Ataxia-telangiectasia (A-T) is a rare inherited disorder resulting from mutations in the ATM gene and characterized by progressive neurodegeneration, immunological abnormalities, and increased infection and cancer susceptibility. There is no cure for A-T, and life expectancy is drastically reduced because of pulmonary disease and cancer. Humoral or T/B-cell deficiency was associated with reduced survival in A-T patients, although the findings remain controversial. Conversely, A-T patients display normal numbers of NK cells, crucial components of the antitumor and antiviral innate immunity. The goal of the present study was to investigate the function of NK cells in A-T. Peripheral blood NK cells of 31 A-T patients were analyzed via flow cytometry to assess their distribution across subpopulations and expression of maturation markers, receptors and effector molecules. Additionally, we assessed the capacity of NK cells to kill K562 cells and to produce IFN-γ in response to IL-12/IL-15/IL-18 stimulation. The plasma levels of soluble ligands for the NKG2D receptor (sNKG2DLs) and cytokines were measured via ELISA. Compared with control NK cells, A-T patient NK cells presented higher frequencies of the CD56bright and CD56dimCD16− subsets and contraction of the highly cytotoxic CD56dim subset that, however, showed a normal maturation pattern. The expression of the main activating/inhibitory receptors was conserved on A-T NK cells, except for the up- and downregulation of PD-1 and NKG2D, respectively. NKG2D downregulation correlated with accumulation of the sNKG2DLs sMICA and sULBP2 in patient plasma. Importantly, A-T NK cells were inefficient at producing IFN-γ upon stimulation and strongly impaired at killing tumor targets, dysfunctions that were reproduced by inhibiting ATM in PBMCs of healthy individuals. Finally, in A-T plasma, we detected elevated levels of IL-6, which correlated with NK-cell phenotypic alterations and reduced IFN-γ response, and increased levels of TGF-β, which correlated with impaired NK-cell cytotoxicity. The present study fills a gap in the field of A-T immunity, revealing exhaustion-associated features and functional impairment of NK cells correlated with increased plasma concentrations of sNKG2DLs and the immunosuppressive cytokines IL-6 and TGF-β. These findings indicate that NK defects can contribute to cancer and infection susceptibility and provide hints for improving current therapies for A-T.

The objective evaluation of movement disorders commonly due to neurological diseases represents a clinical challenge, since traditional diagnostic methods rely on the experience of specialized medical personnel. Recent advancements in video-based technologies have opened new avenues for non-invasive, continuous, and objective monitoring of motor symptoms in both clinical and real-world settings. In this paper, a novel video-based method to assess bradykinesia (i.e., slow and irregular movements) in children affected by a rare neurological disorder, known as Ataxia-Telangiectasia (AT), is presented. Motion features of interest are extracted from videos of patients' hands and healthy subjects' hands performing the clinical task known as Finger Tapping (FT). The obtained results are compared in terms of speed and regularity, in order to demonstrate the feasibility of the proposed method.

With the growing possibilities in genetic testing, the number of genetic disorders associated with dystonia has constantly increased over the last few years. Accurate phenotyping is crucial to guide and interpret genetic analyses in the search for an etiological diagnosis. Although eye movements examination has proven a valuable tool in the assessment of patients with inherited movement disorders such as ataxia or parkinsonism, less is known about the association between eye movement disorders and genetic dystonia. This study aimed to summarize the most frequent eye movement disorders in monogenetic forms of dystonia as classified by the Movement Disorders Society (MDS). More than sixty genetic disorders causing dystonia were repeatedly associated with eye movement disorders. Among these, 24 are classified as DYT genes, 22 were classified by MDS as having another prominent movement disorder, and 19 are genetic disorders that manifest with dystonia but are not included in the MDS classification. Six different eye movement disorders have consistently been reported (saccadic slowing and supranuclear gaze palsy, saccadic initiation failure and oculomotor apraxia, saccadic dysmetria, oculogyric crisis, nystagmus and ophthalmoplegia). The phenotypic association of each disorder with monogenic dystonic diseases, as well as the possible underlying pathophysiological mechanisms, is described here. Our findings suggest that eye movement disorders, along with the movement phenotype, may help delineate subgroups of dystonia by reflecting disruptions in specific brain networks. Therefore, eye movement examination is a crucial part of the neurological evaluation, providing valuable insights into patients with inherited forms of dystonia.

