I disturbi del movimento nelle patologie mitocondriali: risultati di uno studio cross-sectional multicentrico.

Limitate informazioni sono attualmente disponibili sulla caratterizzazione fenotipica e genetica dei disturbi del movimento nelle patologie mitocondriali. Utilizzando il Registro Italiano delle Malattie Mitocondriali abbiamo studiato retrospettivamente una coorte di 197 individui con disturbo del movimento ed esordio della malattia mitocondriale in età pediatrica, confrontandola con il sottogruppo di soggetti non affetti da disturbo del movimento. Con un modulo online di Google abbiamo in seguito ulteriormente approfondito le caratteristiche demografiche, cliniche, genetiche e farmacologiche dei pazienti con disturbo del movimento mitocondriale. Abbiamo ottenuto informazioni su 50 pazienti, con un'età media di esordio della patologia mitocondriale di 6.10 anni, Deviazione Standard (DS) di 5.57 anni (range 0-17 anni). Il disturbo del movimento è esordito ad una età media di 12.79 anni, DS 14.03 (mediana 8 anni, range interquartile di 16.5 anni). La durata media di follow-up per questi pazienti è stata pari a 8.49 anni, DS 7.83 anni (range 1-30 anni). Richiedendo ai vari Centri di segnalare il tipo di disturbo del movimento prevalente all'esordio abbiamo riscontrato una maggiore incidenza di atassia (22/50; 44%), seguita da tremore (8/50;16%), disturbo distonico/atetosico (5/50; 10%), disturbo coreico-ballico (5/50; 10%), disturbo ipocinetico/rigido (5/50; 10%) (Figura 1). Il 36% dei pazienti (18/50) ha presentato nel decorso uno o più tipi di disturbo del movimento differenti da quello evidente all'esordio. In quasi la metà dei pazienti (22/50; 44%) il disturbo del movimento rappresenta il sintomo di esordio della patologia mitocondriale. Nei rimanenti (28/50;56%) il disturbo del movimento è preceduto da altre manifestazioni, delle quali la più frequente è rappresentata dall’epilessia (46.4%), seguita da oftalmoparesi/ptosi (42.9%), compromissione degli organi di senso (35.7%) e disturbi neuromuscolari (32.1%). Le informazioni sui dati neuroradiologici sono disponibili per 46 pazienti, dei quali 5 (11%) presentano una RM dell'encefalo normale. Le alterazioni dei gangli della base risultano il dato di neuroimaging più frequente nella nostra coorte (52%), seguito da alterazioni della sostanza bianca cerebrale (44%), atrofia cerebrale diffusa (42%) e atrofia cerebellare (42%). Alterazioni all’elettromiografia sono state riscontrate in un’alta percentuale dei pazienti della nostra casistica (24/31; 77%); tra i pattern anormali quello miopatico risulta il più frequente. L’elettroneurografia, eseguita in 30 individui affetti, mostra una neuropatia assonale nella metà circa di questi (16/30; 53%). In un quarto del nostro campione (13/50; 26%) è stata somministrata una terapia farmacologica per il disturbo del movimento; in 4/13 (31%) è stata usata una politerapia e in 9/13 una politerapia (69%). Il Clonazepam risulta il farmaco più comunemente prescritto (4/13; 31%), seguito dal Triesifenidile (3/13;23%), dal Levetiracetam (3/13; 23%), dal Baclofen orale (3/13; 23%) e dal Baclofen intratecale (3/13;23%). Tra i farmaci più comunemente prescritti ritroviamo un'efficacia pari al 100% (3/3) del Baclofen intratecale e del 75% (2/3) del Triesifenidile e del Levetiracetam; il Clonazepam è efficace nel 50% dei casi nei quali è stato somministrato (2/4) mentre il Baclofen orale nel 25% (1/3). In conclusione il nostro studio sottolinea l’importanza della condivisione dei dati, soprattutto nell’ambito di patologie rare. Una più accurata descrizione dei disturbi del movimento nell’ambito delle patologie mitocondriali può migliorare il percorso diagnostico, terapeutico e di follow up dei soggetti affetti e consente una più omogenea stratificazione dei pazienti, utile per studi futuri o possibili trial farmacologici

