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The SLC12 gene family consists of SLC12A1-SLC12A9, encoding electroneutral cation-coupled chloride co-transporters. SCL12A2 has been shown to play a role in corticogenesis and therefore represents a strong candidate neurodevelopmental disorder gene. Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurodevelopmental disorders. All had developmental delay or intellectual disability ranging from mild to severe. Two had sensorineural deafness. We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia. The SLC12A2 de novo mutation rate was demonstrated to be significantly elevated in the deciphering developmental disorders cohort. All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes. Analysis of SLC12A2 expression in foetal brain at 16-18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. Gene co-expression analysis in cells robustly expressing SLC12A2 at 16-18 weeks post-conception identified a transcriptomic programme associated with active neurogenesis. We identify SLC12A2 de novo mutations as the cause of a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss and provide further data supporting a role for this gene in human neurodevelopment. [ABSTRACT FROM AUTHOR]

Individuals with mutation in the lysosomal enzyme glucocerebrosidase (GBA) gene are at significantly high risk of developing Parkinson's disease with cognitive deficit. We examined whether visual short-term memory impairments, long associated with patients with Parkinson's disease, are also present in GBA-positive individuals-both with and without Parkinson's disease. Precision of visual working memory was measured using a serial order task in which participants observed four bars, each of a different colour and orientation, presented sequentially at screen centre. Afterwards, they were asked to adjust a coloured probe bar's orientation to match the orientation of the bar of the same colour in the sequence. An additional attentional 'filtering' condition tested patients' ability to selectively encode one of the four bars while ignoring the others. A sensorimotor task using the same stimuli controlled for perceptual and motor factors. There was a significant deficit in memory precision in GBA-positive individuals-with or without Parkinson's disease-as well as GBA-negative patients with Parkinson's disease, compared to healthy controls. Worst recall was observed in GBA-positive cases with Parkinson's disease. Although all groups were impaired in visual short-term memory, there was a double dissociation between sources of error associated with GBA mutation and Parkinson's disease. The deficit observed in GBA-positive individuals, regardless of whether they had Parkinson's disease, was explained by a systematic increase in interference from features of other items in memory: misbinding errors. In contrast, impairments in patients with Parkinson's disease, regardless of GBA status, was explained by increased random responses. Individuals who were GBA-positive and also had Parkinson's disease suffered from both types of error, demonstrating the worst performance. These findings provide evidence for dissociable signature deficits within the domain of visual short-term memory associated with GBA mutation and with Parkinson's disease. Identification of the specific pattern of cognitive impairment in GBA mutation versus Parkinson's disease is potentially important as it might help to identify individuals at risk of developing Parkinson's disease. [ABSTRACT FROM AUTHOR]

Individuals with mutation in the lysosomal enzyme glucocerebrosidase (GBA) gene are at significantly high risk of developing Parkinson’s disease with cognitive deficit. We examined whether visual short-term memory impairments, long associated with patients with Parkinson’s disease, are also present in GBA-positive individuals—both with and without Parkinson’s disease. Precision of visual working memory was measured using a serial order task in which participants observed four bars, each of a different colour and orientation, presented sequentially at screen centre. Afterwards, they were asked to adjust a coloured probe bar’s orientation to match the orientation of the bar of the same colour in the sequence. An additional attentional ‘filtering’ condition tested patients’ ability to selectively encode one of the four bars while ignoring the others. A sensorimotor task using the same stimuli controlled for perceptual and motor factors. There was a significant deficit in memory precision in GBA-positive individuals—with or without Parkinson’s disease—as well as GBA-negative patients with Parkinson’s disease, compared to healthy controls. Worst recall was observed in GBA-positive cases with Parkinson’s disease. Although all groups were impaired in visual short-term memory, there was a double dissociation between sources of error associated with GBA mutation and Parkinson’s disease. The deficit observed in GBA-positive individuals, regardless of whether they had Parkinson’s disease, was explained by a systematic increase in interference from features of other items in memory: misbinding errors. In contrast, impairments in patients with Parkinson’s disease, regardless of GBA status, was explained by increased random responses. Individuals who were GBA-positive and also had Parkinson’s disease suffered from both types of error, demonstrating the worst performance. These findings provide evidence for dissociable signature deficits within the domain of visual short-term memory associated with GBA mutation and with Parkinson’s disease. Identification of the specific pattern of cognitive impairment in GBA mutation versus Parkinson’s disease is potentially important as it might help to identify individuals at risk of developing Parkinson’s disease. [ABSTRACT FROM AUTHOR]

