Improving paediatric movement disorders care: Insights on rating scales utilization and clinical practice.

AIM: This exploratory study evaluates rating scale usage by experts from the European Reference Network for Rare Neurological Diseases (ERN-RND) for paediatric MD, considering factors like diagnosis, intellectual disability, age, and transition to adult care. The aim is to propose a preliminary framework for consistent application. METHODS: A multicentre survey among 25 ERN-RND experts from 10 European countries examined rating scale usage in paediatric MD, categorizing MD into acute, non-progressive, and neurodegenerative types. Factors influencing scale choice and the transition to adult care practices were analysed. A comprehensive literature search was conducted to identify the earliest age of application of these scales in paediatric patients. RESULTS: The study identifies various rating scales and establishes their usage frequencies for different MDs. Experts highlighted the need for standardized scales and proposed preliminary evaluation strategies based on clinical contexts. Challenges in applying scales to young, non-cooperative patients were acknowledged. INTERPRETATION: The study recommends developing standardized rating scales for paediatric MDs to improve evaluations and data collection. It suggests potential scales for specific clinical scenarios to better evaluate disease progression. Comprehensive, patient-centred care remains crucial during the transition to adult care, despite the identified challenges. This exploratory approach aims to enhance patient outcomes and care.

Bilateral Simultaneous Magnetic Resonance-Guided Focused Ultrasound Pallidotomy for Life-Threatening Status Dystonicus.

BACKGROUND: Invasive treatments like radiofrequency stereotactic lesioning or deep brain stimulation of the globus pallidus internus can resolve drug-resistant status dystonicus (SD). However, these open procedures are not always feasible in patients with SD. OBJECTIVE: The aim was to report the safety and efficacy of simultaneous asleep bilateral transcranial magnetic resonance-guided focused ultrasound (MRgFUS) pallidotomy for life-threatening SD. METHODS: We performed bilateral simultaneous MRgFUS pallidotomy under general anesthesia in 2 young patients with pantothenate kinase-associated neurodegeneration and GNAO1 encephalopathy. Both patients had medically refractory SD and severe comorbidities contraindicating open surgery. RESULTS: SD resolved at 4 and 12 days after MRgFUS, respectively. Adverse events (intraoperative hypothermia and postoperative facial paralysis) were mild and transient. CONCLUSION: Bilateral simultaneous MRgFUS pallidotomy under general anesthesia is safe and may be a valid alternative therapeutic option for fragile patients. Further studies are needed to assess long-term efficacy of the procedure.

Long-Term Globus Pallidus Internus Deep Brain Stimulation in Pediatric Non-Degenerative Dystonia: A Cohort Study and a Meta-Analysis.

BACKGROUND: The evidence in the effectiveness of deep brain stimulation in children with medication-refractory non-degenerative monogenic dystonia is heterogeneous and long-term results are sparse. OBJECTIVES: The objective is to describe long-term outcomes in a single-center cohort and compare our results with a meta-analysis cohort form literature. METHODS: We performed a retrospective single-center cohort study including consecutive pediatric patients with non-degenerative genetic or idiopathic dystonia treated with globus pallidus internus deep brain stimulation at our center and a systematic review and individual-patient data meta-analysis with the same inclusion criteria. The primary outcome was the change from baseline in the Burke-Fahn-Marsden Dystonia Rating Scale-movement (BFMDRS-M) score. RESULTS: The clinical cohort included 25 patients with a mean study follow-up of 11.4 years. The meta-analysis cohort included 224 patients with a mean follow-up of 3 years. Overall, the BFMDRS-M mean improvements at 1 year and at last follow-up were 41% and 33% in the clinical cohort and 58.9% and 57.2% in the meta-analysis cohort, respectively. TOR1A-dystonia showed the greatest and most stable BFMDRS-M improvement in both cohorts at 1 year and at last follow-up (76.3% and 74.3% in the clinical cohort; 69.6% and 67.3% in the meta-analysis cohort), followed by SGCE-dystonia (63% and 63.9% in the meta-analysis cohort). THAP1-dystonia (70.1% and 29.8% in the clinical cohort; 52.3% and 42.0% in the meta-analysis cohort) and KMT2B-dystonia (33.3% and 41.3% in the clinical cohort; 38.0% and 26.7% in the meta-analysis cohort) showed a less pronounced or sustained response. CONCLUSION: Globus pallidus deep brain stimulation long-term treatment seems effective with a possible gene-specific differential effect. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