Mitochondrial epilepsy: a cross-sectional nationwide Italian survey

Many aspects of epilepsy in mitochondrial disorders (MDs) need to be further clarified. To this aim, we explored retrospectively a cohort of individuals with MDs querying the "Nationwide Italian Collaborative Network of Mitochondrial Diseases" (NICNMD) database (1467 patients included since 2010 to December 2016). We collected information on age at epilepsy onset, seizure type and frequency, genetic findings, and antiepileptic drugs (AEDs). At the time of our survey, 147/1467 (10%) patients in the NICNMD database had epilepsy. Complete information was available only for 98 patients, 52 males and 46 females, aged 5-92 years (mean age 40.4 ± 18.4; 14/98 children/teenagers and 84 adults). Epilepsy was the presenting feature of MD in 46/98 (47%) individuals, with onset at a median age of 19 years (range, 0.2-68; < 3 years in 14/97 (14%), 3-19 years in 36/97 (37%), > 19 years in 47/97 (49%)). Moreover, 91/98 patients (93%) displayed multiple seizures, with daily or weekly frequency in 25/91 (28%). Interictal EEG was abnormal in 70/78 (90%) patients, displaying abnormal background (47/70; 67%) and/or interictal paroxysms (53/70; 76%). Eighty of 90 patients (89%) displayed a 50-100% reduction of seizures on AEDs; levetiracetam was the most commonly used. Forty-one patients (42%) carried the m.3243A>G mutation, 16 (16%) the m.8344A>G, and 9 (9%) nuclear DNA (nDNA) mutations. Individuals with early-onset seizures mainly carried nDNA mutations and had a more severe epilepsy phenotype, higher seizure frequency, and disorganized background EEG activity. A better definition of epilepsy in MDs may foster the diagnostic workup, management, and treatment of affected patients, and allow more homogeneous patient stratification

Expanding the clinical and genetic spectrum of pathogenic variants in STIM1

Stromal Interaction Molecule 1 (STIM1) is a reticular Ca2+ sensor composed of a luminal and a cytosolic domain. Autosomal dominant mutations in STIM1 cause tubular aggregate myopathy and Stormorken syndrome or its variant York platelet syndrome. We aimed to expand the features related to new variants in STIM1

Movement disorders in children with a mitochondrial disease: A cross-sectional survey from the nationwide italian collaborative network of mitochondrial diseases

none41noMovement disorders are increasingly being recognized as a manifestation of childhood-onset mitochondrial diseases (MDs). However, the spectrum and characteristics of these conditions have not been studied in detail in the context of a well-defined cohort of patients. We retrospectively explored a cohort of individuals with childhood-onset MDs querying the Nationwide Italian Collaborative Network of Mitochondrial Diseases database. Using a customized online questionnaire, we attempted to collect data from the subgroup of patients with movement disorders. Complete information was available for 102 patients. Movement disorder was the presenting feature of MD in 45 individuals, with a mean age at onset of 11 years. Ataxia was the most common movement disorder at onset, followed by dystonia, tremor, hypokinetic disorders, chorea, and myoclonus. During the disease course, most patients (67.7%) encountered a worsening of their movement disorder. Basal ganglia involvement, cerebral white matter changes, and cerebellar atrophy were the most commonly associated neuroradiological patterns. Forty-one patients harbored point mutations in the mitochondrial DNA, 10 carried mitochondrial DNA rearrangements, and 41 cases presented mutations in nuclear-DNA-encoded genes, the latter being associated with an earlier onset and a higher impairment in activities of daily living. Among our patients, 32 individuals received pharmacological treatment; clonazepam and oral baclofen were the most commonly used drugs, whereas levodopa and intrathecal baclofen administration were the most effective. A better delineation of the movement disorders phenotypes starting in childhood may improve our diagnostic workup in MDs, fine tuning management, and treatment of affected patients.mixedTicci C.; Orsucci D.; Ardissone A.; Bello L.; Bertini E.; Bonato I.; Bruno C.; Carelli V.; Diodato D.; Doccini S.; Donati M.A.; Dosi C.; Filosto M.; Fiorillo C.; La Morgia C.; Lamperti C.; Marchet S.; Martinelli D.; Minetti C.; Moggio M.; Mongini T.E.; Montano V.; Moroni I.; Musumeci O.; Pancheri E.; Pegoraro E.; Primiano G.; Procopio E.; Rubegni A.; Scalise R.; Sciacco M.; Servidei S.; Siciliano G.; Simoncini C.; Tolomeo D.; Tonin P.; Toscano A.; Tubili F.; Mancuso M.; Battini R.; Santorelli F.M.Ticci, C.; Orsucci, D.; Ardissone, A.; Bello, L.; Bertini, E.; Bonato, I.; Bruno, C.; Carelli, V.; Diodato, D.; Doccini, S.; Donati, M. A.; Dosi, C.; Filosto, M.; Fiorillo, C.; La Morgia, C.; Lamperti, C.; Marchet, S.; Martinelli, D.; Minetti, C.; Moggio, M.; Mongini, T. E.; Montano, V.; Moroni, I.; Musumeci, O.; Pancheri, E.; Pegoraro, E.; Primiano, G.; Procopio, E.; Rubegni, A.; Scalise, R.; Sciacco, M.; Servidei, S.; Siciliano, G.; Simoncini, C.; Tolomeo, D.; Tonin, P.; Toscano, A.; Tubili, F.; Mancuso, M.; Battini, R.; Santorelli, F. M