Heterozygous GBA gene mutations are the most frequent Parkinson’s disease risk factor. Using Parkinson’s disease patient derived fibroblasts McNeill et al. show that heterozygous GBA mutations reduce glucosylceramidase activity, and are associated with endoplasmic reticulum and oxidative stress. Ambroxol treatment improved glucosylceramidase activity and reduced oxidative stress in these cells.Gaucher disease is caused by mutations in the glucocerebrosidase gene, which encodes the lysosomal hydrolase glucosylceramidase. Patients with Gaucher disease and heterozygous glucocerebrosidase mutation carriers are at increased risk of developing Parkinson’s disease. Indeed, glucocerebrosidase mutations are the most frequent risk factor for Parkinson’s disease in the general population. Therefore there is an urgent need to understand the mechanisms by which glucocerebrosidase mutations predispose to neurodegeneration to facilitate development of novel treatments. To study this we generated fibroblast lines from skin biopsies of five patients with Gaucher disease and six heterozygous glucocerebrosidase mutation carriers with and without Parkinson’s disease. Glucosylceramidase protein and enzyme activity levels were assayed. Oxidative stress was assayed by single cell imaging of dihydroethidium. Glucosylceramidase enzyme activity was significantly reduced in fibroblasts from patients with Gaucher disease (median 5% of controls, P = 0.0001) and heterozygous mutation carriers with (median 59% of controls, P = 0.001) and without (56% of controls, P = 0.001) Parkinson’s disease compared with controls. Glucosylceramidase protein levels, assessed by western blot, were significantly reduced in fibroblasts from Gaucher disease (median glucosylceramidase levels 42% of control, P < 0.001) and heterozygous mutation carriers with (median 59% of control, P < 0.001) and without (median 68% of control, P < 0.001) Parkinson’s disease. Single cell imaging of dihydroethidium demonstrated increased production of cytosolic reactive oxygen species in fibroblasts from patients with Gaucher disease (dihydroethidium oxidation rate increased by a median of 62% compared to controls, P < 0.001) and heterozygous mutation carriers with (dihydroethidium oxidation rate increased by a median of 68% compared with controls, P < 0.001) and without (dihydroethidium oxidation rate increased by a median of 70% compared with controls, P < 0.001) Parkinson’s disease. We hypothesized that treatment with the molecular chaperone ambroxol hydrochloride would improve these biochemical abnormalities. Treatment with ambroxol hydrochloride increased glucosylceramidase activity in fibroblasts from healthy controls, Gaucher disease and heterozygous glucocerebrosidase mutation carriers with and without Parkinson’s disease. This was associated with a significant reduction in dihydroethidium oxidation rate of ∼50% (P < 0.05) in fibroblasts from controls, Gaucher disease and heterozygous mutation carriers with and without Parkinson’s disease. In conclusion, glucocerebrosidase mutations are associated with reductions in glucosylceramidase activity and evidence of oxidative stress. Ambroxol treatment significantly increases glucosylceramidase activity and reduces markers of oxidative stress in cells bearing glucocerebrosidase mutations. We propose that ambroxol hydrochloride should be further investigated as a potential treatment for Parkinson’s disease. [ABSTRACT FROM PUBLISHER]

