encodes the voltage-gated potassium ion channel subfamily D member 3, a six trans-membrane protein (Kv4.3), involved in the transient outward K
current.
defect causes both cardiological and ...neurological syndromes. From a neurological perspective, Kv4.3 defect has been associated to SCA type 19/22, a complex neurological disorder encompassing a wide spectrum of clinical features beside ataxia. To better define the phenotypic spectrum and course of
-related neurological disorder, we review the clinical presentation and evolution in 68 reported cases. We delineated two main clinical phenotypes according to the age of onset. Neurodevelopmental disorder with epilepsy and/or movement disorders with ataxia later in the disease course characterized the early onset forms, while a prominent ataxic syndrome with possible cognitive decline, movement disorders, and peripheral neuropathy were observed in the late onset forms. Furthermore, we described a 37-year-old patient with a de novo
variant c.901T>C (p.Ser301Pro), previously reported in dbSNP as rs79821338, and a clinical phenotype paradigmatic of the early onset forms with neurodevelopmental disorder, epilepsy, parkinsonism-dystonia, and ataxia in adulthood, further expanding the clinical spectrum of this condition.
Over the last years, a constantly increasing number of genetic diseases associated with epilepsy and movement disorders have been recognized. An emerging group of conditions in this field is ...represented by genetic disorders affecting G-protein-coupled receptors (GPCRs)–cAMP signaling. This group of postsynaptic disorders includes genes encoding for proteins highly expressed in the central nervous system and involved in GPCR signal transduction and cAMP production (e.g.,
GNAO1, GNB1, ADCY5, GNAL, PDE2A, PDE10A
, and
HPCA
genes
)
. While the clinical phenotype associated with
ADCY5
and
GNAL
is characterized by movement disorder in the absence of epilepsy,
GNAO1, GNB1, PDE2A, PDE10A
, and
HPCA
have a broader clinical phenotype, encompassing movement disorder, epilepsy, and neurodevelopmental disorders. We aimed to provide a comprehensive phenotypical characterization of genetic disorders affecting the cAMP signaling pathway, presenting with both movement disorders and epilepsy. Thus, we reviewed clinical features and genetic data of 203 patients from the literature with GNAO1, GNB1, PDE2A, PDE10A, and HPCA deficiencies. Furthermore, we delineated genotype–phenotype correlation in GNAO1 and GNB1 deficiency. This group of disorders presents with a highly recognizable clinical phenotype combining distinctive motor, epileptic, and neurodevelopmental features. A severe hyperkinetic movement disorder with potential life-threatening exacerbations and high susceptibility to a wide range of triggers is the clinical signature of the whole group of disorders. The existence of a distinctive clinical phenotype prompting diagnostic suspicion and early detection has relevant implications for clinical and therapeutic management. Studies are ongoing to clarify the pathophysiology of these rare postsynaptic disorders and start to design disease-specific treatments.
Methylmalonic acidaemia with homocystinuria type C (cblC defect) is an inherited error of cobalamin metabolism. Cobalamin deficient processing results in high levels of methylmalonic acid and ...homocysteine. The latter is considered to be a risk factor for multiple sclerosis (MS). We report on the first case of a patient with comorbid cblC defect and MS.
This young male presented at the age of 14 with a relapsing-remitting neurological disorder associated with imaging alterations suggestive of MS. Treatment resulted in a partial clinical improvement with vanishing of white matter lesions. Later on, the emergence of unexpected clinical features led to a metabolic work-up, revealing a cobalamin intracellular defect. Genetic analysis disclosed a single variant in MMACHC (c.482G > A; p.Arg161Gln) and another splicing variant in PRDX1 (c.1-515G > T) that cause the silencing of the wild-type MMACHC allele, so confirming the diagnosis of cblC defect. Although cblC treatment was effective, when 17-year-old he experienced a relapse of neurological symptoms. Further imaging and laboratory studies eventually supported the diagnosis of MS.
While the comorbid association of MS and cblC in our patient may remain anecdotic, we suggest measuring Hcy and MMA levels in young patients with a relapsing-remitting demyelinating disorder, in order not to miss a cblC defect, that requires a specific and effective treatment.
To evaluate clinical phenotype and molecular findings of 157 cases with GNAO1 pathogenic or likely pathogenic variants delineating the clinical spectrum, course, and response to treatments.
Clinical ...phenotype, genetic data, and pharmacological and surgical treatment history of 11 novel cases and 146 previously published patients were analyzed.
Complex hyperkinetic movement disorder (MD) characterizes 88% of GNAO1 patients. Severe hypotonia and prominent disturbance of postural control seem to be hallmarks in the early stages preceding the hyperkinetic MD. In a subgroup of patients, paroxysmal exacerbations became so severe as to require admission to intensive care units (ICU). Almost all patients had a good response to deep brain stimulation (DBS). Milder phenotypes with late-onset focal/segmental dystonia, mild to moderate intellectual disability, and other minor neurological signs (i.e., parkinsonism and myoclonus) are emerging. MRI, previously considered noncontributory to a diagnosis, can show recurrent findings (i.e., cerebral atrophy, myelination and/or basal ganglia abnormalities). Fifty-eight GNAO1 pathogenic variants, including missense changes and a few recurrent splice site defects, have been reported. Substitutions at residues Gly203, Arg209 and Glu246, together with the intronic c.724-8G > A change, account for more than 50% of cases.