A Schematic Approach to Defining the Prevalence of COL VI Variants in Five Years of Next-Generation Sequencing

Objective: To define the prevalence of variants in collagen VI genes through a next-generation sequencing (NGS) approach in undiagnosed patients with suspected neuromuscular disease and to propose a diagnostic flowchart to assess the real pathogenicity of those variants. Methods: In the past five years, we have collected clinical and molecular information on 512 patients with neuromuscular symptoms referred to our center. To pinpoint variants in COLVI genes and corroborate their real pathogenicity, we sketched a multistep flowchart, taking into consideration the bioinformatic weight of the gene variants, their correlation with clinical manifestations and possible effects on protein stability and expression. Results: In Step I, we identified variants in COLVI-related genes in 48 patients, of which three were homozygous variants (Group 1). Then, we sorted variants according to their CADD score, clinical data and complementary studies (such as muscle and skin biopsy, study of expression of COLVI on fibroblast or muscle and muscle magnetic resonance). We finally assessed how potentially pathogenic variants (two biallelic and 12 monoallelic) destabilize COL6A1-A2-A3 subunits. Overall, 15 out of 512 patients were prioritized according to this pipeline. In seven of them, we confirmed reduced or absent immunocytochemical expression of collagen VI in cultured skin fibroblasts or in muscle tissue. Conclusions: In a real-world diagnostic scenario applied to heterogeneous neuromuscular conditions, a multistep integration of clinical and molecular data allowed the identification of about 3% of those patients harboring pathogenetic collagen VI variants

Deoxyguanosine kinase deficiency: natural history and liver transplant outcome

: Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation

Clinical Phenotype of Pediatric and Adult Patients With Spinal Muscular Atrophy With Four SMN2 Copies: Are They Really All Stable?

Objective: The aim of this study was to provide an overview of the clinical phenotypes associated with 4 SMN2 copies.Methods: Clinical phenotypes were analyzed in all the patients with 4 SMN2 copies as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA).Results: The cohort includes 169 patients (102 men and 67 women) with confirmed 4 SMN2 copies (mean age at last follow-up = 36.9 +/- 19 years). Six of the 169 patients were presymptomatic, 8 were classified as type II, 145 as type III (38 type IIIA and 107 type IIIB), and 8 as type IV. The remaining 2 patients were asymptomatic adults identified because of a familial case. The cross-sectional functional data showed a reduction of scores with increasing age. Over 35% of the type III and 25% of the type IV lost ambulation (mean age = 26.8 years +/- 16.3 SD). The risk of loss of ambulation was significantly associated with SMA type (p < 0.0001), with patients with IIIB and IV less likely to lose ambulation compared to type IIIA. There was an overall gender effect with a smaller number of women and a lower risk for women to lose ambulation. This was significant in the adult (p = 0.009) but not in the pediatric cohort (p = 0.43).Interpretation: Our results expand the existing literature on natural history of 4 SMN2 copies confirming the variability of phenotypes in untreated patients, ranging from type II to type IV and an overall reduction of functional scores with increasing age

Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naïve patients with spinal muscular atrophy and following switch from other therapiesResearch in context

Summary: Background: Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5 kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 days–72 months) and weight (3.2–17 kg) range, also including patients previously treated with other drugs. Methods: 46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients with at least 6 month follow-up after OA infusion. 19/67 were treatment naïve when treated with OA. Motor function was measured with the CHOP-INTEND. Findings: CHOP-INTEND changes varied among age groups. Baseline score and age at OA treatment best predicted changes. A mixed model post-hoc analysis showed that in patients treated before the age of 24 months the CHOP-INTEND changes were already significant 3 months after OA while in those treated after the age of 24 months the difference was only significant 12 months after OA. Adverse events occurred in 51/67. The risk for elevated transaminases serum levels was higher in older patients. This was also true for weight and for pre-treatment with nusinersen when analysed individually. A binomial negative regression analysis showed that only age at OA treatment had a significant effect on the risk of elevated transaminases. Interpretation: Our paper describes OA 12-month follow-up showing efficacy across various age and weight groups not targeted by clinical trials. The study identifies prognostic factors for safety and efficacy in treatment selection. Funding: None