Objectives: To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease. Methods: A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. The right:left asymmetry index and striatal asymmetry index was calculated. Results: Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). The asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations. Conclusions: The asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess a cohort of Gaucher disease patients and their heterozygous carrier relatives for potential clinical signs of early neurodegeneration. Gaucher disease patients (n = 30), heterozygous glucocerebrosidase mutation carriers (n = 30), and mutation-negative controls matched by age, sex, and ethnicity (n = 30) were recruited. Assessment was done for olfactory function (University of Pennsylvania Smell Identification Test), cognitive function (Mini-Mental State Examination, Montreal Cognitive Assessment), rapid eye movement sleep disorder, autonomic symptoms, and parkinsonian motor signs (Unified Parkinson's Disease Rating Scale part III, Purdue pegboard). Olfactory function scores were significantly lower in Gaucher disease patients ( P = .010) and heterozygous carriers ( P < .001) than in controls. Cognitive assessment scores were significantly lower in Gaucher disease patients ( P = .002) and carriers ( P = .002) than in controls. Unified Parkinson's Disease Rating Scale motor subscale scores were significantly higher in Gaucher disease patients ( P < .001) and heterozygotes ( P = .0010) than in controls. There was no difference in scores for symptoms of rapid eye movement sleep disorder or autonomic dysfunction. Impairment of olfaction, cognition, and parkinsonian motor signs occurs more frequently in Gaucher disease patients and carriers than in controls, which may indicate the early stages of neurodegeneration. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Distal myopathies are a clinically and genetically heterogenous group of disorders in which the distal limb musculature is selectively or disproportionately affected. Precisely defining specific categories is a challenge because of overlapping clinical phenotypes, making it difficult to decide which of the many known causative genes to screen in individual cases. In this study we define the distinguishing magnetic resonance imaging findings in myotilin myopathy by studying 8 genealogically unrelated cases due to the same point mutation in TTID. Proximally, the vastii, biceps femoris and semimembranosus were involved with sparing of gracilis and sartorius. Distally, soleus, gastrocnemius, tibialis anterior, extensor hallicus and extensor digitorum were involved. This pattern contrasts with other distal myopathies and provides further support for the role of imaging in the clinical investigation of muscle disease. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism resulting from mutations of the ceruloplasmin gene. To better define the neurological phenotype of aceruloplasminemia we reviewed reports of published cases and sought details of unpublished ones. We identified 32 published reports and 1 unpublished case. The age at diagnosis ranged from 16 to 71 years with a mean of 51. For the 28 homozygous cases the most common presentation was with cognitive impairment (12/28, 42%) accompanied by craniofacial dyskinesia (8/28, 28%), cerebellar ataxia (13/28, 46%) and retinal degeneration (21/28, 75%). Four heterozygotes presented with cerebellar signs or tremor, whilst 1 had chorea-athetosis. There were no genotype-phenotype associations, but homozygotes tended to have severer disease. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. People with Multiple Sclerosis (pwMS) prioritise gait as the most valuable function to be affected by MS. Physiotherapy plays a key role in managing gait impairment in MS. There is little evidence on the effectiveness of physiotherapy for severe MS. Objective. To undertake a systematic review and meta-analysis of the literature to identify evidence for the effectiveness of physiotherapy for gait impairment in severe MS. Methods. The available literature was systematically searched, using a predetermined protocol, to identify research studies investigating a physiotherapy intervention for mobility in people with severe MS (EDSS ≥ 6.0). Data on mobility related endpoints was extracted. Meta-analysis was performed where a given mobility end point was reported in at least 3 studies. Results. 37 relevant papers were identified, which included 788 pwMS. Seven mobility-related endpoints were meta-analysed. Robot-Assisted Gait Training (RAGT) was found to improve performance on the 6-minute walk test, 10-metre walk test, fatigue severity scale, and Berg Balance Scale. Neither body weight supported training nor conventional walking training significantly improved any mobility-related outcomes. Conclusion. Physiotherapy interventions are feasible for mobility in severe MS. There is some evidence for the effectiveness of RAGT. [ABSTRACT FROM AUTHOR]

Abstract: Both Gaucher disease patients and heterozygous glucocerebrosidase mutation carriers are at increased risk of Parkinson's disease. Retinal thinning has been reported in early Parkinson's disease. Here we used optical coherence tomography to demonstrate thinning of the retinal ganglion cell layer in Gaucher disease patients and carriers who manifest clinical markers of potential early neurodegeneration. Optical coherence tomography may help identify Gaucher disease patients and carriers at increased risk of developing Parkinson's disease. [Copyright &y& Elsevier]

