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.
The aim of this study was to estimate the frequency of falls in people with Huntington's disease (HD) and make a preliminary assessment of tools appropriate for assessing the risk of falling.
...Observational study.
Hospital clinic.
24 people with HD.
Balance was assessed using the Berg Balance Scale (BBS) and Timed "Up & Go" (TUG) test. Walking speed over 10 m was recorded. Long-term monitoring of walking activity was undertaken. Unified Huntington Disease Rating Scale (UHDRS) motor, Functional Assessment Scale (FAS), Independence Scale (IS) and Total Functional Capacity (TFC) scores were obtained as well as data about falls and stumbles. Differences between "recurrent fallers" (>or=2 falls/year) and "non-fallers" (<or=1 fall/year) for the range of outcome measures were investigated and probabilities calculated.
Mean (SD) age (years) of people with HD (n = 24) tested was 56.6 (11.7) and BMI (kg/m(2)) 24.7 (5.5). Median (range) UHDRS motor scores were 48 (28-80). Ten (41.6%) patients reported <or=1 fall and 14 (58.3%) >or=2 falls in the previous 12 months. Recurrent fallers walked less (p<0.01) and slower than non-fallers. Their balance (BBS) (p<0.01) was worse and TUG scores were higher (p<0.01). People with HD had increased risk of falls if TUG scores were >or=14 s or BBS scores <or=40.
A high proportion of HD patients have recurrent falls, and the BBS and TUG appear to be useful in falls risk assessment.
Patients suffering from Parkinson's disease (PD) display cognitive and neuropsychiatric dysfunctions, especially with disease progression. Although these impairments have been reported to impact more ...heavily upon a patient's quality of life than any motor dysfunctions, there are currently no interventions capable of adequately targeting these non-motor deficits.
Utilizing a rodent model of PD, we investigated whether cell replacement therapy, using intrastriatal transplants of human-derived ventral mesencephalic (hVM) grafts, could alleviate cognitive and neuropsychiatric, as well as motor, dysfunctions.
Rats with unilateral 6-hydroxydopamine lesions to the medial forebrain bundle were tested on a complex operant task that dissociates motivational, visuospatial and motor impairments sensitive to the loss of dopamine. A subset of lesioned rats received intrastriatal hVM grafts of ~9weeks gestation. Post-graft, rats underwent repeated drug-induced rotation tests and were tested on two versions of the complex operant task, before post-mortem analysis of the hVM tissue grafts.
Post-graft behavioural testing revealed that hVM grafts improved non-motor aspects of task performance, specifically visuospatial function and motivational processing, as well as alleviating motor dysfunctions.
We report the first evidence of human VM cell grafts alleviating both non-motor and motor dysfunctions in an animal model of PD. This intervention, therefore, is the first to improve cognitive and neuropsychiatric symptoms long-term in a model of PD.
•Non-motor dysfunctions affect quality of life in Parkinson's disease.•We tested whether human-derived foetal dopamine cells could improve these deficits.•Human dopamine cells improved rotational bias and movement impairments in a rat model.•Non-motor dysfunctions, specifically visuospatial and motivational deficits, improved.•This is the first evidence of improved non-motor deficits from human dopamine cells.
Purpose
Sub-clinical muscle involvement, including myopathic changes and mitochondrial dysfunction of skeletal muscle, has been reported in people with Huntington’s disease (HD). Muscle strength was ...evaluated using a hand-held dynamometer. Reliability and validity in people with HD were determined.
Method
Isometric muscle strength of 6 lower limb muscle groups was measured in 20 people with HD and matched healthy controls. People with HD were evaluated with the Unified Huntington’s Disease Rating Scales (UHDRS). Within session reliability using intra-class correlation coefficients (ICC) was calculated. Discriminant and convergent validity was also evaluated.