Spinocerebellar ataxia-21 (SCA21) is an autosomal dominant neurodegenerative disorder due to pathogenic variants of the TMEM240 gene. Its clinical presentation usually includes slowly progressive cerebellar ataxia, myoclonus-dystonia syndrome, cognitive impairment, and behavioral problems. Here, we reported the first patient with SCA21 presenting with a developmental and epileptic encephalopathy with seizure onset during late childhood, a seizure semeiology including atonic, clonic, myoclonic seizures, and absences with eyelid myoclonia and an EEG pattern characterized by diffuse spike and wave discharges. Epilepsy was associated with a progressive motor deterioration (the International Cooperative Ataxia Rating Scale-ICARS Total Ataxia score switched from 23/100 to 35/100 over a period of 2 years), a worsening of a preexisting tremor, and a disabling drowsiness. Nonverbal measure of intellectual functioning revealed a moderate intellectual disability (Leiter-R: brief IQ 40; fluid reasoning 52). The epileptogenic mechanisms involving TMEM240 might be correlated with disinhibition of excitotoxic networks due to the loss of Purkinje cells in the cerebellum, but also damage in neuronal bioenergetic pathways and synaptic vesicular trafficking within cortico-cerebellar and thalamo-cerebellar circuits.

Spinocerebellar ataxias (SCAs) are characterized by substantial phenotypic variability. Among them, SCA42 is a rare non-expansion entity presenting with slowly progressive cerebellar syndrome but whose clinical spectrum may be also wider. A 53-year-old male presented with progressive myoclonus-ataxia and intellectual disability. Genetic screening revealed a novel c.3835G > A (p. Asp1279Asn) variant in the CACNA1G gene. SCA42 is a rare non-expansion SCA caused by mutations in CACNA1G on chromosome 17q21, encoding the Ca(V)3.1, a low-threshold voltage-gated T-type calcium channel. The novel variant we identified is potentially involved in channel activity. This case expands the knowledge regarding CACNA1G-associated phenotype and highlights the importance of genetic screening in myoclonus-ataxia disorders.

IntroductionNegative myoclonus (NM) is an involuntary movement caused by a sudden interruption of muscular activity, resulting in gait problems and falls.ObjectiveTo establish frequency, clinical impact, and neurophysiology of NM in progressive myoclonus ataxia (PMA) patients.MethodsClinical, neurophysiological, and genetic data of 14 PMA individuals from University Medical Centre Groningen (UMCG) Expertise Center Movement Disorder Groningen were retrospectively collected. Neurophysiological examination included video-electromyography-accelerometry assessment in all patients and electroencephalography (EEG) examination in 13 individuals. Jerk-locked (or silent period-locked) back-averaging and cortico-muscular coherence (CMC) analysis aided the classification of myoclonus.ResultsNM was present in 6 (NM+) and absent in 8 (NM-) PMA patients. NM+ individuals have more frequent falls (100% vs. 37.5%) and higher scores on the Gross Motor Function Classification System (GMFCS) (4.3 +/- 0.74 vs. 2.5 +/- 1.2) than NM- individuals. Genetic background of NM+ included GOSR2 and SEMA6B, while that of NM- included ATM, KCNC3, NUS1, STPBN2, and GOSR2. NM was frequently preceded by positive myoclonus (PM) and silent-period length was between 88 and 194 ms. EEG epileptiform discharges were associated with NM in 2 cases. PM was classified as cortical in 5 NM+ and 2 NM- through EEG inspection, jerk-locked back-averaging, or CMC analysis.DiscussionNeurophysiological examination is crucial for detecting NM that could be missed on clinical examination due to a preceding PM. Evidence points to a cortical origin of NM, an association with more severe motor phenotype, and suggests the presence of genetic disorders causing either a PMA or progressive myoclonus epilepsy, rather than pure PMA phenotype. (c) 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Appendix S1. Supplementary material. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Supplementary Table 1. Movement disorders in subjects harboring a CLTC pathogenic variant. Video 1. Segment 1 – Pre-treatment. The girl shows bradykinesia, postural instability, lack of postural reactions, and dystonic postures in the attempt to stand. With walking, possible with truncal support, dystonic gait and upper limbs dystonic posturing become evident. Segment 2 – Post-treatment. After 2 months of treatment (selegiline titrated up to 5 mg/day) the child could stand autonomously, and bradykinesia and postural control improved allowing functional voluntary movements of the upper limbs. Walking was possible with frontal hand support with improved speed and reduced lower limb dystonia. Hypomimia is still evident (no blinking can be seen) and gaze pursuit is now possible with less evident nodding head movements. Saccadic latency is still present but with a shorter delay. Post-treatment follow-up: On follow-up, there is a reduction of limb dysmetria and less trunk oscillation while in a standing position. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Aim: 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.Method: Clinical phenotype, genetic data, and pharmacological and surgical treatment history of 11 novel cases and 146 previously published patients were analyzed.Results: 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.Interpretation: 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.

