Phospholipase A2 associated neurodegeneration (PLAN) is a major phenotype of autosomal recessive Neurodegeneration with Brain Iron Accumulation (NBIA). We describe the clinical phenotypes, ...neuroimaging features and PLA2G6 mutations in 5 children, of whom 4 presented with infantile neuroaxonal dystrophy (INAD). One other patient was diagnosed with the onset of PLAN in childhood, and our report highlights the diagnostic challenges associated with this atypical PLAN subtype. In this series, the neuroradiological relevance of classical PLAN features as well as apparent claval hypertrophy’ is explored. Novel PLA2G6 mutations were identified in all patients. PLAN should be considered not only in patients presenting with a classic INAD phenotype but also in older patients presenting later in childhood with non-specific progressive neurological features including social communication difficulties, gait disturbance, dyspraxia, neuropsychiatric symptoms and extrapyramidal motor features.
There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and ...prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.
The first part of this experimental program was to determine the structural bond properties of lightweight concrete incorporating solid waste oil palm shell (OPS) as coarse aggregate and also to ...compare its behaviour with other types of lightweight aggregate concretes. Other properties of OPS concrete namely the split tensile strength, modulus of rupture and modulus of elasticity were also determined. The structural bond properties were determined through pull-out test. The results showed that the experimental bond strength of OPS concrete was much higher than the design bond strength as stipulated by BS 8110. In general, the properties of OPS concrete compared well with that of other structural lightweight concretes and the results obtained encourage the use of OPS as aggregates for the production of structural lightweight concrete. The second part of the experimental program investigates the durability performance of OPS concrete through water permeability and water absorption tests.
The SLC39A14, SLC30A10 and SLC39A8 are considered to be key genes involved in manganese (Mn) homeostasis in humans. Mn levels in plasma and urine are useful tools for early recognition of these ...disorders. We aimed to explore further biomarkers of Mn deposition in the central nervous system in two siblings presenting with acute dystonia and hypermanganesemia due to mutations in SLC39A14. These biomarkers may help clinicians to establish faster and accurate diagnosis and to monitor disease progression after chelation therapy is administered.
A customized gene panel for movement disorders revealed a novel missense variant (c.311G > T; p.Ser104Ile) in SLC39A14 gene in two siblings presenting at the age of 10 months with acute dystonia and motor regression. Mn concentrations were analyzed using inductively coupled mass spectrometry in plasma and cerebrospinal fluid, disclosing elevated Mn levels in the index case compared to control patients. Surprisingly, Mn values were 3-fold higher in CSF than in plasma. We quantified the pallidal index, defined as the ratio between the signal intensity in the globus pallidus and the subcortical frontal white matter in axial T1-weighted MRI, and found significantly higher values in the SLC39A14 patient than in controls. These values increased over a period of 10 years, suggesting the relentless pallidal accumulation of Mn. Following genetic confirmation, a trial with the Mn chelator Na
CaEDTA led to a reduction in plasma Mn, zinc and selenium levels. However, parents reported worsening of cervical dystonia, irritability and sleep difficulties and chelation therapy was discontinued.
Our study expands the very few descriptions of patients with SLC39A14 mutations. We report for the first time the elevation of Mn in CSF of SLC39A14 mutated patients, supporting the hypothesis that brain is an important organ of Mn deposition in SLC39A14-related disease. The pallidal index is an indirect and non-invasive method that can be used to rate disease progression on follow-up MRIs. Finally, we propose that patients with inherited defects of manganese transport should be initially treated with low doses of Na
CaEDTA followed by gradual dose escalation, together with a close monitoring of blood trace elements in order to avoid side effects.
Neurodegeneration associated with brain iron accumulation (NBIA) comprises a heterogeneous group of disorders in which disruption of cellular mechanisms leads to accumulation of iron in the basal ...ganglia. This group includes patients with recently discovered mutations in the PLA2G6 gene encoding a calcium-independent phospholipase A2 enzyme that catalyzes the hydrolysis of glycerophospholipids. Previously, children with PLA2G6 mutations have been diagnosed with several different disorders and we wished to better define the phenotype of PLA2G6- associated neurodegeneration.