BACKGROUND: VPS16 pathogenic variants have been recently associated with inherited dystonia. Most patients affected by dominant VPS16-related disease display early-onset isolated dystonia with prominent oromandibular, bulbar, cervical, and upper limb involvement, followed by slowly progressive generalization. CASES: We describe six newly reported dystonic patients carrying VPS16 mutations displaying unusual phenotypic features in addition to dystonia, such as myoclonus, choreoathetosis, pharyngospasm and freezing of gait. Response to bilateral Globus Pallidus Internus Deep Brain Stimulation (GPi-DBS) is reported in three of them, associated with significant improvement of dystonia but only minor effect on other hyperkinetic movements. Moreover, five novel pathogenic/likely pathogenic variants are described. CONCLUSIONS: This case collection expands the genetic and clinical spectrum of VPS16-related disease, prompting movement disorder specialists to suspect mutations of this gene not only in patients with isolated dystonia.

Generation of two human iPSC lines, HMGUi004-A and FINCBi004-A, from fibroblasts of MPAN patients carrying pathogenic recessive mutations in the gene C19orf12.

Mitochondrial membrane Protein-Associated Neurodegeneration (MPAN) is a lethal neurodegenerative disorder caused by mutations in the human gene C19orf12. The molecular mechanisms underlying the disorder are still unclear, and no established therapy is available. Here, we describe the generation and characterization of two human induced pluripotent stem cell (iPSC) lines derived from skin fibroblasts of two MPAN patients carrying homozygous recessive mutations in C19orf12. These iPSC lines represent a useful resource for future investigations on the pathology of MPAN, as well as for the development of successful treatments.

Systematic review of drug therapy for chorea in NXK2-1-related disorders: Efficacy and safety evidence from case studies and series.

BACKGROUND: The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. METHODS: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. RESULTS: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. CONCLUSIONS: The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.

GNAO1-related movement disorder: An update on phenomenology, clinical course, and response to treatments.

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.

Variants in ATP5F1B are associated with dominantly inherited dystonia.

ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.

Kearns-Sayre syndrome: expanding spectrum of a "novel" mitochondrial leukomyeloencephalopathy.

Kearns-Sayre syndrome (KSS) is a rare mitochondrial disease associated to a widespread cerebral leukodystrophy. MRI shows a typical centripetal pattern where U-fibers are mainly affected with a relative spare of periventricular white matter. Recently, different patterns of spinal cord involvement have been described in KSS. Here we report 4 new cases with typical cerebral leukodystrophy associated with spinal cord lesions. A pattern characterized by abnormal signal intensity in the H gray matter and posterior columns was found in 2 patients, while the remaining 2 presented a peculiar involvement of the spinal trigeminal nuclei at the junction of low medulla and cervical cord. MRI spinal cord involvement in KSS is probably an underestimated finding and should be evaluated in the diagnostic work up of these patients.

Socio-demographic characteristics and psychopathological assessment in a sample of 13 paediatric patients with functional neurological disorders: A preliminary report.

This observational study aims to characterize, from a socio-demographic and psychopathological perspective, a sample of children with Functional Neurological Disorders (FND). Thirteen paediatric patients (below 18 years old) with FND and their parents completed a battery of anamnestic and neuropsychological tests, assessing socio-demographic status, cognitive level, behavioural and emotional issues, depression, anxiety, alexithymic traits and dissociative symptoms. Five patients presented movement disorders (tremor, myoclonus and gait disorder), three patients psychogenic non-epileptic seizures and five patients sensitivity disturbances (pain, anaesthesia and paraesthesia). Cognitive profile was normal in 11 patients; academic performance was good in nine patients, but three had a diagnosis of Specific Learning Difficulty or Attention Deficit Hyperactivity Disorder. Precipitating events occurred in 11 patients. At the self-report questionnaires, mean scores close to the clinical cut off were documented with respect to affective and somatic problems. At the parent-report questionnaires, clinically significant mean scores were observed in the subscales assessing anxious-depressive symptoms and somatic complaints. We speculate that paediatric FND patients, although acknowledging the relevance of somatic symptoms, have difficulties in recognizing internal emotional states (that, instead, are easily recognized by their parents). The case of one FND patient was described. These preliminary data might help identifying different clinical phenotypes of paediatric FND.

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 fibres 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.