Kate Sinclair

Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-Methyl-D-aspartate receptor or dopamine-2 receptor

Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against N‐methyl‐D‐aspartate receptor (NMDAR).

Mutations in the GlyT2 Gene (SLC6A5) Are a Second Major Cause of Startle Disease

Background: Hereditary startle disease is caused by genetic defects in inhibitory glycine receptor and transporter genes. Results: Loss of function mutations in SLC6A5, with novel mechanisms of action, were identified in 17 individuals with startle disease. Conclusion: Recessive mutations in SLC6A5 represent a second major cause of startle disease. Significance: Genetic screening for startle disease should encompass both presynaptic and postsynaptic causes of disease. Hereditary hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, leading to hypertonia and apnea episodes. Missense, nonsense, frameshift, splice site mutations, and large deletions in the human glycine receptor α1 subunit gene (GLRA1) are the major known cause of this disorder. However, mutations are also found in the genes encoding the glycine receptor β subunit (GLRB) and the presynaptic Na+/Cl−-dependent glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of SLC6A5 in 93 new unrelated human hyperekplexia patients revealed 20 sequence variants in 17 index cases presenting with homozygous or compound heterozygous recessive inheritance. Five apparently unrelated cases had the truncating mutation R439X. Genotype-phenotype analysis revealed a high rate of neonatal apneas and learning difficulties associated with SLC6A5 mutations. From the 20 SLC6A5 sequence variants, we investigated glycine uptake for 16 novel mutations, confirming that all were defective in glycine transport. Although the most common mechanism of disrupting GlyT2 function is protein truncation, new pathogenic mechanisms included splice site mutations and missense mutations affecting residues implicated in Cl− binding, conformational changes mediated by extracellular loop 4, and cation-π interactions. Detailed electrophysiology of mutation A275T revealed that this substitution results in a voltage-sensitive decrease in glycine transport caused by lower Na+ affinity. This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease.

Intrauterine growth restriction due to uteroplacental vascular insufficiency leads to increased hypoxia-induced cerebral apoptosis in newborn piglets

Uteroplacental vascular insufficiency in humans is a common cause of intrauterine growth restriction (IUGR) and is associated with an increased incidence of perinatal asphyxia and neurodevelopmental disorders compared to normal weight newborns. Experimental models that provide an opportunity to analyze the pathogenesis of these relationships are limited. Here, we used neonatal pigs from large litters in which there were piglets of normal birth weight (for controls) and of low birth weight (for uteroplacental vascular insufficiency). Hypoxia was induced in paired littermates by reducing the fraction of inspired oxygen to 4% for 25 min. Brain tissue was collected 4 h post-hypoxia. Cerebral levels of apoptosis were quantified morphologically and verified with caspase-3 activity and TUNEL. Expression of Bcl-2, Bcl-XL and Bax proteins was investigated using immunohistochemistry. Cellular positivity for Bcl-2 was consistently higher in the non-apoptotic white matter of the hypoxic IUGR animals compared with their littermates and reached significance at P < 0.05 in several pairs of littermates. Alterations in Bax showed a trend towards higher expression in the hypoxic IUGR littermates but rarely reached significance. The IUGR piglets showed a significantly greater amount of apoptosis in response to the hypoxia than the normal weight piglets, suggesting an increased vulnerability to apoptosis in the IUGR piglets.

Seizures, ataxia, developmental delay and the general paediatrician : Glucose transporter 1 deficiency syndrome

Aim  Glucose transporter 1 deficiency syndrome (GLUT1‐DS) is an important condition for the general paediatrician’s differential armamentarium. We describe a case series of eight patients in order to raise awareness of this treatable neurometabolic condition. The diagnosis of GLUT1‐DS is suggested by a decreased absolute cerebrospinal fluid (CSF) glucose value (<2.2 mmol/L) or lowered CSF: plasma glucose ratio (<0.4).

