Publications by authors named "Giovanna Zorzi"

85 Publications

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

Brain 2021 Aug 11. Epub 2021 Aug 11.

Undiagnosed Diseases Program, National Institutes of Health, Bethesda, MD 20892-2152, USA.

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.
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http://dx.doi.org/10.1093/brain/awab299DOI Listing
August 2021

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

Clin Epigenetics 2021 Aug 11;13(1):157. Epub 2021 Aug 11.

Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 3K7, Canada.

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.
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http://dx.doi.org/10.1186/s13148-021-01145-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359374PMC
August 2021

Pediatric Paroxysmal Exercise-Induced Neurological Symptoms: Clinical Spectrum and Diagnostic Algorithm.

Front Neurol 2021 1;12:658178. Epub 2021 Jun 1.

Unit of Child Neurology, Department of Pediatric Neuroscience, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Carlo Besta, Milan, Italy.

Paroxysmal exercise-induced neurological symptoms (PENS) encompass a wide spectrum of clinical phenomena commonly presenting during childhood and characteristically elicited by physical exercise. Interestingly, few shared pathogenetic mechanisms have been identified beyond the well-known entity of paroxysmal exercise-induced dyskinesia, PENS could be part of more complex phenotypes including neuromuscular, neurodegenerative, and neurometabolic disease, epilepsies, and psychogenetic disorders. The wide and partially overlapping phenotypes and the genetic heterogeneity make the differential diagnosis frequently difficult and delayed; however, since some of these disorders may be treatable, a prompt diagnosis is mandatory. Therefore, an accurate characterization of these symptoms is pivotal for orienting more targeted biochemical, radiological, neurophysiological, and genetic investigations and finally treatment. In this article, we review the clinical, genetic, pathophysiologic, and therapeutic landscape of paroxysmal exercise induced neurological symptoms, focusing on phenomenology and differential diagnosis.
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http://dx.doi.org/10.3389/fneur.2021.658178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203909PMC
June 2021

THAP1 Dystonia with Globus Pallidus T2 Hypointensity: A Report of Two Cases.

Mov Disord 2021 06 5;36(6):1463-1464. Epub 2021 Mar 5.

Unit of Neuroradiology, Foundation IRCCS Carlo Besta Neurological Institute, Milan, Italy.

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http://dx.doi.org/10.1002/mds.28555DOI Listing
June 2021

YY1-Related Dystonia: Clinical Aspects and Long-Term Response to Deep Brain Stimulation.

Mov Disord 2021 06 27;36(6):1461-1462. Epub 2021 Feb 27.

Ken and Ruth Davee Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

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http://dx.doi.org/10.1002/mds.28547DOI Listing
June 2021

The first case of Cri du Chat syndrome with dystonia.

Clin Neurol Neurosurg 2021 02 31;201:106459. Epub 2020 Dec 31.

Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Neurosciences, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.

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http://dx.doi.org/10.1016/j.clineuro.2020.106459DOI Listing
February 2021

Sleep Exacerbations and Facial Twitching: Diagnostic Clues for ADCY5-Related Dyskinesias.

Neuropediatrics 2021 06 29;52(3):208-211. Epub 2020 Dec 29.

Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padua, Padua, Italy.

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http://dx.doi.org/10.1055/s-0040-1721685DOI Listing
June 2021

Fosmetpantotenate Randomized Controlled Trial in Pantothenate Kinase-Associated Neurodegeneration.

Mov Disord 2021 06 16;36(6):1342-1352. Epub 2020 Nov 16.

Research and Development, Retrophin, Inc., San Diego, California, USA.

Background: Pantothenate kinase-associated neurodegeneration (PKAN) currently has no approved treatments.

Objectives: The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression.

Methods: This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL.

Results: Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was -0.09 (-1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups.

Conclusions: Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246547PMC
June 2021

Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.

Ann Neurol 2020 11 21;88(5):867-877. Epub 2020 Sep 21.

Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Objectives: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses.

Methods: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells.

Results: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 10 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function.

Interpretation: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.
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http://dx.doi.org/10.1002/ana.25879DOI Listing
November 2020

Heterozygous variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.

J Med Genet 2021 07 31;58(7):475-483. Epub 2020 Jul 31.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.

Background: Dominant and recessive variants in the gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance.

Methods: In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous variants, and extensively review the available literature to improve current classification of -related disorders.

Results: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain.

