Novel fluid biomarkers to differentiate frontotemporal dementia and dementia with Lewy bodies from Alzheimer's disease: A systematic review

RATIONALE: Frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) are two common forms of neurodegenerative dementia, subsequent to Alzheimer's disease (AD). AD is the only dementia that includes clinically validated cerebrospinal fluid (CSF) biomarkers in the diagnostic criteria. FTD and DLB often overlap with AD in their clinical and pathological features, making it challenging to differentiate between these conditions. AIM: This systematic review aimed to identify if novel fluid biomarkers are useful in differentiating FTD and DLB from AD. Increasing the certainty of the differentiation between dementia subtypes would be advantageous clinically and in research. METHODS: PubMed and Scopus were searched for studies that quantified and assessed diagnostic accuracy of novel fluid biomarkers in clinically diagnosed patients with FTD or DLB, in comparison to patients with AD. Meta-analyses were performed on biomarkers that were quantified in 3 studies or more. RESULTS: The search strategy yielded 614 results, from which, 27 studies were included. When comparing bio-fluid levels in AD and FTD patients, neurofilament light chain (NfL) level was often higher in FTD, whilst brain soluble amyloid precursor protein β (sAPPβ) was higher in patients with AD. When comparing bio-fluid levels in AD and DLB patients, α-synuclein ensued heterogeneous findings, while the noradrenaline metabolite (MHPG) was found to be lower in DLB. Ratios of Aβ42/Aβ38 and Aβ42/Aβ40 were lower in AD than FTD and DLB and offered better diagnostic accuracy than raw amyloid-β (Aβ) concentrations. CONCLUSIONS: Several promising novel biomarkers were highlighted in this review. Combinations of fluid biomarkers were more often useful than individual biomarkers in distinguishing subtypes of dementia. Considering the heterogeneity in methods and results between the studies, further validation, ideally with longitudinal prospective designs with large sample sizes and unified protocols, are fundamental before conclusions can be finalised

The genetics of intellectual disability: advancing technology and gene editing [version 1; peer review: 2 approved]

Intellectual disability (ID) is a neurodevelopmental condition affecting 1–3% of the world’s population. Genetic factors play a key role causing the congenital limitations in intellectual functioning and adaptive behavior. The heterogeneity of ID makes it more challenging for genetic and clinical diagnosis, but the advent of large-scale genome sequencing projects in a trio approach has proven very effective. However, many variants are still difficult to interpret. A combined approach of next-generation sequencing and functional, electrophysiological, and bioinformatics analysis has identified new ways to understand the causes of ID and help to interpret novel ID-causing genes. This approach offers new targets for ID therapy and increases the efficiency of ID diagnosis. The most recent functional advancements and new gene editing techniques involving the use of CRISPR–Cas9 allow for targeted editing of DNA in in vitro and more effective mammalian and human tissue-derived disease models. The expansion of genomic analysis of ID patients in diverse and ancient populations can reveal rare novel disease-causing genes

