We report the clinical and genetic features of a Caucasian girl who presented a severe neurodevelopmental disorder with drug‐resistant epilepsy, hypotonia, severe gastro‐esophageal reflux and brain ...magnetic resonance imaging anomalies. WES uncovered a novel variant in homozygosis (g.197092814_197092824delinsC) in HECW2 gene that encodes the E3 ubiquitin‐protein ligase HECW2. This protein induces ubiquitination and is implicated in the regulation of several important pathways involved in neurodevelopment and neurogenesis. Furthermore, de novo heterozygous missense variants in this gene have been associated with neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL). The homozygous variant of our patient disrupts the splice donor site of intron 22 and causes the elimination of exon 22 (r.3766_3917+1del) leading to an in‐frame deletion of the protein (p.Leu1256_Trp1306del). Functional studies showed a twofold increase of its RNA expression, while the protein expression level was reduced by 60%, suggesting a partial loss‐of‐function mechanism of pathogenesis. Thus, this is the first patient with NDHSAL caused by an autosomal recessive splicing variant in HECW2.
This study identified the first patient with NDHSAL caused by an autosomal recessive splicing variant in HECW2 gene. The novel variant in homozygosis (g.197092814_197092824delinsC) produces the elimination of exon 22 (r.3765_3917del) leading to an in‐frame deletion of the protein (p.Leu1256_Trp1306del) and a 60% reduction in its expression level.
Gluten related disorders (GRD) represent a wide spectrum of clinical manifestations that are triggered by the ingestion of gluten. Coeliac disease (CD) or gluten sensitive enteropathy is the most ...widely recognised, but extra-intestinal manifestations have also been increasingly identified and reported. Such manifestations may exist in the absence of enteropathy. Gluten sensitivity (GS) is another term that has been used to include all GRD, including those where there is serological positivity for GS related antibodies in the absence of an enteropathy. Gluten ataxia (GA) is the commonest extraintestinal neurological manifestation and it has been the subject of many publications. Other movement disorders (MDs) have also been reported in the context of GS. The aim of this review was to assess the current available medical literature concerning MDs and GS with and without enteropathy. A systematic search was performed while using PubMed database. A total of 48 articles met the inclusion criteria and were included in the present review. This review highlights that the phenomenology of gluten related MDs is broader than GA and demonstrates that gluten-free diet (GFD) is beneficial in a great percentage of such cases.
Heterozygous gain-of-kinase function variants in
LRRK2
(leucine-rich repeat kinase 2) cause 1–2% of all cases of Parkinson’s disease (PD) albeit with incomplete and age-dependent penetrance. All ...pathogenic LRRK2 mutations reside within the two catalytic domains of LRRK2—either in its kinase domain (e.g. G2019S) with modest effect or its ROC-COR GTPase domain (e.g. R1441G/H) with large effect on LRRK2 kinase activity. We have previously reported assays to interrogate LRRK2 kinase pathway activity in human bio-samples measuring phosphorylation of its endogenous substrate Rab10, that mirrors LRRK2 kinase activation status. Here, we isolated neutrophils from fresh peripheral blood from 101 participants including 42 LRRK2 mutation carriers (21 with the G2019S and 21 with the R1441G mutations), 27 patients with idiopathic PD, and 32 controls. Using a dual approach, LRRK2 dependent Rab10 phosphorylation at Threonine 73 (pRab10
Thr73
) was measured by quantitative multiplexed immunoblotting for pRab10
Thr73
/total Rab10 as well as targeted mass-spectrometry for absolute pRab10
Thr73
occupancy. We found a significant over fourfold increase in pRab10
Thr73
phosphorylation in carriers of the LRRK2 R1441G mutation irrespective of clinical disease status. The effect of the LRRK2 G2019S mutation did not reach statistical significance. Furthermore, we show that LRRK2 phosphorylation at Serine 935 is not a marker for LRRK2 kinase activity in human neutrophils. When analysing pRab10
Thr73
phosphorylation in post-mortem brain samples, we observed overall high variability irrespective of clinical and LRRK2 mutation status and attributed this mainly to the adverse effect of the peri- and post-mortem period on the stability of posttranslational modifications such as protein phosphorylation. Overall, in vivo LRRK2 dependent pRab10
Thr73
phosphorylation in human peripheral blood neutrophils is a specific, robust and promising biomarker for significant LRRK2 kinase hyperactivation, as with the LRRK2 R1441G mutation. Additional readouts and/or assays may be needed to increase sensitivity to detect modest LRRK2 kinase activation, as with the LRRK2 G2019S mutation. Our assays could be useful for patient stratification and target engagement studies for LRRK2 kinase inhibitors.