Conclusion: The present study further enlarges the clinical and mutational spectrum of -related disorders by describing a large series of patients with dominantly inherited pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.
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http://dx.doi.org/10.1136/jmedgenet-2020-107007DOI Listing
July 2021

Long term perceptions of illness and self after Deep Brain Stimulation in pediatric dystonia: A narrative research.

Eur J Paediatr Neurol 2020 May 22;26:61-67. Epub 2020 Feb 22.

Department of Paediatric Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Background: Deep Brain Stimulation (DBS) is increasingly used in pediatric patients affected by isolated dystonia, with excellent results. Despite well documented long-term effects on motor functioning, information on quality of life and social adaptation is almost lacking.

Objectives: The present study aims to explore the experience of illness and the relation with the device in adult patients suffering from dystonia who underwent DBS surgery in pediatric age.

Methods: A narrative inquiry approach was used to collect patients' narratives of their experience with dystonia and DBS stimulator. A written interview was administered to 8 patients over 18 years old with generalized isolated dystonia who had undergone pallidal DBS implantation in childhood. A thematic analysis was realized to examine the narratives collected.

Results: Five main themes emerged: "relationship with the disease", "experience related to DBS procedure", "relationship with one's own body", "fears", "thoughts about future". Despite a general satisfaction in relation to DBS intervention, some patients expressed difficulties, such as the acceptance of changes in one's own body, concerns and fears regarding the device and the future, also considering the critical phase of transition from childhood to adulthood.

Conclusions: These results suggest that further research is needed to understand the contribution of psychological, as much as medical, aspects to the overall outcome of the intervention. The present explorative study encourages a deeper investigations of psychological aspects of patients, in order to plan a tailored care path and to decide whether to suggest a psychological support, both before and after the intervention.
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http://dx.doi.org/10.1016/j.ejpn.2020.02.010DOI Listing
May 2020

Deep brain stimulation versus pallidotomy for status dystonicus: a single-center case series.

J Neurosurg 2019 Dec 20:1-11. Epub 2019 Dec 20.

1Neurosurgery Department, Functional Neurosurgery Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta.

Objective: First-line pharmacological therapies have shown limited efficacy in status dystonicus (SD), while surgery is increasingly reported as remediable in refractory cases. In this context, there is no evidence regarding which neurosurgical approach is the safest and most effective. The aim of this study was to assess the clinical outcomes and surgery-related complications of globus pallidus internus deep brain stimulation (GPi DBS) and pallidotomy for the treatment of drug-resistant SD.

Methods: The authors reviewed the records of patients with drug-resistant SD who had undergone GPi DBS or pallidotomy at their institution between 2003 and 2017. The severity of the dystonia was evaluated using the Barry-Albright Dystonia (BAD) Scale. Surgical procedures were performed bilaterally in all cases.

Results: Fourteen patients were eligible for inclusion in the study. After surgery, the mean follow-up was 40.6 ± 30 months. DBS ended the dystonic storm in 87.5% of cases (7/8), while pallidotomy had a success rate of 83.3% (5/6). No significant differences were observed between the two techniques in terms of failure rates (risk difference DBS vs pallidotomy -0.03, 95% CI -0.36 to 0.30), SD mean resolution time (DBS 34.8 ± 19 days, pallidotomy 21.8 ± 20.2 days, p > 0.05), or BAD scores at each postoperative follow-up (p > 0.05). The long-term hardware complication rate after DBS was 37.5%, whereas no surgery-related complications were noted following pallidotomy.

Conclusions: The study data suggest that DBS and pallidotomy are equally safe and effective therapies for drug-resistant SD. The choice between the two techniques should be tailored on a case-by-case basis, depending on factors such as the etiology and evolution pattern of the underlying dystonia and the clinical conditions at the moment of SD onset. Given the limitation of the low statistical power of this study, further multicentric investigations are needed to confirm its findings.
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http://dx.doi.org/10.3171/2019.10.JNS191691DOI Listing
December 2019

Pallidal Deep Brain Stimulation in DYT6 Dystonia: Clinical Outcome and Predictive Factors for Motor Improvement.

J Clin Med 2019 Dec 6;8(12). Epub 2019 Dec 6.

Department of Women's and Children's Health, Karolinska Institutet, 17176 Stockholm, Sweden.