Results
UHDRS motor scores of people with HD ranged from 28 to 80. Reliability of strength testing was excellent (ICC 0.86 to 0.98). People with HD had on average about half the strength of healthy matched controls. UHDRS motor scores and strength scores were significantly correlated (convergent) providing a further indication of validity of strength testing.
Conclusions
The hand-held dynamometer is a reliable and valid measurement tool to detect strength differences between people with HD and a matched control group. There is significant reduction in lower limb muscle strength in HD which does not appear to have been described previously.
Nepal is one of the most landslide‐prone countries in the world, with year‐on‐year impacts resulting in loss of life and imposing a chronic impediment to sustainable livelihoods. Living with ...landslides is a daily reality for an increasing number of people, so establishing the nature of landslide hazard and risk is essential. Here we develop a model of landslide susceptibility for Nepal and use this to generate a nationwide geographical profile of exposure to rainfall‐triggered landslides. We model landslide susceptibility using a fuzzy overlay approach based on freely‐available topographic data, trained on an inventory of mapped landslides, and combine this with high resolution population and building data to describe the spatial distribution of exposure to landslides. We find that whilst landslide susceptibility is highest in the High Himalaya, exposure is highest within the Middle Hills, but this is highly spatially variable and skewed to on average relatively low values. Around 4 × 106 Nepalis (∼15% of the population) live in areas considered to be at moderate or higher degree of exposure to landsliding (>0.25 of the maximum), and critically this number is highly sensitive to even small variations in landslide susceptibility. Our results show a complex relationship between landslides and buildings, that implies wider complexity in the association between physical exposure to landslides and poverty. This analysis for the first time brings into focus the geography of the landslide exposure and risk case load in Nepal, and demonstrates limitations of assessing future risk based on limited records of previous events.
Plain Language Summary
Mountain region populations are disproportionately impacted by landslide hazards that result in seasonal disruption and loss of life, and restrict longer‐term sustainable development opportunities. Crucially, effective management of landslide risk requires an understanding of both where landslides are likely to occur but also how they intersect with where people live. To address this, we use a numerical model to identify locations that are more likely to experience landsliding in the future, based on a map of where landslides have occurred in the past. We then combine this with population and building data to consider how people's exposure to landsliding varies across Nepal. We find that although landslides are most likely within the higher mountain areas, the low population numbers here mean that people's exposure to landsliding is relatively limited. Similarly, the higher population centers are typically in areas where landsliding is less likely to occur. Locations with relatively high exposure instead generally occur in isolated pockets at the intersection between landslide likelihood and population density within moderate relief areas of Nepal. Understanding this spatial variability in landslide exposure is important for informing future risk‐sensitive land use planning and resource allocation.
Key Points
Landslide susceptibility and population distribution generate highly spatially variable exposure to landslides across Nepal
44% of land in Nepal has moderate‐high landslide susceptibility, whilst <15% of the population has moderate‐high exposure to landsliding
Caution is needed in using short‐term landslide occurrence data to assess future risks due to rapidly changing susceptibility and exposure
Inherited white-matter disorders are a broad class of diseases for which treatment and classification are both challenging. Indeed, nearly half of the children presenting with a leukoencephalopathy ...remain without a specific diagnosis. Here, we report on the application of high-throughput genome and exome sequencing to a cohort of ten individuals with a leukoencephalopathy of unknown etiology and clinically characterized by hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), as well as the identification of compound-heterozygous and homozygous mutations in cytoplasmic aspartyl-tRNA synthetase (DARS). These mutations cause nonsynonymous changes to seven highly conserved amino acids, five of which are unchanged between yeast and man, in the DARS C-terminal lobe adjacent to, or within, the active-site pocket. Intriguingly, HBSL bears a striking resemblance to leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate (LBSL), which is caused by mutations in the mitochondria-specific DARS2, suggesting that these two diseases might share a common underlying molecular pathology. These findings add to the growing body of evidence that mutations in tRNA synthetases can cause a broad range of neurologic disorders.
