Fever-Induced and Early Morning Paroxysmal Dyskinesia in a Man With GNB1 Encephalopathy

non richiest

Motor, epileptic, and developmental phenotypes in genetic disorders affecting G protein coupled receptors-cAMP signaling

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

Bradykinesia and dystonia

Background: Bradykinesia has been reported in patients with dystonia. Despite this, the pathophysiological mechanisms of bradykinesia in dystonia remain largely unknown. Methods: We here performed a comprehensive literature search and reviewed clinical and experimental studies on bradykinesia in patients with dystonia. Results: Many studies have documented the presence of bradykinesia in patients with idiopathic and inherited isolated dystonia, regardless of the presence of parkinsonism. In addition, bradykinesia has been observed as a side effect in dystonic patients who have undergone deep brain stimulation, in those with functional dystonia as well as in those with combined dystonia, e.g., dystonia-parkinsonism. These clinical and experimental findings support the hypothesis that dysfunction in a brain network involving the basal ganglia, primary sensorimotor cortex, and cerebellum may play a key role in the pathophysiology of both bradykinesia and dystonia. Conclusion: Bradykinesia is frequently observed in dystonia. We may gain insights into the pathophysiological underpinnings of two distinct movement disorders by investigating this issue. Furthermore, a deeper understanding of bradykinesia in dystonia may have terminological implications in this field

GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome

OBJECTIVE: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. METHODS: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. RESULTS: Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. CONCLUSIONS: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia

The recurrent pathogenic Pro890Leu substitution in CLTC causes a generalized defect in synaptic transmission in Caenorhabditis elegans

De novo CLTC mutations underlie a spectrum of early-onset neurodevelopmental phenotypes having developmental delay/intellectual disability (ID), epilepsy, and movement disorders (MD) as major clinical features. CLTC encodes the widely expressed heavy polypeptide of clathrin, a major component of the coated vesicles mediating endocytosis, intracellular trafficking, and synaptic vesicle recycling. The underlying pathogenic mechanism is largely unknown. Here, we assessed the functional impact of the recurrent c.2669C > T (p.P890L) substitution, which is associated with a relatively mild ID/MD phenotype. Primary fibroblasts endogenously expressing the mutated protein show reduced transferrin uptake compared to fibroblast lines obtained from three unrelated healthy donors, suggesting defective clathrin-mediated endocytosis. In vitro studies also reveal a block in cell cycle transition from G0/G1 to the S phase in patient's cells compared to control cells. To demonstrate the causative role of the p.P890L substitution, the pathogenic missense change was introduced at the orthologous position of the Caenorhabditis elegans gene, chc-1 (p.P892L), via CRISPR/Cas9. The resulting homozygous gene-edited strain displays resistance to aldicarb and hypersensitivity to PTZ, indicating defective release of acetylcholine and GABA by ventral cord motor neurons. Consistently, mutant animals show synaptic vesicle depletion at the sublateral nerve cords, and slightly defective dopamine signaling, highlighting a generalized deficit in synaptic transmission. This defective release of neurotransmitters is associated with their secondary accumulation at the presynaptic membrane. Automated analysis of C. elegans locomotion indicates that chc-1 mutants move slower than their isogenic controls and display defective synaptic plasticity. Phenotypic profiling of chc-1 (+/P892L) heterozygous animals and transgenic overexpression experiments document a mild dominant-negative behavior for the mutant allele. Finally, a more severe phenotype resembling that of chc-1 null mutants is observed in animals harboring the c.3146 T > C substitution (p.L1049P), homologs of the pathogenic c.3140 T > C (p.L1047P) change associated with a severe epileptic phenotype. Overall, our findings provide novel insights into disease mechanisms and genotype-phenotype correlations of CLTC-related disorders

Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile

Background: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact. Results: We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the “episignature” associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression. Conclusions: We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches

De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy, and movement disorder. We evaluated a large cohort of patients (n=25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor, and ataxia. Later in the disease course they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration, and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibers and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders

