遺伝性ジストニア

BACKGROUND: Sensory tricks (also termed "alleviating maneuvers") are voluntary maneuvers that transiently alleviate dystonic postures or movements and represent a hallmark clinical feature of dystonia with diagnostic and mechanistic significance. Despite extensive phenomenological description, the evidence base has not been systematically synthesized. OBJECTIVES: To characterize the prevalence, phenomenology, clinical effects, predictors, neurobiological mechanisms, and translational relevance of alleviating maneuvers in dystonia, and to prospectively evaluate the feasibility of quantitative synthesis across predefined outcome domains. METHODS: A systematic review with a prespecified nested quantitative synthesis was conducted using a preregistered PROSPERO protocol (CRD420251175065). The nested component was defined a priori as a domain-restricted analytic strategy in which random-effects meta-analysis was planned where ≥ 3 conceptually comparable studies were available, and in which the feasibility of pooling was itself treated as a primary methodological outcome. PubMed, Scopus, and the Cochrane Library were searched from inception. Studies reporting original empirical data on alleviating maneuvers in human dystonia of any etiology were included. Qualitative synthesis examined phenomenology, clinical effects, predictors, mechanisms, and translational applications. Heterogeneity was examined separately along clinical, methodological, and outcome-level dimensions. RESULTS: Of 631 records, 53 studies met inclusion criteria; 31 contributed to qualitative synthesis and 26 to nested quantitative analyses, with 4 contributing to both. No eligible studies in functional or tardive dystonia were identified. Alleviating maneuvers were reported across dystonia subtypes, with prevalence ranging from 13% to 90%; the largest registry cohort (n = 1477) reported effective maneuvers in 68.7% of patients. Acute motor improvements of 30%-50% in head deviation were reported during trick execution, although effects were transient. Responsiveness was associated with shorter disease duration and better response to botulinum toxin. No domain met criteria for formal meta-analysis; structural barriers were predominantly methodological and outcome-level rather than clinical. CONCLUSIONS: Alleviating maneuvers are a clinically consistent and mechanistically informative feature of dystonia, but their magnitude, durability, and predictors remain inconsistently measured. Standardized paradigms and outcome reporting are required to enable quantitative synthesis and sham-controlled evaluation of device-based alleviating-maneuver analogues.

INTRODUCTION: Deep brain stimulation (DBS) has increasingly become an accepted therapy for pediatric patients with medically refractory dystonia. Most pediatric dystonia patients are unable to tolerate the DBS procedure under local anesthesia or awake anesthesia. Therefore, general anesthesia is a potentially feasible choice. However, the negative impacts of general anesthetics may impair the quality of intraoperative microelectrode recording (MER). Additionally, pediatric dystonia patients frequently present with comorbidities including difficult airway, cardiovascular dysfunction, respiratory impairment, and metabolic disorders, which collectively posing challenges to perioperative management. METHODS: In this study, we retrospectively reviewed the anesthetic managements for 32 pediatric dystonia patients who received DBS surgery in our center, and analyzed the safety profile and adverse effects. RESULTS AND CONCLUSIONS: We found that general anesthesia with endotracheal intubation might be a feasible anesthetic regimen for this pediatric dystonia patient population. Challenges regarding the anesthetic management of these patients mainly come from the potential impacts of general anesthetics on MER quality, patients' fragility secondary to severe dystonia, and the pathophysiological disorders associated with comorbid conditions. Therefore, meticulous perioperative monitors are required and special concerns should be paid to preventing perioperative complications caused by anesthetic procedure and some rare but serious hereditary metabolic disorders.

BACKGROUND: Despite established clinical diagnostic criteria for Parkinson's disease and the neurodegeneration-related atypical parkinsonian syndromes (progressive supranuclear palsy/PSP, corticobasal degeneration syndrome/CBD, multiple system atrophy with parkinsonian or cerebellar predominance/MSA-P/C, and dementia with Lewy bodies/DLB), the differential diagnosis from rare hereditary and acquired disorders presenting with parkinsonism can be challenging. METHODS: Based on a PubMed search, relevant original studies and review articles were analyzed to identify rare hereditary and acquired disorders associated with parkinsonism. Secondary parkinsonian syndromes resulting from medication or toxin exposure were excluded but are summarized in an overview. RESULTS: Without claiming completeness, the major hereditary and acquired disorders associated with parkinsonism were summarized in tabular form. Selected entities were described in more detail in short profiles focusing on those with therapeutic modifiability, characteristic pattern-like constellations of findings, or notable pathophysiological mechanisms. Paradigmatic cerebral MRI patterns are illustrated. CONCLUSIONS: A broad spectrum of rare acquired and genetic entities can manifest with clinically relevant parkinsonian syndromes. Frequently, parkinsonism occurs in combination with other neurological features of variable severity, including extrapyramidal-hyperkinetic symptoms (dystonia/chorea), cerebellar signs (ataxia), pontomesencephalic involvement (oculomotor disturbances, bulbar dysarthria/dysphagia), motor neuron signs (spasticity and/or amyotrophic paresis), cognitive or neuropsychiatric symptoms, and epilepsy.For several disease groups - such as neurodegeneration with brain iron accumulation (NBIA), Wilson's disease, and primary familial brain calcification (PFBC) - distinctive MRI patterns are diagnostically informative.A relevant subset of disorders exhibits at least a partial and sometimes transient presynaptic dopaminergic deficit responsive to dopaminergic medication (e.g., certain NBIA forms, spinocerebellar ataxias/SCA, cerebrotendinous xanthomatosis/CTX).Neuropathologically, some of these disorders are associated with secondary synucleinopathies (e.g., MPAN), tauopathies (e.g., IgLON5 syndrome) or TDP-43 (e.g., Perry syndrome/DCTN1).