Radiological Imaging in Ataxia Telangiectasia: a Review

The human genetic disorder ataxia telangiectasia (A-T) is characterised by neurodegeneration, immunodeficiency, radiosensitivity, cell cycle checkpoint defects, genomic instability and cancer predisposition. Progressive cerebellar ataxia represents the most debilitating aspect of this disorder. At present, there is no therapy available to cure or prevent the progressive symptoms of A-T. While it is possible to alleviate some of the symptoms associated with immunodeficiency and deficient lung function, neither the predisposition to cancer nor the progressive neurodegeneration can be prevented. Significant effort has focused on improving our understanding of various clinical, genetic and immunological aspects of A-T; however, little attention has been directed towards identifying altered brain structure and function using MRI. To date, most imaging studies have reported radiological anomalies in A-T. This review outlines the clinical and biological features of A-T along with known radiological imaging anomalies. In addition, we briefly discuss the advent of high-resolution MRI in conjunction with diffusion-weighted imaging, which enables improved investigation of the microstructural tissue environment, giving insight into the loss in integrity of motor networks due to abnormal neurodevelopmental or progressive neurodegenerative processes. Such imaging approaches have yet to be applied in the study of A-T and could provide important new information regarding the relationship between mutation of the ataxia telangiectasia mutated (ATM) gene and the integrity of motor circuitry.

Increased cerebral lactate during hypoxia may be neuroprotective in newborn piglets with intrauterine growth restriction

Intrauterine growth restriction (IUGR) can increase susceptibility to perinatal hypoxic brain injury for reasons that are unknown. Previous studies of the neonatal IUGR brain have suggested that the cerebral mitochondrial capacity is reduced but the glycolytic capacity increased relative to normal weight (NW) neonates. In view of these two factors, we hypothesized that the generation of brain lactate during a mild hypoxic insult would be greater in neonatal IUGR piglets compared to NW piglets. Brain lactate/N-acetylaspartate (NAA) ratios and apparent diffusion coefficients (ADCs) were determined by proton magnetic resonance spectroscopy and imaging of the brain before, during and after hypoxia in seven neonatal piglets with asymmetric IUGR and six NW piglets. During hypoxia, IUGR piglets had significantly higher brain lactate/NAA ratios than NW piglets (P=0.046). The lactate response in the IUGR piglets correlated inversely with apoptosis in the thalamus and frontal cortex of the brain measured 4 h post hypoxia (Pearsons r=0.86, P<0.05). Apoptosis in IUGR piglets with high brain lactate was similar to that in the NW piglets whereas IUGR piglets with low brain lactate had significantly higher apoptosis than NW piglets (P=0.019). ADCs in the high lactate IUGR piglets were significantly lower during hypoxia than in all the other piglets. This signifies increased diffusion of water into brain cells during hypoxia, possibly in response to increased intracellular osmolality caused by high intracellular lactate concentrations. These findings support previous studies showing increased susceptibility to hypoxic brain injury in IUGR neonates but suggest that increased glycolysis during hypoxia confers neuroprotection in some IUGR piglets.

Nutritional status of patients with ataxia-telangiectasia: A case for early and ongoing nutrition support and intervention.

Ataxia‐telangiectasia (A‐T) is a rare genomic syndrome resulting in severe disability. Chronic childhood disorders can profoundly influence growth and development. Nutrition‐related issues in A‐T are not well described, and there are no nutritional guidelines. This study investigated the nutrition‐related characteristics and behaviours of Australian A‐T patients attending a national clinic.

