Serum Leptin Levels in Treatment-Naive Patients with Clinically Isolated Syndrome or Relapsing-Remitting Multiple Sclerosis

Several studies have investigated leptin levels in patients with multiple sclerosis (MS) with somewhat conflicting results. They have all focused on patients with established relapsing-remitting (RR) MS but have not specifically looked at patients with clinically isolated syndrome (CIS) suggestive of MS, in the early stages of disease. In this study, serum leptin levels were measured in 89 treatment-naïve patients with CIS (53 patients) or RRMS (36 patients) and 73 controls searching for differences between the groups and for associations with several disease parameters. The expected significant sexual dimorphism in leptin levels (higher levels in females) was observed in both MS patients and controls. Increased leptin levels were found in female patients with RRMS compared to female controls (P=.003) and female CIS patients (P=.001). Female CIS patients had comparable levels to controls. Leptin levels correlated positively to disease duration, but not to EDSS, in female patients with RRMS. The results of the present study do not indicate involvement of leptin in the early stages of MS. Normal leptin levels in patients with CIS suggest that leptin does not have a pathogenic role. The ratio leptin/BMI increases during disease course in female MS patients in a time-dependent and disability-independent manner

Neuromyelitis Optica Spectrum Disease with Positive Autoimmune Indices: A Case Report and Review of the Literature

A 45-year-old female suffering from severe thoracic pain was admitted to the emergency department of our hospital. Thorough clinical examination revealed paresis of the left lower limb and sensory deficit at the level of the Th4 vertebra. MRI of the thoracic spine demonstrated a lesion at the level of Th1–Th7. Despite initial improvement following i.v. corticosteroid administration, the patient's clinical status deteriorated, with recurrence of myelitis and extension of the lesion to Th12. She developed paraparesis, hyperreflexia and spasticity of both legs, symmetrical sensory deficit below Th4, and sphincter dysfunction. Differential diagnosis included infectious, metabolic, neoplastic/paraneoplastic, and ischemic causes as well as multiple sclerosis. NMO IgG was found positive and led to the diagnosis of longitudinal extensive transverse myelitis (LETM) in the NMO spectrum disorders. Administration of immunosuppressive therapy resulted in gradual improvement of the patient's clinical status and stabilization for five years. In the setting of LETM, patients with antiaquaporin 4 IgGs can present features of coexisting systemic involvement. A thorough differential diagnosis is required to guide appropriate therapy

Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing

Hereditary Spastic Paraplegia (HSP) is a syndrome characterised by lower limb spasticity, occurring alone or in association with other neurological manifestations, such as cognitive impairment, seizures, ataxia or neuropathy. HSP occurs worldwide, with different populations having different frequencies of causative genes. The Greek population has not yet been characterised. The purpose of this study was to describe the clinical presentation and molecular epidemiology of the largest cohort of HSP in Greece, comprising 54 patients from 40 families. We used a targeted next-generation sequencing (NGS) approach to genetically assess a proband from each family. We made a genetic diagnosis in >50% of cases and identified 11 novel variants. Variants in SPAST and KIF5A were the most common causes of autosomal dominant HSP, whereas SPG11 and CYP7B1 were the most common cause of autosomal recessive HSP. We identified a novel variant in SPG11, which led to disease with later onset and may be unique to the Greek population and report the first nonsense mutation in KIF5A. Interestingly, the frequency of HSP mutations in the Greek population, which is relatively isolated, was very similar to other European populations. We confirm that NGS approaches are an efficient diagnostic tool and should be employed early in the assessment of HSP patients

High frequency of the expanded C9ORF72 hexanucleotide repeat in familial and sporadic Greek ALS patients.

An intronic expansion of a hexanucleotide GGGGCC repeat in the C9ORF72 gene has recently been shown to be an important cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in familial and sporadic cases. The frequency has only been defined in a small number of populations where the highest sporadic rate was identified in Finland (21.1%) and the lowest in mainland Italy (4.1%). We examined the C9ORF72 expansion in a series of 146 Greek ALS cases, 10.95% (n = 16) of cases carried the pathological expansion defined as greater than 30 repeats. In the 10 familial ALS probands, 50% (n = 5) of them carried a pathologically large expansion. In the remaining 136 sporadic ALS cases, 11 were carriers (8.2%). None of the 228 Greek controls carried an expanded repeat. The phenotype of our cases was spinal (13/16) or bulbar (3/16) ALS, the familial cases were all spinal ALS and none of our cases had behavioral frontotemporal dementia. Expansions in the C9ORF72 gene therefore represent a common cause of ALS in Greece and this test will be diagnostically very important to implement in the Greek population. The frequency is higher than other populations with the exception of Finland and this may be due to Greece being a relatively isolated population