PRUNE1: a disease-causing gene for secondary microcephaly

In their Letter to the Editor, Karakaya et al. (2017) present an interesting case report describing the clinical course involving secondary microcephaly of a 3-year-old Turkish boy found to be homozygous for a frameshift mutation in PRUNE1 identified through whole exome sequencing. The child presented with congenital hypotonia, contractures and global developmental delay with respiratory insufficiency and seizures developing in the first year of life. The authors note that the affected child’s head circumference plotted on the 75th centile at birth, and that by 38 months of age he had developed microcephaly. Neuroimaging at 14 months revealed cerebral and cerebellar atrophy consistent with other patients described with Prune syndrome (Karaca et al., 2015; Costain et al., 2017; Zollo et al., 2017). Although the child had abnormal neurology from birth, there was a period of early developmental regression. Peripheral spasticity in the lower extremities and optic atrophy were not documented until 38 months. In addition to the PRUNE1 variant, Karakaya et al. also identified a second homozygous variant in the CCDC14 gene in the Turkish child’s whole exome sequencing data that, while listed to have an allele count of 108 in the current Genome Aggregation Database (gnomAD) release, is notably absent in homozygous fashion (Lek et al., 2016). CCDC14 is known to be expressed in human brain, reported to negatively regulate centriole duplication and interact with proteins previously associated with primary microcephaly (Firat-Karalar et al., 2014). Thus, while it seems likely that the homozygous PRUNE1 variant is primarily responsible for the clinical presentation in the Turkish child, it is impossible to determine whether there may be any phenotypical contribution from this additional homozygous sequence variant. Recently, Costain et al. (2017) described a homozygous consensus splice site variant in PRUNE1 (c.521-2A4G; NM_021222.1) in a 2-year-old Oji-Cre male who presented with congenital hypotonia and talipes, whose head circumference was large at birth ( +3 standard deviations), but by 2 years and 2 months plotted on the 50th centile, with a weight and height on the 95th and 75th centiles, respectively. However, it should be noted that the child’s father is macrocephalic ( +4 standard deviations), the published clinical photographs at 2 years 5 months of age illustrate bitemporal narrowing, a sloping forehead and large ears, consistent with a developing microcephaly, and neuroimaging revealed cortical and cerebellar atrophy. He developed respiratory insufficiency shortly after birth, and infantile spasms in the first year of life (Costain et al., 2017). It remains to be determined how the phenotypical outcomes stemming from proposed loss-of-function mutations defined by Karakaya et al. and Costain et al., relate to missense mutations published by Karaca et al. and also Zollo et al., which are likely to involve at least partial gain-of-function outcomes in PRUNE1 activity. However, as more cases are investigated and published, the phenotype associated with autosomal recessive Prune neurodevelopmental disorder, and the functional outcomes of PRUNE1 mutation, are becoming clearer. It is now apparent that while some patients have a small head at birth and others a head circumference in the normal range, the key component of the microcephaly is that it is progressive, and associated with characteristic neuroimaging findings with a thin or hypoplastic corpus callosum and cortical and cerebellar atrophy developing in early childhood. Although all patients with Prune syndrome described to date are neurologically impaired from birth, there also appears to be a neurodegenerative component with progression of the disorder. In our manuscript, we described clinical overlap of Prune syndrome with the neurodegenerative condition associated with homozygous mutations in TBCD (Zollo et al., 2017). TBCD encodes one of the five tubulin-specific chaperones that are required for a/b-tubulin de novo heterodimer formation and the disorder is characterized by developmental regression, seizures, optic atrophy and secondary microcephaly, cortical atrophy with delayed myelination, cerebellar atrophy and thinned corpus callosum (Edvardson et al., 2016; Flex et al., 2016; Miyake et al., 2016; Pode-Shakked et al., 2017). The neurodegenerative phenotype documented in the Turkish child by Karakaya et al. further demonstrates the similarities with the TBCD disorder and Prune syndrome, and confirms optic atrophy to be a feature of Prune syndrome. Interestingly, it is also becoming clear that respiratory insufficiency is a common feature of Prune syndrome, having been documented by Karakaya et al. and in the Oji-Cre child, as well as the youngest affected Omani child described in our manuscript

R1352Q CACNA1A Variant in a Patient with Sporadic Hemiplegic Migraine, Ataxia, Seizures and Cerebral Oedema: A Case Report

Mutations in the CACNA1A gene show a wide range of neurological phenotypes including hemiplegic migraine, ataxia, mental retardation and epilepsy. In some cases, hemiplegic migraine attacks can be triggered by minor head trauma and culminate in encephalopathy and cerebral oedema. A 37-year-old male without a family history of complex migraine experienced hemiplegic migraine attacks from childhood. The attacks were usually triggered by minor head trauma, and on several occasions complicated with encephalopathy and cerebral oedema. Genetic testing of the proband and unaffected parents revealed a de novo heterozygous nucleotide missense mutation in exon 25 of the CACNA1A gene (c.4055G>A, p.R1352Q). The R1352Q CACNA1A variant shares the phenotype with other described CACNA1A mutations and highlights the interesting association of trauma as a precipitant for hemiplegic migraine. Subjects with early-onset sporadic hemiplegic migraine triggered by minor head injury or associated with seizures, ataxia or episodes of encephalopathy should be screened for mutations. These patients should also be advised to avoid activities that may result in head trauma, and anticonvulsants should be considered as prophylactic migraine 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

Identification of common genetic markers of paroxysmal neurological disorders using a network analysis approach