Pallidal deep brain stimulation is an established treatment in dystonia. Available data on the effect in DYT-THAP1 dystonia (also known as DYT6 dystonia) are scarce and long-term follow-up studies are lacking. In this retrospective, multicenter follow-up case series of medical records of such patients, the clinical outcome of pallidal deep brain stimulation in DYT-THAP1 dystonia, was evaluated. The Burke Fahn Marsden Dystonia Rating Scale served as an outcome measure. Nine females and 5 males were enrolled, with a median follow-up of 4 years and 10 months after implant. All benefited from surgery: dystonia severity was reduced by a median of 58% (IQR 31-62, = 0.001) at last follow-up, as assessed by the Burke Fahn Marsden movement subscale. In the majority of individuals, there was no improvement of speech or swallowing, and overall, the effect was greater in the trunk and limbs as compared to the cranio-cervical and orolaryngeal regions. No correlation was found between disease duration before surgery, age at surgery, or preoperative disease burden and the outcome of deep brain stimulation. Device- and therapy-related side-effects were few. Accordingly, pallidal deep brain stimulation should be considered in clinically impairing and pharmaco-resistant DYT-THAP1 dystonia. The method is safe and effective, both short- and long-term.
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http://dx.doi.org/10.3390/jcm8122163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947218PMC
December 2019

EMG-based vibro-tactile biofeedback training: effective learning accelerator for children and adolescents with dystonia? A pilot crossover trial.

J Neuroeng Rehabil 2019 11 27;16(1):150. Epub 2019 Nov 27.

NearLab, Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.

Background: This study is aimed at better understanding the role of a wearable and silent ElectroMyoGraphy-based biofeedback on motor learning in children and adolescents with primary and secondary dystonia.

Methods: A crossover study with a wash-out period of at least 1 week was designed; the device provides the patient with a vibration proportional to the activation of an impaired target muscle. The protocol consisted of two 5-day blocks during which subjects were trained and tested on a figure-8 writing task: their performances (at different levels of difficulty) were evaluated in terms of both kinematics and muscular activations on day 1 and day 5, while the other 3 days were purely used as training sessions. The training was performed with and without using the biofeedback device: the week of use was randomized. Data were collected on 14 subjects with primary and secondary (acquired) dystonia (age: 6-19 years).

Results: Results comparing kinematic-based and EMG-based outcome measures pre- and post-training showed learning due to practice for both subjects with primary and secondary dystonia. On top of said learning, an improvement in terms of inter-joint coordination and muscular pattern functionality was recorded only for secondary dystonia subjects, when trained with the aid of the EMG-based biofeedback device.

Conclusions: Our results support the hypothesis that children and adolescents with primary dystonia in which there is intact sensory processing do not benefit from feedback augmentation, whereas children with secondary dystonia, in which sensory deficits are often present, exhibit a higher learning capacity when augmented movement-related sensory information is provided. This study represents a fundamental investigation to address the scarcity of noninvasive therapeutic interventions for young subjects with dystonia.
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http://dx.doi.org/10.1186/s12984-019-0620-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882366PMC
November 2019

Status dystonicus induced by deep brain stimulation surgery.

Neurol Sci 2020 03 18;41(3):729-730. Epub 2019 Oct 18.

Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, UHN, Division of Neurology, University of Toronto, 399 Bathurst St, 7McL412, Toronto, ON, M5T 2S8, Canada.

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http://dx.doi.org/10.1007/s10072-019-04083-zDOI Listing
March 2020

Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study.

Mov Disord 2019 10 19;34(10):1516-1527. Epub 2019 Jun 19.

Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Background: Childhood-onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood-onset dystonia.

Objective: To define the frequency of KMT2B mutations in a cohort of dystonic patients aged <18 years at onset, the associated clinical and radiological phenotype, and the natural history of disease.

Methods: Whole-exome sequencing or customized gene panels were used to screen a cohort of 65 patients who had previously tested negative for all other known dystonia-associated genes.

Results: We identified 14 patients (21.5%) carrying KMT2B variants, of which 1 was classified as a variant of unknown significance. We also identified 2 additional patients carrying pathogenic mutations in GNAO1 and ATM. Overall, we established a definitive genetic diagnosis in 23% of cases. We observed a spectrum of clinical manifestations in KMT2B variant carriers, ranging from generalized dystonia to short stature or intellectual disability alone, even within the same family. In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudocranial generalization. Eight patients underwent pallidal DBS with a median decrease of Burke-Fahn-Marsden Dystonia Rating Scale-Motor score of 38.5% in the long term. We also report on 4 asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance.