Extracellular Charge Adsorption Influences Intracellular Electrochemical Homeostasis in Amphibian Skeletal Muscle

The membrane potential measured by intracellular electrodes, Em, is the sum of the transmembrane potential difference (E1) between inner and outer cell membrane surfaces and a smaller potential difference (E2) between a volume containing fixed charges on or near the outer membrane surface and the bulk extracellular space. This study investigates the influence of E2 upon transmembrane ion fluxes, and hence cellular electrochemical homeostasis, using an integrative approach that combines computational and experimental methods. First, analytic equations were developed to calculate the influence of charges constrained within a three-dimensional glycocalyceal matrix enveloping the cell membrane outer surface upon local electrical potentials and ion concentrations. Electron microscopy confirmed predictions of these equations that extracellular charge adsorption influences glycocalyceal volume. Second, the novel analytic glycocalyx formulation was incorporated into the charge-difference cellular model of Fraser and Huang to simulate the influence of extracellular fixed charges upon intracellular ionic homeostasis. Experimental measurements of Em supported the resulting predictions that an increased magnitude of extracellular fixed charge increases net transmembrane ionic leak currents, resulting in either a compensatory increase in Na+/K+-ATPase activity, or, in cells with reduced Na+/K+-ATPase activity, a partial dissipation of transmembrane ionic gradients and depolarization of Em

Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn

Bi-allelic variants in peroxiredoxin 3 (PRDX3) have only recently been associated with autosomal recessive spinocerebellar ataxia characterized by early onset slowly progressive cerebellar ataxia, variably associated with hyperkinetic and hypokinetic features, accompanied by cerebellar atrophy and occasional olivary and brainstem involvement. Herein, we describe a further simplex case carrying a reported PRDX3 variant as well as two additional cases with novel variants. We report the first Brazilian patient with SCAR32, replicating the pathogenic status of a known variant. All presented cases from the Brazilian and Indian populations expand the phenotypic spectrum of the disease by displaying prominent neuroradiological findings. SCAR32, although rare, should be included in the differential diagnosis of sporadic or recessive childhood and adolescent-onset pure and complex cerebellar ataxia

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification

Spastic paraplegia preceding PSEN1-related familial Alzheimer's disease.

Introduction: We investigated the frequency, neuropathology, and phenotypic characteristics of spastic paraplegia (SP) that precedes dementia in presenilin 1 (PSEN1) related familial Alzheimer's disease (AD). Methods: We performed whole exome sequencing (WES) in 60 probands with hereditary spastic paraplegia (HSP) phenotype that was negative for variants in known HSP-related genes. Where PSEN1 mutation was identified, brain biopsy was performed. We investigated the link between HSP and AD with PSEN1 in silico pathway analysis and measured in vivo the stability of PSEN1 mutant γ-secretase. Results: We identified a PSEN1 variant (p.Thr291Pro) in an individual presenting with pure SP at 30 years of age. Three years later, SP was associated with severe, fast cognitive decline and amyloid deposition with diffuse cortical plaques on brain biopsy. Biochemical analysis of p.Thr291Pro PSEN1 revealed that although the mutation does not alter active γ-secretase reconstitution, it destabilizes γ-secretase-amyloid precursor protein (APP)/amyloid beta (Aβn) interactions during proteolysis, enhancing the production of longer Aβ peptides. We then extended our analysis to all 226 PSEN1 pathogenic variants reported and show that 7.5% were associated with pure SP onset followed by cognitive decline later in the disease. We found that PSEN1 cases manifesting initially as SP have a later age of onset, are associated with mutations located beyond codon 200, and showed larger diffuse, cored plaques, amyloid-ring arteries, and severe CAA. Discussion: We show that pure SP can precede dementia onset in PSEN1-related familial AD. We recommend PSEN1 genetic testing in patients presenting with SP with no variants in known HSP-related genes, particularly when associated with a family history of cognitive decline

NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network.

Congenital heart defects can be caused by mutations in genes that guide cardiac lineage formation. Here, we show deletion of NKX2-5, a critical component of the cardiac gene regulatory network, in human embryonic stem cells (hESCs), results in impaired cardiomyogenesis, failure to activate VCAM1 and to downregulate the progenitor marker PDGFRα. Furthermore, NKX2-5 null cardiomyocytes have abnormal physiology, with asynchronous contractions and altered action potentials. Molecular profiling and genetic rescue experiments demonstrate that the bHLH protein HEY2 is a key mediator of NKX2-5 function during human cardiomyogenesis. These findings identify HEY2 as a novel component of the NKX2-5 cardiac transcriptional network, providing tangible evidence that hESC models can decipher the complex pathways that regulate early stage human heart development. These data provide a human context for the evaluation of pathogenic mutations in congenital heart disease.Nat Commun 2018 Apr 10; 9(1):1373