Parkinsonism in children: Clinical classification and etiological spectrum

Infantile- and childhood-onset parkinsonism is mainly due to genetic alterations and is an exceedingly rare condition, unlike Parkinson's disease (PD), which is one of the most common neurologic disorders in adulthood. The clinical characterization of parkinsonism during early stages of neuromotor development is controversial due to the lack of consensus regarding the clinical criteria of PD or parkinsonism in the immature brain. The classification here proposed is based on a review of conditions that emerge during infancy and childhood, with key symptoms evocative of adult parkinsonism. The proposed nosography is based on age at presentation, clinical features, outcome, and etiological background. It includes developmental parkinsonism, infantile degenerative parkinsonism, parkinsonism in the setting of neurodevelopmental disorders, parkinsonism in the setting of multisystem brain diseases, juvenile parkinsonism and dystonia-parkinsonism, and acquired parkinsonism. The subgroups denoting peculiar clinical presentations as a consequence of disease impact on the immature brain are developmental parkinsonism due to monoamine metabolic disorders and infantile degenerative parkinsonism caused by DAT and WASR2 defects. More tardive parkinsonisms occur in genetic conditions that cause a generalized derangement of neurodevelopmental processes, such as those due to MECP2, NR4A2, SCN1A, and RAB39B. Some conditions presenting with neurodevelopmental disorder can progress later, disclosing their neurodegenerative nature (i.e. WDR45 and KCND3). Finally, new emerging conditions with childhood-onset parkinsonism arise from the cumulative effect of multiple genetic lesions

GLUT1 DEFICIENCY: A MILD PHENOTYPE IN A 4 YEARS OLD FEMALE WITH EARLY ONSET ABSENCES AND ATAXIA

Introduction: Glucose (GLUT1) transporter 1 deficiency (OMIM 606777) is a polymorphic syndrome including an epileptic encephalopathy, early onset absences, complex movement disorders and developmental delay. Case report: We present the case of a 4 year old female with episodes of recurrent staring since the age of 3 months and fluctuating ataxic gait when awakening since the age of 2 years and 6 months. Symptoms were exacerbated at awakening and with fasting. Psychomotor development was only mildly impaired. Electroencephalogram evidenced diffuse epileptiform discharges with the prominent involvement of the anterior regions. Seizures have been well controlled with valproic acid. Brain MRI was negative. Lumbar puncture showed a CSF/blood glucose ratio of 0,28.Molecular investigation on SLC2A1 gene revelaed a heterozygosis for the mutation c.274 C>T (p.Arg92Trp). Discussion: GLUT1 deficiency have an expanding phenotype. Our experience evidences that the pattern of GLUT 1 deficiency includes different ranges of clinical severity. This is probably due to differences in the functional impairment of the transporter

PHENOTYIPING AND DIAGNOSTIC TIMING IN NGS-DIAGNOSED GENETIC DEVELOPMENTAL ENCEPHALOPATHIES WITH EPILEPSY AND MOVEMENT DISORDERS

Objective: To characterize the relevance of phenotyping and diagnostic timing to achieve a molecular-genetic diagnosis in developmental encephalopathies with epilepsy and movement disorders (DEEMD). Methods: A retrospective analysis of patients (period 2010-2020) with genetically confirmed DEEMD was realized. According to their movement disorders phenotype, patients were divided in Group A (hyperkinetic movement disorders) and Group B (hypokinetic movement disorders). Clinical info, compatibility with published phenotypes, timing for the etiological diagnosis and the temporal distribution of the diagnostic delay were collected. Statistical analysis (SPSS26.0) included: descriptive parameters, Chi2-test, ANOVA and Bonferrori correction for groups comparisons (p= 0.05). Results: 61 patients (32 females and 29 males), with a mean age of 15,77±9.31 years and 37 different genetic diseases, were recruited. The mean age at the molecular genetics diagnosis was 8.69±8.83 years with a mean diagnostic delay of 6.29±8.12years. The diagnostic yield of molecular genetic investigations was higher in the period 2015-2020. Group A included 47 patients (27 females and 20 males) and Group B had 14 patients (5 females and 9 males). The mean diagnostic delay was longer in Group B (13,47±13,60 versus 4,15 ±3,38 years). In Group A an earlier onset of seizures was observed (2,77±3,29 versus 4,05±3,9 years) while the onset of movement disorders was noticed earlier in Group B (2,5±3,59 versus 3,21±3,61 years). The initial epileptic manifestations mainly included generalized motor onset seizures (Group A) and focal seizures with impaired awareness and motor onset (Group B). The compatibility with published phenotypes was higher in Group A Conclusions: The reported cohort analysis suggested a) variable combinations of epilepsy and movement disorders phenotypes in genetically determined DEEMD b) a higher diagnostic difficulty in patients with hypokinetic movement disorders