We describe a cohort of patients with PLA2G6-associated neurodegeneration (PLAN). Although patients with PLAN have previously been diagnosed with infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and Karak syndrome, they display a characteristic clinical and radiologic phenotype. PLA2G6 mutational analysis will negate the need for more invasive diagnostic procedures such as tissue biopsy.

1 H MRS has great potential for the clinical investigation of childhood brain tumours, but the low incidence in, and difficulties of performing trials on, children have hampered progress in this area. Most studies have used a long-TE, thus limiting the metabolite information obtained, and multivariate analysis has been largely unexplored. Thirty-five children with untreated cerebellar tumours (18 medulloblastomas, 12 pilocytic astrocytomas and five ependymomas) were investigated using a single-voxel short-TE PRESS sequence on a 1.5 T scanner. Spectra were analysed using LCModel TM to yield metabolite profiles, and key metabolite assignments were verified by comparison with high-resolution magic-angle-spinning NMR of representative tumour biopsy samples. In addition to univariate metabolite comparisons, the use of multivariate classifiers was investigated. Principal component analysis was used for dimension reduction, and linear discriminant analysis was used for variable selection and classification. A bootstrap cross-validation method suitable for estimating the true performance of classifiers in small datasets was used. The discriminant function coefficients were stable and showed that medulloblastomas were characterised by high taurine, phosphocholine and glutamate and low glutamine, astrocytomas were distinguished by low creatine and high N-acetylaspartate, and ependymomas were differentiated by high myo-inositol and glycerophosphocholine. The same metabolite features were seen in NMR spectra of ex vivo samples. Successful classification was achieved for glial-cell (astrocytoma þ ependymoma) versus non-glial-cell (medulloblastoma) tumours, with a bootstrap 0.632 þ error, e B.632þ , of 5.3%. For astrocytoma vs medulloblastoma and astrocytoma vs medulloblastoma vs ependymoma classification, the e B.632þ was 6.9% and 7.1%, respectively. The study showed that 1 H MRS detects key differences in the metabolite profiles for the main types of childhood cerebellar tumours and that discriminant analysis of metabolite profiles is a promising tool for classification. The findings warrant confirmation by larger multi-centre studies.

ObjectivesThis UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs.MethodsRetrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping.ResultsFifty-six patients were defined as early-onset (n = 23) if symptomatic < 28 days of age, late-onset (n = 23) if symptomatic later, or selectively screened perinatally due to a familial proband (n = 10). The median follow-up was 12.4 years (range 0–53). Long-term outcomes in all groups showed a similar neurological phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy-like symptoms (6/52) and abnormal neuroimaging (12/21). Neuroimaging findings included parenchymal infarcts (4/21), focal white matter hyperintensity (4/21), cortical or cerebral atrophy (4/21), nodular heterotopia (2/21) and reduced creatine levels in white matter (4/4). 4/21 adult patients went to mainstream school without the need of additional educational support and 1/21 lives independently. Early-onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early-onset and half of late-onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. ASL was sequenced (n = 19) and 20 mutations were found. Plasma argininosuccinate was higher in early-onset compared to late-onset patients.ConclusionsOur study further defines the natural history of argininosuccinic aciduria and genotype–phenotype correlations. The neurological phenotype does not correlate with the severity of hyperammonaemia and plasma argininosuccinic acid levels. The disturbance in nitric oxide synthesis may be a contributor to the neurological disease. Clinical trials providing nitric oxide to the brain merit consideration.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-017-0022-x) contains supplementary material, which is available to authorized users.

Management of brain tumours in children would benefit from improved non-invasive diagnosis, characterisation and prognostic biomarkers. Metabolite profiles derived from in-vivo MRS have been shown to provide such information. Studies indicate that using optimum a priori information on metabolite contents in the construction of linear combination (LC) models of MR spectra leads to improved metabolite profile estimation. Glycine (Gly) is usually neglected in such models due to strong overlap with myo-inositol (mI) and a low concentration in normal brain. However, biological studies indicate that Gly is abundant in high-grade brain tumours. This study aimed to investigate the quantitation of Gly in paediatric brain tumours using MRS analysed by LCModel, and its potential as a non-invasive biomarker of malignancy. Single-voxel MRS was performed using PRESS (TR 1500 ms, TE 30 ms/135 ms) on a 1.5 T scanner. Forty-seven cases (18 high grade (HG), 17 low grade (LG), 12 ungraded) were retrospectively selected if both short-TE and long-TE MRS (n = 33) or short-TE MRS and high-resolution magic-angle spinning (HRMAS) of matched surgical samples (n = 15) were available. The inclusion of Gly in LCModel analyses led to significantly reduced fit residues for both short-TE and long-TE MRS (p < 0.05). The Gly concentrations estimated from short-TE MRS were significantly correlated with the long-TE values (R = 0.91, p < 0.001). The Gly concentration estimated by LCModel was significantly higher in HG versus LG tumours for both short-TE (p < 1e-6) and long-TE (p = 0.003) MRS. This was consistent with the HRMAS results, which showed a significantly higher normalised Gly concentration in HG tumours (p < 0.05) and a significant correlation with the normalised Gly concentration measured from short-TE in-vivo MRS (p < 0.05). This study suggests that glycine can be reliably detected in paediatric brain tumours using in-vivo MRS on standard clinical scanners and that it is a promising biomarker of tumour aggressiveness.

To determine if apparent diffusion coefficients (ADC) can discriminate between posterior fossa brain tumours on a multicentre basis. A total of 124 paediatric patients with posterior fossa tumours (including 55 Medulloblastomas, 36 Pilocytic Astrocytomas and 26 Ependymomas) were scanned using diffusion weighted imaging across 12 different hospitals using a total of 18 different scanners. Apparent diffusion coefficient maps were produced and histogram data was extracted from tumour regions of interest. Total histograms and histogram metrics (mean, variance, skew, kurtosis and 10th, 20th and 50th quantiles) were used as data input for classifiers with accuracy determined by tenfold cross validation. Mean ADC values from the tumour regions of interest differed between tumour types, (ANOVA P < 0.001). A cut off value for mean ADC between Ependymomas and Medulloblastomas was found to be of 0.984 × 10−3 mm2 s−1 with sensitivity 80.8% and specificity 80.0%. Overall classification for the ADC histogram metrics were 85% using Naïve Bayes and 84% for Random Forest classifiers. The most commonly occurring posterior fossa paediatric brain tumours can be classified using Apparent Diffusion Coefficient histogram values to a high accuracy on a multicentre basis.