Abstract: To determine the frequency of mutations responsible for Gaucher''s disease, we systematically sequenced the GBA1 gene as part of a molecular characterization of 73 adult patients in the United Kingdom. Five hitherto unknown pathogenic variants were identified, one of which is a splice site change; the others are novel missense mutations. Given that GBA1 gene mutations are an important risk factor for the development of Parkinson''s disease, we contend that a complete analysis and molecular characterization of both the known and novel GBA1 variants will be needed before the biochemical processes underlying this genetic association can be fully understood. [Copyright &y& Elsevier]

Genetic testing is a key decision-making point for people with motor neuron disease (MND); to establish eligibility for clinical trials, better understand the cause of their condition, and confirm the potential risk to relatives, who may be able to access predictive testing. Given the wide-reaching implications of MND genetic and predictive testing, it is essential that families are given adequate information, and that staff are provided with appropriate training. In this report we overview the information resources available to people with MND and family members around genetic testing, and the educational and training resources available to staff, based on information obtained through a freedom of information request to UK-based NHS Trusts. MND Association resources were most commonly used in information sharing, though we highlight distinctions between neurology and genetics centers. No respondents identified comprehensive training around MND genetic testing. We conclude with practice implications and priorities for the development of resources and training. [ABSTRACT FROM AUTHOR]

The heterogenous aetiology of Parkinson's disease is increasingly recognized; both mitochondrial and lysosomal dysfunction have been implicated. Powerful, clinically applicable tools are required to enable mechanistic stratification for future precision medicine approaches. The aim of this study was to characterize bioenergetic dysfunction in Parkinson's disease by applying a multimodal approach, combining standardized clinical assessment with midbrain and putaminal 31-phosphorus magnetic resonance spectroscopy (31P-MRS) and deep phenotyping of mitochondrial and lysosomal function in peripheral tissue in patients with recent-onset Parkinson's disease and control subjects. Sixty participants (35 patients with Parkinson's disease and 25 healthy controls) underwent 31P-MRS for quantification of energy-rich metabolites [ATP, inorganic phosphate (Pi) and phosphocreatine] in putamen and midbrain. In parallel, skin biopsies were obtained from all research participants to establish fibroblast cell lines for subsequent quantification of total intracellular ATP and mitochondrial membrane potential (MMP) as well as mitochondrial and lysosomal morphology, using high content live cell imaging. Lower MMP correlated with higher intracellular ATP (r = −0.55, P = 0.0016), higher mitochondrial counts (r = −0.72, P < 0.0001) and higher lysosomal counts (r = −0.62, P = 0.0002) in Parkinson's disease patient-derived fibroblasts only, consistent with impaired mitophagy and mitochondrial uncoupling. 31P-MRS-derived posterior putaminal Pi/ATP ratio variance was considerably greater in Parkinson's disease than in healthy controls (F-tests, P = 0.0036). Furthermore, elevated 31P-MRS-derived putaminal, but not midbrain Pi/ATP ratios (indicative of impaired oxidative phosphorylation) correlated with both greater mitochondrial (r = 0.37, P = 0.0319) and lysosomal counts (r = 0.48, P = 0.0044) as well as lower MMP in both short (r = −0.52, P = 0.0016) and long (r = −0.47, P = 0.0052) mitochondria in Parkinson's disease. Higher 31P-MRS midbrain phosphocreatine correlated with greater risk of rapid disease progression (r = 0.47, P = 0.0384). Our data suggest that impaired oxidative phosphorylation in the striatal dopaminergic nerve terminals exceeds mitochondrial dysfunction in the midbrain of patients with early Parkinson's disease. Our data further support the hypothesis of a prominent link between impaired mitophagy and impaired striatal energy homeostasis as a key event in early Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background: Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD. Objectives: To investigate the safety and tolerability of high‐dose UDCA in PD and determine midbrain target engagement. Methods: The UP (UDCA in PD) study was a phase II, randomized, double‐blind, placebo‐controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31‐phosphorus magnetic resonance spectroscopy (31P‐MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS‐UPDRS‐III) and objective, motion sensor‐based quantification of gait impairment. Results: UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain 31P‐MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor‐based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS‐UPDRS‐III failed to detect a difference between treatment groups. Conclusions: High‐dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease‐modifying effect of UDCA in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The article presents a study focusing on clinical and family history study of parkinson's disease (PD) in heterozygous glucocerebrosidase mutation (GBA) carriers. It states that Type I Gaucher disease (GD), the most common lysosomal storage disorder is caused by recessive glucocerebrosidase mutations. It shows that the more severe cognitive dysfunction in PDGBA implies that there may be a widespread cortical pathology than in PD-S.

