to HPV vaccination, with varying degrees of content detail, vs. 27.8% with highly dissuasive content in relation to HPV vaccination. The most frequent type of site is the blog or forum. The information found is frequently incomplete, poorly structured, and often lacking in updates, bibliography and adequate citations, as well as sound credibility criteria (scientific association accreditation and/or trust mark system). MATERIALS AND METHODS: Descriptive cross-sectional study of the results of 14 web searches. Comprehensive analysis of results based on general recommendation given (favorable/dissuasive), as well as compliance with pre-established criteria, namely design, content and credibility. Sub-analysis of results according to site category: general information, blog / forum and press. CONCLUSIONS: Google, as a tool which users employ to locate medical information and advice, is not specialized in providing information that is necessarily rigorous or valid from a scientific perspective. Search results and ranking based on Google's generalized algorithms can lead users to poorly grounded opinions and statements, which may impact HPV vaccination perception and subsequent decision making.

Paraparesia espástica tropical vista desde un contexto ibérico. Réplica / Tropical spastic paraparesis viewed from an Iberian context. Reply

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Paraparesia espástica tropical en una región no tropical / Tropical spastic paraparesis in a non tropical region

Introducción. El virus linfótropo humano de células T tipo 1 (HTLV-1) es el agente causal de la paraparesia espástica tropical. Su prevalencia, elevada en determinadas áreas tropicales, es baja en Europa y Norteamérica. Casos clínicos. Se describen dos casos de paraparesia espástica tropical en varones naturales y residentes en Galicia. Se realizaron estudios analíticos en la sangre y el líquido cefalorraquídeo (LCR), exámenes neurofisiológicos y resonancia magnética craneal y medular. En ambos pacientes, la presentación clínica fue la de una mielopatía crónica, con cuadro tórpido y progresivo que evolucionó a paraparesia espástica. Un paciente desarrolló uveítis antes de la clínica neurológica. En los dos casos, el estudio del LCR demostró leve pleocitosis linfoide, ligera hiperproteinorraquia, bandas oligoclonales negativas y anticuerpos anti-HTLV-1 positivos. La reacción en cadena de la polimerasa para HTLV-1 resultó positiva en ambos casos. La resonancia magnética raquídea resultó normal en un paciente y mostró en el otro hiperseñal medular dorsal, que desapareció tras el tratamiento. No se demostraron datos de polineuropatía periférica. Recibieron corticoides e interferón alfa, con leve mejoría y estabilización del cuadro clínico. La anamnesis dirigida reveló antecedentes de contactos sexuales de riesgo en regiones endémicas de HTLV-1. Conclusiones. La uveítis asociada a HTLV-1 podría ser predictora de paraparesia espástica tropical. Ésta es probablemente una entidad infradiagnosticada (alto porcentaje de portadores asintomáticos, clínica insidiosa y bajo índice de sospecha en áreas no endémicas). Debe considerarse su diagnóstico en zonas no tropicales que reciben inmigrantes de áreas endé- micas y también en regiones con una tradicional emigración a regiones tropicales (AU)

Introduction. Human T-lymphotropic virus 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a prevalent disease in certain tropical regions endemic for HTLV-1, being a rare entity in areas such as Europe and North America. Case reports. We report two new cases of HAM/TSP in Caucasians, native from Galicia, Spain. Serum and cerebrospinal fluid (CSF) analysis, clinical neurophysiologic studies and brain and spinal cord MRI scans were performed. Both patients presented a progressive chronic myelopathy, evolving to spastic paraparesis; one of them presenting with uveitis, prior to the onset of neurological symptoms. CSF analysis revealed mild lymphocytic pleocytosis and increased protein concentration with positive anti-HTLV-1 antibodies. Polymerase chain reaction was positive for HTLV-1. Oligoclonal bands were not detected. In one of the patients, MRI scans did not reveal abnormalities whilst in the other there was an elongated high intensity lesion at the thoracic spinal cord level, which resolved after treatment. No evidence of peripheral neuropathy was found. Corticosteroids and interferon alpha therapy was started, with moderate functional improvement. A history of unprotected sexual relationships while travelling to HTLV-1 endemic areas was revealed. Conclusions. HTLV-1-associated uveitis may predict HAM/TSP. HAM/TSP is probably an underdiagnosed disease due to the high prevalence of asymptomatic carriers, insidious clinical presentation and low suspicion index in non-endemic regions for HTLV-1. In non-tropical countries, HAM/TSP should not only be suspected in migrants from endemic areas for HTLV-1, but also in patients from communities with a tradition of migration to tropical countries (AU)

Delirio de infestación asociado a deterioro cognitivo leve de etiología vascular. Buena respuesta a dosis bajas de quetiapina / Delusional parasitosis associated to mild cognitive impairment of vascular causation. Good response to low doses of quetiapine

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