Detailed review of the clinical and genetic features of 14 and radiologic features of 13 of these patients with PLA2G6 mutations was undertaken.
Median age of symptom presentation was 14 months. One third of the cohort presented following an intercurrent illness. The children had progressive cognitive and motor skill regression, with evidence of axial hypotonia, four limb spasticity, bulbar dysfunction, and strabismus. All patients developed cerebellar ataxia and dystonia. Most patients had optic atrophy. Brain imaging demonstrated cerebellar cortical atrophy and gliosis in all patients. Changes consistent with increased iron deposition were identified in the globus pallidus and substantia nigra. Novel corpus callosum changes are also reported.
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.
In 2016, two research groups independently identified microdeletions and pathogenic variants in the lysine-specific histone methyltransferase 2B gene, KMT2B in patients with early-onset progressive ...dystonia. KMT2B-dystonia (DYT28) is emerging as an important and frequent cause of childhood-onset progressive generalised dystonia and is estimated to potentially account for up to 10% of early-onset generalised dystonia. Herein, we review variants in KMT2B associated with dystonia, as well as the clinical phenotype, treatment and underlying disease mechanisms. Furthermore, in context of this newly identified condition, we summarise our approach to the genetic investigation of paediatric dystonia.
•Microdeletions and intragenic variants in KMT2B are associated with early onset progressive dystonia, with predominant cervical and oromandibular involvement.•GPI-DBS should be considered early in the disease course, as medical therapy is of limited benefit.•Microarray should be included in first tier genetic testing in children and adults with dystonia.
Purpose. To evaluate the effectiveness and safety of accelerated corneal collagen cross-linking (ACXL) in patients below 14 years of age with progressive keratoconus. Materials and Methods. Thirty ...eyes of 18 patients with established progressive keratoconus underwent preoperative and postoperative visual acuity assessment, topography, and specular microscopy prior to ACXL and were followed up for 24 months. Results. Mean age of the patients was 12.7 years with ten males and eight females. There was an improvement in the mean postoperative uncorrected distant visual acuity (from 0.76 ± 0.26 to 0.61 ± 0.25 ; P = 0.005 ), mean corrected distant visual acuity (from 0.24 ± 0.19 to 0.12 ± 0.12 ; P < 0.001 ), mean spherical refraction (from - 3.04 DS ± 3.60 to - 2.38 DS ± 3.37 ; P = 0.28 ), mean cylinder (from - 3.63 DC ± 1.82 to - 2.80 DC ± 1.48 ; P = 0.008 ), and spherical equivalent (from - 4.70 D ± 3.86 to - 3.75 D ± 3.49 ; P = 0.15 ). Three eyes of two patients with vernal keratoconjunctivitis (VKC) showed progression. There were no intra- or postoperative complications. Conclusion. In pediatric patients ACXL is an effective and safe procedure for the management of keratoconus. Optimal management of VKC is important to arrest the progression of keratoconus.
β propeller protein-associated neurodegeneration (BPAN) is the most common neurodegeneration with brain iron accumulation disorder. Typical radiologic findings are T2 hypointensity in the substantia ...nigra and globus pallidus, as well as a T1 halolike substantia nigra hyperintense signal surrounding a hypointense central area. However, these findings are often subtle or absent on initial scans, risking diagnostic delay. In this study, we sought to investigate radiologic findings that could aid in the early diagnosis of BPAN.
A retrospective cohort study was performed in a national referral center, including all pediatric patients with confirmed pathogenic
mutations and consistent clinical semiology. MR imaging findings were independently reported by 2 pediatric neuroradiologists.
Fifteen patients were included in the study, and 27 scans were available for review. The initial neuroimaging study was undertaken at a mean age of 3.2 years. Iron deposition was uncommon in patients younger than 4 years of age. Neuroradiologic features from very early on included dentate, globus pallidus, and substantia nigra swelling, as well as a thin corpus callosum and small pontine volume. Optic nerve thinning was also present in all patients.
Our study highlights the key early MR imaging features of BPAN. Iron deposition in the globus pallidus and substantia nigra is not common in children younger than 4 years of age; clinicians should not be deterred from suspecting BPAN in the presence of the findings described in this study and the appropriate clinical context.
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