Objective
Dystonia is characterised by sustained muscular contractions frequently producing repetitive, twisting and patterned movements. The primary aim of this systematic review was to establish ...how quality of life (QoL) is affected in idiopathic focal, multifocal and segmental dystonia. This review aimed to evaluate variations in QoL between different subtypes of dystonia, identify the determinants of QoL and assess the effects of different treatments on QoL.
Methodology
A systematic computer-based literature search was conducted using the PubMed database to search for papers on QoL in idiopathic focal, segmental, multifocal and generalized dystonia. We identified 75 studies meeting our inclusion criteria. Information was extracted regarding prevalence, demographics and response to treatment where indicated.
Results
This review revealed QoL to be a significant yet often overlooked issue in idiopathic dystonia. Data consistently showed that dystonia has a negative effect on QoL in patients compared to healthy controls, when measured using disease-specific and generic QoL measures. The majority of studies (
n
= 25) involved patients with cervical dystonia, followed by benign-essential blepharospasm (
n
= 10). Along with the beneficial effect to the dystonia symptoms, treatment using Botulinum Toxin and Deep Brain Stimulation is also effective in improving overall QoL across the majority of subtypes.
Conclusion
The findings demonstrate that patients’ QoL should routinely be assessed and monitored, as this may affect subsequent management. Further research will allow for more robust management of factors contributing to impaired QoL, aside from the physical defects found in dystonia.
Parkinson's disease (PD) is characterized by a great clinical heterogeneity. Nevertheless, the biological drivers of this heterogeneity have not been completely elucidated and are likely to be ...complex, arising from interactions between genetic, epigenetic, and environmental factors. Despite this heterogeneity, the clinical patterns of monogenic forms of PD have usually maintained a good clinical correlation with each mutation once a sufficient number of patients have been studied. Mutations in LRRK2 are the most commonly known genetic cause of autosomal dominant PD known to date. Furthermore, recent genome-wide association studies have revealed variations in LRRK2 as significant risk factors also for the development of sporadic PD. The LRRK2-R1441G mutation is especially frequent in the population of Basque ascent based on a possible founder effect, being responsible for almost 50% of cases of familial PD in our region, with a high penetrance. Curiously, Lewy bodies, considered the neuropathological hallmark of PD, are absent in a significant subset of LRRK2-PD cases. Indeed, these cases appear to be associated with a less aggressive primarily pure motor phenotype. The aim of our research is to examine the clinical phenotype of R1441G-PD patients, more homogeneous when we compare it with sporadic PD patients or with patients carrying other LRRK2 mutations, and reflect on the value of the observed correlation in the genetic forms of PD. The clinical heterogeneity of PD leads us to think that there may be as many different diseases as the number of people affected. Undoubtedly, genetics constitutes a relevant key player, as it may significantly influence the phenotype, with differences according to the mutation within the same gene, and not only in familial PD but also in sporadic forms. Thus, extending our knowledge regarding genetic forms of PD implies an expansion of knowledge regarding sporadic forms, and this may be relevant due to the future therapeutic implications of all forms of PD.