Infantile or childhood-onset complex hyperkinetic MD (chorea and/or dystonia) with or without paroxysmal exacerbations, associated hypotonia, and developmental disorders should prompt research for GNAO1 mutations. DBS effectively controls and prevents severe exacerbations and should be considered early in patients with specific GNAO1 variants and refractory MD. Prospective and natural history studies are necessary to define genotype-phenotype correlations further and clarify neurological outcomes.
•Severe hypotonia seems to be an hallmark in the early stages.•Milder non-paroxysmal dystonic phenotypes are now emerging and associated with 724-8G > A variant.•Gpi-DBS could be considered effective in controlling severe MD exacerbations.•MRI shows, especially in severe cases, cerebral atrophy, myelination and/or basal ganglia abnormalities.•Substitutions at residues 203, 209 and 246 are highly associated with severe MD exacerbations.
SUMMARY
When dealing with node or link failures in software‐defined networking (SDN), the network capability to establish an alternative path depends on controller reachability and on the round‐trip ...times between controller and involved switches. Moreover, current SDN data plane ions for failure detection, such as OpenFlow “Fast‐failover,” do not allow programmers to tweak switches' detection mechanism, thus leaving SDN operators relying on proprietary management interfaces (when available) to achieve guaranteed detection and recovery delays. We propose SPIDER, an OpenFlow‐like pipeline design that provides (i) a detection mechanism based on switches' periodic link probing and (ii) fast reroute of traffic flows even in the case of distant failures, regardless of controller availability. SPIDER is based on stateful data plane ions such as OpenState or P4, and it offers guaranteed short (few milliseconds or less) failure detection and recovery delays, with a configurable trade‐off between overhead and failover responsiveness. We present here the SPIDER pipeline design, behavioral model, and analysis on flow tables' memory impact. We also implemented and experimentally validated SPIDER using OpenState (an OpenFlow 1.3 extension for stateful packet processing) and P4, showing numerical results on its performance in terms of recovery latency and packet loss.
We present SPIDER, a design for a packet forwarding pipeline to perform sub‐millisecond failure detection and rerouting directly in the switch fast‐path, ie, without requiring the intervention of the slow control plane. SPIDER is based on recent advances in stateful data plane ions for software‐defined networking, such as OpenState or P4. We present prototype implementations and numerical results on switches' memory impact and performances in recovery latency and packet loss.
No studies have investigated voluntary movement abnormalities and their neurophysiological correlates in patients with parkinsonism due to inherited primary monoamine neurotransmitter (NT) disorders. ...Nine NT disorders patients and 16 healthy controls (HCs) were enrolled. Objective measurements of repetitive finger tapping were obtained using a motion analysis system. Primary motor cortex (M1) excitability was assessed by recording the input/output (I/O) curve of motor-evoked potentials (MEP) and using a conditioning test paradigm for short-interval intracortical inhibition (SICI) assessment. M1 plasticity-like mechanisms were indexed according to MEPs amplitude changes after the paired associative stimulation protocol. Patient values were considered abnormal if they were greater or lower than two standard deviations from the average HCs value. Patients with aromatic amino acid decarboxylase, tyrosine hydroxylase, and 6-pyruvoyl-tetrahydropterin synthase defects showed markedly reduced velocity (5/5 patients), reduced movement amplitude, and irregular rhythm (4/5 patients). Conversely, only 1 out of 3 patients with autosomal-dominant GTPCH deficiency showed abnormal movement parameters. Interestingly, none of the patients had a progressive reduction in movement amplitude or velocity during the tapping sequence (no sequence effect). Reduced SICI was the most prominent neurophysiological abnormality in patients (5/9 patients). Finally, the I/O curve slope correlated with movement velocity and rhythm in patients. We provided an objective assessment of finger tapping abnormalities in monoamine NT disorders. We also demonstrated M1 excitability changes possibly related to alterations in motor execution. Our results may contribute to a better understanding of the pathophysiology of juvenile parkinsonism due to dopamine deficiency.
Fatigue is a non-specific symptom that is common in chronic diseases and represents one of the most disabling symptoms in Parkinson’s disease. PD patients often experience cognitive deficits related ...above all to executive functions. The relationship between cognitive changes and fatigue in PD patients has not been explored in depth. The Attention Network Test (ANT) is a rapid, widely used test to measure the efficiency of three attentional networks, i.e., alerting, orienting, and executive, by evaluating reaction times (RTs) in response to visual stimuli. To assess the association between fatigue and the efficiency of the attentional networks, according to the Posnerian view, ANT was administered to 15 parkinsonian patients with fatigue (PFS-16 > 2.95), 17 parkinsonian patients without fatigue, and 37 age- and sex-matched healthy controls. Anxiety, depression, quality of sleep, and quality of life were also assessed. Parkinsonian patients displayed significantly longer RTs and lower executive network efficiency than controls. Patients with fatigue displayed significantly lower executive network efficiency than patients without fatigue. Moreover, patients with fatigue exhibited a lower accuracy than either patients without fatigue or controls. Finally, patients without fatigue displayed a more efficient alerting network than either patients with fatigue or controls. Although the pathogenesis of fatigue is multifactorial, our results indicate that fatigue may be closely related to an alteration of the striato-thalamo-cortical loop connecting the neostriatum to the prefrontal cortex, which is also responsible for the executive dysfunction that is typical of Parkinson’s disease.
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