A patient-derived olfactory stem cell disease model for ataxia-telangiectasia

The autosomal recessive disorder ataxia-telangiectasia (A-T) is characterized by genome instability, cancer predisposition and neurodegeneration. Although the role of ataxia-telangiectasia mutated (ATM) protein, the protein defective in this syndrome, is well described in the response to DNA damage, its role in protecting the nervous system is less clear. We describe the establishment and characterization of patient-specific stem cells that have the potential to address this shortcoming. Olfactory neurosphere (ONS)-derived cells were generated from A-T patients, which expressed stem cell markers and exhibited A-T molecular and cellular characteristics that included hypersensitivity to radiation, defective radiation-induced signaling and cell cycle checkpoint defects. Introduction of full-length ATM cDNA into these cells corrected defects in the A-T cellular phenotype. Gene expression profiling and pathway analysis revealed defects in multiple cell signaling pathways associated with ATM function, with cell cycle, cell death and DNA damage response pathways being the most significantly dysregulated. A-T ONS cells were also capable of differentiating into neural progenitors, but they were defective in neurite formation, number of neurites and length of these neurites. Thus, ONS cells are a patient-derived neural stem cell model that recapitulate the phenotype of A-T, do not require genetic reprogramming, have the capacity to differentiate into neurons and have potential to delineate the neurological defect in these patients.

Motor pathway degeneration in young ataxia telangiectasia patients: A diffusion tractography study.

Background Our understanding of the effect of ataxia–telangiectasia mutated gene mutations on brain structure and function is limited. In this study, white matter motor pathway integrity was investigated in ataxia telangiectasia patients using diffusion MRI and probabilistic tractography. Methods Diffusion MRI were obtained from 12 patients (age range: 7–22 years, mean: 12 years) and 12 typically developing age matched participants (age range 8–23 years, mean: 13 years). White matter fiber tracking and whole tract statistical analyses were used to assess quantitative fractional anisotropy and mean diffusivity differences along the cortico-ponto-cerebellar, cerebellar-thalamo-cortical, somatosensory and lateral corticospinal tract length in patients using a linear mixed effects model. White matter tract streamline number and apparent fiber density in patient and control tracts were also assessed. Results Reduced fractional anisotropy along all analyzed patient tracts were observed (p < 0.001). Mean diffusivity was significantly elevated in anterior tract locations but was reduced within cerebellar peduncle regions of all patient tracts (p < 0.001). Reduced tract streamline number and tract volume in the left and right corticospinal and somatosensory tracts were observed in patients (p < 0.006). In addition, reduced apparent fiber density in the left and right corticospinal and right somatosensory tracts (p < 0.006) occurred in patients. Conclusions Whole tract analysis of the corticomotor, corticospinal and somatosensory pathways in ataxia telangiectasia showed significant white matter degeneration along the entire length of motor circuits, highlighting that ataxia–telangiectasia gene mutation impacts the cerebellum and multiple other motor circuits in young patients.

Altered corticomotor-cerebellar integrity in young ataxia telangiectasia patients

Magnetic resonance imaging (MRI) research in identifying altered brain structure and function in ataxia‐telangiectasia, an autosomal recessive neurodegenerative disorder, is limited. Diffusion‐weighted MRI were obtained from 11 ataxia telangiectasia patients (age range, 7‐22 years; mean, 12 years) and 11 typically developing age‐matched participants (age range, 8‐23 years; mean, 13 years). Gray matter volume alterations in patients were compared with those of healthy controls using voxel‐based morphometry, whereas tract‐based spatial statistics was employed to elucidate white matter microstructure differences between groups. White matter microstructure was probed using quantitative fractional anisotropy and mean diffusivity measures. Reduced gray matter volume in both cerebellar hemispheres and in the precentral‐postcentral gyrus in the left cerebral hemisphere was observed in ataxia telangiectasia patients compared with controls (P < 0.05, corrected for multiple comparisons). A significant reduction in fractional anisotropy in the cerebellar hemispheres, anterior/posterior horns of the medulla, cerebral peduncles, and internal capsule white matter, particularly in the left posterior limb of the internal capsule and corona radiata in the left cerebral hemisphere, was observed in patients compared with controls (P < 0.05). Mean diffusivity differences were observed within the left cerebellar hemisphere and the white matter of the superior lobule of the right cerebellar hemisphere (P < 0.05). Cerebellum‐localized gray matter changes are seen in young ataxia telangiectasia patients along with white matter tract degeneration projecting from the cerebellum into corticomotor regions. The lack of cortical involvement may reflect early‐stage white matter motor pathway degeneration within young patients.