NC-IUPHAR (International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification) and its subcommittees provide authoritative reports on the nomenclature and pharmacology of ...G protein-coupled receptors (GPCRs) that summarize their structure, pharmacology, and roles in physiology and pathology. These reports are published in Pharmacological Reviews (http://www.iuphar.org/nciuphar_arti.html) and through the International Union of Pharmacology (IUPHAR) Receptor Database web site (http://www.iuphar-db.org/iuphar-rd). The essentially complete sequencing of the human genome has allowed the cataloging of all of the human gene sequences potentially encoding GPCRs. The IUPHAR Receptor List (http://www.iuphar-db.org/iuphar-rd/list/index.htm) presents this catalog giving IUPHAR-approved nomenclature (where available), known ligands, and gene names for all of these potential receptors (excluding sensory receptors and pseudogenes) together with links to curated sequence, descriptive information, and additional links in the Entrez Gene database (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene). This list is a major new initiative of NC-IUPHAR that, through continuing curation, defines the target of our ongoing receptor classification and invites further input from the scientific community.
Aim
Uteroplacental insufficiency in rats reduces nephron endowment, leptin concentrations and programmes cardiorenal disease in offspring. Cross‐fostering growth‐restricted (Restricted) offspring ...onto a mother with normal lactation restores leptin concentrations and nephron endowment. This study aimed to determine whether the reduced nephron endowment in Restricted offspring is due to delayed glomerular formation and dysregulation of renal genes regulating branching morphogenesis, apoptosis or leptin signalling. Furthermore, we aimed to investigate whether cross‐fostering Restricted offspring onto Control mothers could improve glomerular maturation and restore renal gene abundance.
Methods
Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on gestation day 18 (E18). Kidneys were collected at E20, postnatal day 1 (PN1) and PN7. An additional cohort was cross‐fostered onto separate mothers at birth and kidneys collected at PN7.
Results
Kidneys were lighter in the Restricted group, but weight was restored with cross‐fostering. At E20, abundance of Bax, Flt1 and Vegfa was increased in Restricted offspring, while Ret and Bcl2 transcripts were increased only in Restricted females. At PN7, abundance of Gdnf and Ret was higher in Restricted offspring, as was Casp3. Restricted offspring had a wider nephrogenic zone with more immature glomeruli suggesting a delayed or extended nephrogenic period. Cross‐fostering had subtle effects on gene abundance and glomerular maturity.
Conclusion
Uteroplacental insufficiency induced apoptosis in the developing kidney and delayed and extended nephrogenesis. Cross‐fostering Restricted offspring onto Control mothers had beneficial effects on kidney growth and renal maturity, which may contribute to the restoration of nephron endowment.
3-M syndrome is a primordial growth disorder caused by mutations in CUL7, OBSL1 or CCDC8. 3-M patients typically have a modest response to GH treatment, but the mechanism is unknown. Our aim was to ...screen 13 clinically identified 3-M families for mutations, define the status of the GH-IGF axis in 3-M children and using fibroblast cell lines assess signalling responses to GH or IGF1. Eleven CUL7, three OBSL1 and one CCDC8 mutations in nine, three and one families respectively were identified, those with CUL7 mutations being significantly shorter than those with OBSL1 or CCDC8 mutations. The majority of 3-M patients tested had normal peak serum GH and normal/low IGF1. While the generation of IGF binding proteins by 3-M cells was dysregulated, activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls. Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells. The prevalence of 3-M mutations was 69% CUL7, 23% OBSL1 and 8% CCDC8. The GH-IGF axis evaluation could reflect a degree of GH resistance and/or IGF1 resistance. This is consistent with the signalling data in which the CUL7(-/-) cells showed impaired IGF1 signalling, CCDC8(-/-) cells showed impaired GH signalling and the OBSL1(-/-) cells showed impairment in both pathways. Dysregulation of the GH-IGF-IGF binding protein axis is a feature of 3-M syndrome.
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