A letter to the editor which discusses the impact of colonic scleroderma on the occurrence of anastomotic failure is presented.

A letter to the editor is presented which reports on the case of a 78-year-old female with chorea associated with trazodone use.

Presents a letter to the editor on the influence of codon 129 polymorphism of the prion protein gene on cognitive performance in Down's syndrome subjects.

Background: Cerebellar Ataxias are a group of gait disorders resulting from dysfunction of the cerebellum, commonly characterised by slowly progressing incoordination that manifests as problems with balance and walking leading to considerable disability. There is increasing acceptance of gait analysis techniques to quantify subtle gait characteristics that are unmeasurable by current clinical methods This systematic review aims to identify the gait characteristics able to differentiate between Cerebellar Ataxia and healthy controls.Methods: Following systematic search and critical appraisal of the literature, gait data relating to preferred paced walking in Cerebellar Ataxia was extracted from 21 studies. A random-effect model meta-analysis was performed for 14 spatiotemporal parameters. Quality assessment was completed to detect risk of bias.Results: There is strong evidence that compared with healthy controls, Cerebellar Ataxia patients walk with a reduced walking speed and cadence, reduced step length, stride length, and swing phase, increased walking base width, stride time, step time, stance phase and double limb support phase with increased variability of step length, stride length, and stride time.Conclusion: The consensus description provided here, clarifies the gait pattern associated with ataxic gait disturbance in a large cohort of participants. High quality research and reporting is needed to explore specific genetic diagnoses and identify biomarkers for disease progression in order to develop well-evidenced clinical guidelines and interventions for Cerebellar Ataxia. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about the use of case studies to teach junior doctors regarding medical publishing.

Here we report the case of a young boy with developmental delay, thin sparse hair, early closure of the anterior fontanel, bilateral choanal atresia, brachyturicephaly; and dysmorphic features closely resembling those seen in trichorhinophalangeal syndrome (TRPS). These features include sparse hair, sparse lateral eyebrows, a bulbous pear shaped nose, a long philtrum, thin lips, small/hypoplastic nails, pes planovalgus; bilateral cone-shaped epiphyses at the proximal 5th phalanx, slender long bones, coxa valga, mild scoliosis, and delayed bone age. Given that TRPS had been excluded by a thorough genetic analysis, whole exome sequencing was performed and a heterozygous likely pathogenic variant was identified in the FBXO11 gene (NM_001190274.2: c.1781A > G; p. His594Arg), confirming the diagnosis of the newly individualized IDDFBA syndrome: Intellectual Developmental Disorder, dysmorphic Facies, and Behavioral Abnormalities (OMIM# 618,089). Our findings further delineate the clinical spectrum linked to FBXO11 and highlight the importance of investigating further cases with mutations in this gene to establish a potential genotype-phenotype correlation. [ABSTRACT FROM AUTHOR]

SOX11 syndrome is a rare condition caused by deletions or de novo point mutations of the SOX11 gene. SOX11 is a transcription factor gene that plays an important role in brain development. The aim of this study was to quantitatively evaluate the behavioural profiles of individuals with SOX11 syndrome. The Vineland Adaptive Behaviour Scales 3 (VABS-3) and the Social Responsiveness Scale 2 (SRS-2) were completed by parents of 21 children and young adults with SOX11 syndrome. Most were found to have borderline (33 %) or mild (39 %) impairment in adaptive behaviour, with more difficulties in communication and daily living than socialisation in the cohort overall. Most (90 %) were found to exhibit clinically relevant levels of autistic traits, with 62 % scoring in the "severe" range, though social motivation was observed to be a relative strength in the cohort overall. This study presents the first standardised evaluation of adaptive behaviour and autistic traits of individuals with SOX11 syndrome. This will improve clinicians, educators and parents' understanding of SOX11 syndrome. • This study reports the first evaluation of adaptive behaviour and autistic traits of individuals with SOX11 syndrome. • Most individuals with SOX11 have borderline or mild impairment in adaptive behaviour. • Most individuals with SOX11 have clinically relevant levels of autistic traits. • Social motivation is a relative strength in SOX11 syndrome. [ABSTRACT FROM AUTHOR]