BACKGROUND: Pathogenic loss-of-function variants in the KMT2B gene cause a rare autosomal dominant disorder with two major phenotypes: KMT2B-related dystonia (DYT-KMT2B) and KMT2B-related neurodevelopmental disorder (KMT2B-NDD). Central precocious puberty (CPP) has been documented as a comorbidity in patients with DYT-KMT2B, but has not been reported as the primary clinical manifestation of the disorder in patients without dystonia. Deletions or pathogenic variants in the STS gene cause X-linked ichthyosis (XLI). Concurrent KMT2B and STS alterations have not been well characterised, and GnRH analogue therapy for CPP in KMT2B-related disorders has not been previously described. CASE PRESENTATION: An 8-year-10-month-old male presented with a 1-2-year history of progressive increase in penile length and girth. Physical examination revealed distinctive craniofacial dysmorphism, classic ichthyotic scaling, pubertal changes consistent with precocious puberty, and normal muscle tone without dystonic features. Biochemical testing confirmed markedly elevated serum total testosterone, a positive gonadotropin-releasing hormone (GnRH) stimulation test consistent with CPP, and bone age advanced by 1.2 years relative to chronological age. Neurocognitive assessment identified mild intellectual disability. Family-based whole-exome sequencing and copy number variation (CNV) analysis identified a de novo heterozygous pathogenic nonsense variant in KMT2B (NM_014727.3: c.4213del, p.Leu1405Ter) and a hemizygous pathogenic full-coding deletion of STS. The patient was treated with leuprorelin acetate for CPP and topical emollients for XLI. At 3-month follow-up, physical signs of puberty remained stable. GnRHa stimulation test showed indicating but incomplete suppression of the hypothalamic-pituitary-gonadal axis. The ichthyotic skin lesions improved markedly with topical therapy. The leuprorelin acetate dose was subsequently increased. The patient is continuing on the current regimen with close monitoring. CONCLUSION: Precocious puberty has been reported in eleven patients with KMT2B-related dystonia. This case documents the co-occurrence of a KMT2B-related disorder and XLI in a patient, and provides documentation of GnRH analogue therapy and structured endocrine follow-up for CPP in this population. KMT2B haploinsufficiency may contribute to premature activation of the hypothalamic-pituitary-gonadal axis through disruption of ERα-mediated transcriptional regulation and altered epigenetic programming at key hypothalamic developmental genes. Clinically, children with KMT2B-related disorders should undergo comprehensive endocrine assessment to facilitate early diagnosis and timely intervention.

BACKGROUND: Although de novo causation in dystonia is widely acknowledged, there have been only a few trio-sequencing analyses in this field. We sought to prioritise de novo variants in dystonia and characterise the clinical and molecular features associated with the top gene candidate identified after genomic matchmaking. METHODS: We (re)assessed exome-sequencing data for de novo variants in genes with strong mutational constraint in a sample of 257 dystonia trios. Via data sharing, we collected information on individuals with variants in KLC1, encoding a subunit of the axonal-transport motor protein kinesin-1. Biophysical, biochemical, and functional studies, including differential scanning fluorimetry, X-ray crystallography, fluorescence-polarisation measurements, and immunoprecipitation from cells were performed for representative KLC1 variants. FINDINGS: Missense and loss-of-function de novo variants in constrained genes without implication in autosomal dominant or X-linked conditions were found in 11.7% (30/257) of cases with dystonia. We then ascertained 7 unrelated patients with movement and neurodevelopmental disorders who harboured distinct, predicted deleterious de novo KLC1 missense variants. These variants clustered within the cargo adaptor-binding tetratricopeptide repeat domain and 3 variants mapped to an identical amino-acid position. Highly similar infantile-onset dystonic-spastic phenotypes were observed in the subjects with the recurrently affected residue. For all functionally tested variants, we observed changes in KLC1 stability and/or altered binding behaviour to known kinesin-1 interactors, such as JIP3, previously associated with dystonia and neurodevelopmental impairment. INTERPRETATION: Our research supports the existence of a kinesinopathy linked to KLC1, featuring phenotypic overlap with diseases related to mutational defects of key interactors of KLC1. The full dystonia de-novo variant compendium is reported as a resource for additional disease-gene discovery. FUNDING: Else Kröner-Fresenius-Stiftung, German Federal Ministry of Education and Research, Technical University of Munich-Institute for Advanced Study, EU Renewal and Resilience Plan, Czech Ministry of Health, European Union-Next Generation EU, Italian Ministry for Universities and Research.