We report the case of a Caucasian Spanish boy, who showed profound neonatal hypotonia, feeding difficulties, apnea, severe developmental delay, epilepsy, bilateral convergent strabismus, poor verbal ...language development and a large brainstem. Whole-exome sequence uncovered a novel
de novo
mutation in the purine-rich element binding protein A gene (
PURA
; NM_005859.4:c.72del:p.(Gly25AlafsTer53)) that encodes the transcriptional activator protein Pur-alpha (PURA). Mutations in this gene have been identified in patients with PURA syndrome, a rare disorder characterized by an early hypotonia, developmental delay, severe intellectual disability with or without epilepsy, and disability in expressive language development. Although, up to 75 cases have been identified worldwide, to the best of our knowledge, this is the first patient described with a brainstem larger than normal. In conclusion, our data expand both genetic and phenotypic spectrum associated with
PURA
gene mutations.
Pain is a frequent and debilitating non-motor symptom of Idiopathic Parkinson's Disease (IPD). The present study investigated the prevalence of pain and specifically peripheral neuropathic pain (PNP) ...in IPD, and ascertained any impact of PNP on quality of life (QoL).
Patients with IPD and age- and gender-matched controls were screened for overall pain using the King's Parkinson's Pain Scale (KPPS). PNP was assessed using the Michigan Neuropathy Screening Instrument (MNSI). QoL was assessed using the 36-Item Short Form Survey (SF-36).
Fifty-one patients and 51 age and gender matched controls were recruited. The prevalence of overall pain was similar in the two groups (88.2% versus 94.1%, p = 0.487). However, patients with IPD had higher KPPS scores in fluctuation-related (4.9 ± 6.9 vs 1.1 ± 2.6, p < 0.001), nocturnal (6.6 ± 7.5 vs 1.7 ± 4.2, p < 0.001) and oro-facial (0.6 ± 2.0 vs 0.0 ± 0.0, p = 0.040) domains compared to controls.
Patients with IPD experienced more PNP compared to healthy control subjects (35.3% versus 13.7%, p = 0.011).
After adjusting for age, gender, disease duration and overall KPSS score, PNP correlated negatively with physical functioning score (beta −0.290, p = 0.036), emotional role limitations score (beta −0.319, p = 0.032) and general health perception score (beta −0.342, p = 0.014) domains of SF-36.
Peripheral neuropathic pain is prevalent in IPD and has a significant impact on QoL. The presence of burning pain is suggestive of small fibre neuropathy, but this symptom is not featured in KPSS and, therefore, a revision of the KPSS should be considered.
•Peripheral neuropathic pain is prevalent in Parkinson's disease.•Peripheral neuropathic pain correlates with poor quality of life.•A revision of the KPSS to include peripheral pain is needed.
•A rapid presumption diagnosis of botulism should be made based on key symptoms-signs.•Post exercise facilitation represents a simple and reliable diagnostic test.•Antitoxin may not be necessary in ...patients with late-presenting mild clinical picture.
Botulism is a life-threatening presynaptic disorder of the neuromuscular transmission produced by the neurotoxin elaborated by the botulinum neurotoxin-producing clostridia. We describe the management of a case series of 14 patients, members of 5 different families that were exposed to home-canned tuna and developed symptoms compatible with a mild clinical presentation of foodborne botulism. The electrophysiological study of the index case represented a reliable diagnostic test as it demonstrated a slight presynaptic dysfunction of the neuromuscular junction. Definite diagnosis was later confirmed by microbiological tests. Out of 14, only 3 patients presenting with a shorter period from symptom onset and with signs of multiple cranial neuropathies received botulinum antitoxin. All the patients remained stable and recovered progressively. Treatment with antitoxin may not be necessary in patients with late-presenting disease and mild and stable clinical picture.
Elevated urine bis(monoacylglycerol)phosphate (BMP) levels have been found in gain-of-kinase function LRRK2 G2019S mutation carriers. Here, we have expanded urine BMP analysis to other Parkinson's ...disease (PD) associated mutations and found them to be consistently elevated in carriers of LRRK2 G2019S and R1441G/C as well as VPS35 D620N mutations. Urine BMP levels are promising biomarkers for patient stratification and potentially target engagement in clinical trials of emerging targeted PD therapies.
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