Background: Five to 25% of patients with PD carry glucocerebrosidase gene mutations, and 10% to 30% of glucocerebrosidase carriers will develop PD by age 80. Stratification of PD risk in glucocerebrosidase carriers provides an opportunity to target disease-modifying therapies.Objective: Cross-sectional and longitudinal survey of prodromal PD signs among glucocerebrosidase carriers.Design: Prospective assessment of 82 glucocerebrosidase mutation carriers and 35 controls over 4 to 5 years for prodromal clinical PD features.Results: At all time points, olfactory (measured using University of Pennsylvania Smell Identification Test) and cognitive (Montreal Cognitive Assessment) function and the International Parkinson and Movement Disorder Society UPDRS parts II and III scores were significantly worse amongst glucocerebrosidase mutation carriers. Progression to microsmia (odds ratio: 8.5; 95% confidence interval: 2.6-28.2; P < 0.05) and mild cognitive impairment (odds ratio: 4.2; 95% confidence interval: 1.1-16.6; P < 0.05) were more rapid compared to controls. Those with worse olfaction also had worse cognition (OR, 1.5; 95% CI: 0.0-2.8; P < 0.05) and depression (OR, 1.3; 95% CI: 0.6-2.8; P < 0.05). No participants reached the MDS prodromal PD diagnostic criteria before PD diagnosis. One participant developed PD. He did not fulfill the International Parkinson and Movement Disorder Society prodromal PD criteria before diagnosis.Conclusion: Assessment of individual and clustered PD prodromal features may serve as a useful tool to identify high-risk subjects for conversion to PD. As a result of the low conversion rate in our glucocerebrosidase mutation carriers to date, prospective validation is needed in larger cohorts to establish the profile of these features in PD convertors. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism. [ABSTRACT FROM AUTHOR]

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms “mental retardation”. To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus. [ABSTRACT FROM AUTHOR]

Warburg Micro syndrome and Martsolf syndrome are heterogenous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Previously, identification of mutations in RAB3GAP1 and RAB3GAP2 in both these syndromes implicated dysregulation of the RAB3 cycle (which controls calcium-mediated exocytosis of neurotransmitters and hormones) in disease pathogenesis. RAB3GAP1 and RAB3GAP2 encode the catalytic and noncatalytic subunits of the hetrodimeric enzyme RAB3GAP (RAB3GTPase-activating protein), a key regulator of the RAB3 cycle. We performed autozygosity mapping in five consanguineous families without RAB3GAP1/2 mutations and identified loss-of-function mutations in RAB18. A c.71T > A (p.Leu24Gln) founder mutation was identified in four Pakistani families, and a homozygous exon 2 deletion (predicted to result in a frameshift) was found in the fifth family. A single family whose members were compound heterozygotes for an anti-termination mutation of the stop codon c.619T > C (p.X207QextX20) and an inframe arginine deletion c.277_279 del (p.Arg93 del) were identified after direct gene sequencing and multiplex ligation-dependent probe amplification (MLPA) of a further 58 families. Nucleotide binding assays for RAB18(Leu24Gln) and RAB18(Arg93del) showed that these mutant proteins were functionally null in that they were unable to bind guanine. The clinical features of Warburg Micro syndrome patients with RAB3GAP1 or RAB3GAP2 mutations and RAB18 mutations are indistinguishable, although the role of RAB18 in trafficking is still emerging, and it has not been linked previously to the RAB3 pathway. Knockdown of rab18 in zebrafish suggests that it might have a conserved developmental role. Our findings imply that RAB18 has a critical role in human brain and eye development and neurodegeneration. [ABSTRACT FROM AUTHOR]

The article offers information on a study which examines the pathology and olfactory impairment in neurodegenerative disorders with brain iron accumulation (NBIA). It examines an olfactory tissue from NBIA patients and a mouse model for iron deposition. It shows that hyposmia in NBIA is associated with ferritin and iron deposition in the olfactory system.