GNAO1 variants are typically associated with severe, early-onset movement disorders (MDs) with life-threatening and drug-resistant paroxysmal exacerbations, neurodevelopmental disorders, and epilepsy. Recently, the phenotypic spectrum has broadened to include milder phenotypes with late-onset dystonia, minor cognitive impairment, and other neurological signs, including parkinsonism and myoclonus. GNAO1 haploinsufficiency has been evoked as a putative mechanism underlying milder clinical presentations.1, 2 To date, however, the functional consequences of this class of variants have not yet been evaluated. We report on an 8-year-old boy with subtle neurological signs, including generalized tonic–clonic seizures during fever, mild language impairment, dystonic postures of lower limbs during walking, and occasional tongue dyskinetic movements (see Data S1 for more details and Video 1). A next generation sequencing–based epilepsy panel revealed a de novo NM_020988.3:c.163_164del variant in GNAO1. No additional candidate variants were identified. Reverse transcription polymerase chain reaction showed an approximately 50% decrease in the expression of the endogenous GNAO1 gene in cells from the affected child compared with cells from the unaffected father (Figs. 1A and S2), suggesting nonsense-mediated mRNA decay (NMD). If translated, the c.163_164delAT allele was predicted to generate a truncated protein (p.Ile55Hisfs*3). As expected, Western blotting performed in transiently transfected HEK293T cells revealed the lack of the truncated form of Gαo (Fig. 1B), which was not restored by MG132 or bafilomycin treatments, inhibitors of the ubiquitin/proteasome and autophagy pathways, respectively. These findings demonstrate that the c.163_164delAT transcript undergoes NMD, leading to GNAO1 haploinsufficiency. Genotype/phenotype correlations in GNAO1 encephalopathy are still far from being elucidated. Recent studies suggest that pathogenic variants have a loss-of-function effect on Gαo-mediated signaling,3-7 but the consequences on G-beta-gamma subunit (Gβγ) signaling that regulates cyclic adenosine monophosphate production remain unclear. Emerging data show that haploinsufficiency is associated with milder clinical features and later onset than missense changes underlying developmental and epileptic encephalopathy type 17 (Mendelian inheritance in man [MIM]#615473) or neurodevelopmental disorder with involuntary movements (MIM#617493). This finding has important implications. First, given the different phenotypic output, variants associated with the canonical form of GNAO1 encephalopathy cannot have a simple loss-of-function effect; rather, they behave as dominant-negative alleles or alter Gα/Gβγ association, as recently shown for a subset of changes.3-7 Second, the phenotype associated with GNAO1 haploinsufficiency is likely attributed to increased levels of free Gβγ in the brain, which, in turn, could lead to increased receptor-independent Gβγ signaling in neurons. Finally, the association of GNAO1 haploinsufficiency with a subtle but distinctive phenotype may help to design a proper gene therapy strategy. Allele-specific silencing by antisense oligonucleotides or short-interfering RNAs is unlikely to be a reasonable approach because 50% of the gene dosage is not neutral and single nucleotide substitutions hardly confer a complete discrimination for allele-specific targeting. In contrast, AAV-mediated gene supplementation coupled with silencing of the mutant allele is expected to effectively alleviate the disease phenotype. Our findings also indicate that GNAO1 variants may be more frequent than previously estimated and encourage testing for this gene in patients with mild neurological signs featuring epilepsy and/or MDs without a definite diagnosis. The progression into more severe phenotypes, and possible neurological deterioration induced by triggering events, typical for this condition, deserve a careful and prolonged clinical follow-up. Written informed consent for offline and online video distribution of the video material was obtained from parents and is available upon request. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. We thank the patient and his family for participating in this study. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. S.G.: 1A, 1B, 2B, 2C, 3A, 3B M.N.: 1A, 1B, 3A, 3B M.R.: 2B, 2C E.F.: 3B E.M.: 3B L.P.: 3B E.P.: 2B, 2C F.P.: 3B R.G.: 3B V.L.: 1A, 1B, 3A, 3B S.M.: 1A, 1B, 2B, 2C, 3A, 3B None. The data that support the findings of this study are available on request from the corresponding author. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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.

The GNB1 gene encodes the guanine nucleotide-binding protein subunit beta-1 (Gß1), a component of the heterotrimeric G-protein complex that is ubiquitously expressed in the central ner-vous system and highly enriched in medium spiny neu-rons (MSNs). The Gß1 subunit is of Gß γ dimer, which primarily inter-acts with the G α o subunit. The G α o subunit is the small G-protein encoded by the best known GNAO1 gene, which is with a complex developmental encephalopathy with hyperkinetic movement epilepsy. of transducing cAMP of lead-ing to loss of independent walking at the age of 9 years. The patient remained stable up to the age of 20 years when two severe paroxysmal dyskinetic episodes during pneumonia required intensive care admission. After these episodes paroxysmal dyskinetic episodes appeared, typically occurring after awakening in the early morning and lasting 2 – 4 hours, with a frequency of 2 – 3 per month (Video 3).

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.