Emerging data have established links between paroxysmal neurological disorders or psychiatric disorder, such as migraine, ataxia, movement disorders and epilepsy. Common gene signatures such as expression, protein interaction and the associated signalling pathways link genes in these associated disorders, with the object to predict unknown disease or risk genes. In this study, we used gene interaction networks to investigate common gene signatures associated with the above phenotypes. In total, 19 candidate genes were used for making an interaction network which further revealed 39 associated genes (including KCNA1, SCN2A, CACNA1A, KCNM4, KCNO3, SCN1B and CACNB4) implicated in paroxysmal neurological disorders development and progression. The meta-regression analysis showed the strongest association of SCN2A with genes involved in schizophrenia and neurodevelopmental disorders. Importantly, our analysis showed KCNMA1 as a common gene signature with a link to epilepsy, movement disorders and wide paroxysmal neurological presentations—with the greatest potential risk of being a disease gene in a paroxysmal or psychiatric disorder. Further gene interaction analysis is required to identify unidentified gene interactions which may be targets for future drugs development

Space Launch System Booster Separation Supersonic Powered Testing with Surface and Off-Body Measurements

A wind tunnel test was run in the NASA Langley Unitary Plan Wind Tunnel simulating the separation of the two solid rocket boosters (SRB) from the core stage of the NASA Space Launch System (SLS). The test was run on a 0.9% scale model of the SLS Block 1B Cargo (27005) configuration and the SLS Block 1B Crew (28005) configuration at a Mach of 4.0. High pressure air was used to simulate plumes from the booster separation motors located at the nose and aft skirt of the two boosters. Force and moment data were taken on both SRBs and on the core stage. Schlieren still photos and video were recorded throughout testing. A set of points were acquired using Cross-correlation Doppler Global Velocimetry (CCDGV) readings to get 3 component velocity measurements between the core and the left-hand SRB. The CCDGV laser was utilized to record flow visualization in the same location, between the core and the left-hand SRB. Pressure Sensitive Paint data were taken on a separate set of runs. Computational Fluid Dynamics (CFD) runs were computed on a subset of the wind tunnel data points for comparison. A combination of the force/moment, CCDGV and Pressure Sensitive Paint (PSP) data (as well as schlieren images) at the CFD-specified test conditions will be used te the CFD simulations that will be used to build an SLS booster separation database flight conditions

A de novo dominant mutation in KIF1A associated with axonal neuropathy, spasticity and autism spectrum disorder

Mutations in the kinesin family member 1A (KIF1A) gene have been associated with a wide range of phenotypes including recessive mutations causing hereditary sensory neuropathy and hereditary spastic paraplegia and de novo dominant mutations causing a more complex neurological disorder affecting both the central and peripheral nervous system. We identified by exome sequencing a de novo dominant missense variant, (c.38G>A, p.R13H), within an ATP binding site of the kinesin motor domain in a patient manifesting a complex phenotype characterized by autism spectrum disorder (ASD), spastic paraplegia and axonal neuropathy. The presence of ASD distinguishes this case from previously reported patients with de novo dominant mutations in KIF1A

3′-UTR SNP rs2229611 in G6PC1 affects mRNA stability, expression and Glycogen Storage Disease type-Ia risk

The frequency of rs2229611, previously reported in Chinese, Caucasians, Japanese and Hispanics, was investigated for the first time in Indian ethnicity. We analyzed its role in the progression of Glycogen Storage Disease type-Ia (GSD-Ia) and breast cancer. Genotype data on rs2229611 revealed that the risk of GSD-Ia was higher (P = 0.0195) with CC compared to TT/TC genotypes, whereas no such correlation was observed with breast cancer cases. We observed a strong linkage disequilibrium (LD) among rs2229611 and other disease causing G6PC1 variants (| D′| = 1, r2 = 1). Functional validation performed in HepG2 cells using luciferase constructs showed significant (P < 0.05) decrease in expression than wild-type 3′-UTR due to curtailed mRNA stability. Furthermore, AU-rich elements (AREs) mediated regulation of G6PC1 expression characterized using 3′-UTR deletion constructs showed a prominent decrease in mRNA stability. We then examined whether miRNAs are involved in controlling G6PC1 expression using pmirGLO-UTR constructs, with evidence of more distinct inhibition in the reporter function with rs2229611. These data suggests that rs2229611 is a crucial regulatory SNP which in homozygous state leads to a more aggressive disease phenotype in GSD-Ia patients. The implication of this result is significant in predicting disease onset, progression and response to disease modifying treatments in patients with GSD-Ia