Conclusions: KMT2B mutations are frequent in childhood-onset dystonia and cause a complex neurodevelopmental syndrome, often featuring growth retardation and intellectual disability as additional phenotypic features. A dramatic and long-lasting response to DBS is characteristic of DYT-KMT2B dystonia. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27771DOI Listing
October 2019

Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study.

Lancet Neurol 2019 07;18(7):631-642

Department of Hematology Oncology, UCSF Benioff Children's Hospital and Research Center Oakland, Oakland, CA, USA.

Background: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder characterised by progressive generalised dystonia and brain iron accumulation. We assessed whether the iron chelator deferiprone can reduce brain iron and slow disease progression.

Methods: We did an 18-month, randomised, double-blind, placebo-controlled trial (TIRCON2012V1), followed by a pre-planned 18-month, open-label extension study, in patients with PKAN in four hospitals in Germany, Italy, England, and the USA. Patients aged 4 years or older with a genetically confirmed diagnosis of PKAN, a total score of at least 3 points on the Barry-Albright Dystonia (BAD) scale, and no evidence of iron deficiency, neutropenia, or abnormal hepatic or renal function, were randomly allocated (2:1) to receive an oral solution of either deferiprone (30 mg/kg per day divided into two equal doses) or placebo for 18 months. Randomisation was done with a centralised computer random number generator and with stratification based on age group at onset of symptoms. Patients were allocated to groups by a randomisation team not masked for study intervention that was independent of the study. Patients, caregivers, and investigators were masked to treatment allocation. Co-primary endpoints were the change from baseline to month 18 in the total score on the BAD scale (which measures severity of dystonia in eight body regions) and the score at month 18 on the Patient Global Impression of Improvement (PGI-I) scale, which is a patient-reported interpretation of symptom improvement. Efficacy analyses were done on all patients who received at least one dose of the study drug and who provided a baseline and at least one post-baseline efficacy assessment. Safety analyses were done for all patients who received at least one dose of the study drug. Patients who completed the randomised trial were eligible to enrol in a single-arm, open-label extension study of another 18 months, in which all participants received deferiprone with the same regimen as the main study. The trial was registered on ClinicalTrials.gov, number NCT01741532, and EudraCT, number 2012-000845-11.

Findings: Following a screening of 100 prospective patients, 88 were randomly assigned to the deferiprone group (n=58) or placebo group (n=30) between Dec 13, 2012, and April 21, 2015. Of these, 76 patients completed the study (49 in the deferiprone group and 27 in the placebo group). After 18 months, the BAD score worsened by a mean of 2·48 points (SE 0·63) in patients in the deferiprone group versus 3·99 points (0·82) for patients in the control group (difference -1·51 points, 95% CI -3·19 to 0·16, p=0·076). No subjective change was detected as assessed by the PGI-I scale: mean scores at month 18 were 4·6 points (SE 0·3) for patients in the deferiprone group versus 4·7 points (0·4) for those in the placebo group (p=0·728). In the extension study, patients continuing deferiprone retained a similar rate of disease progression as assessed by the BAD scale (1·9 points [0·5] in the first 18 months vs 1·4 points [0·4] in the second 18 months, p=0·268), whereas progression in patients switching from placebo to deferiprone seemed to slow (4·4 points [1·1] vs 1·4 points [0·9], p=0·021). Patients did not detect a change in their condition after the additional 18 months of treatment as assessed by the PGI-I scale, with mean scores of 4·1 points [0·2] in the deferiprone-deferiprone group and of 4·7 points [0·3] in the placebo-deferiprone group. Deferiprone was well tolerated and adverse events were similar between the treatment groups, except for anaemia, which was seen in 12 (21%) of 58 patients in the deferiprone group, but was not seen in any patients in the placebo group. No patient discontinued therapy because of anaemia, and three discontinued because of moderate neutropenia. There was one death in each group of the extension study and both were secondary to aspiration. Neither of these events was considered related to deferiprone use.

Interpretation: Deferiprone was well tolerated, achieved target engagement (lowering of iron in the basal ganglia), and seemed to somewhat slow disease progression at 18 months, although not significantly, as assessed by the BAD scale. These findings were corroborated by the results of an additional 18 months of treatment in the extension study. The subjective PGI-I scale was largely unchanged during both study periods, indicating that might not be an adequate tool for assessment of disease progression in patients with PKAN. Our trial provides the first indication of a decrease in disease progression in patients with neurodegeneration with brain iron accumulation. The extensive information collected and long follow-up of patients in the trial will improve the definition of appropriate endpoints, increase the understanding of the natural history, and thus help to shape the design of future trials in this ultra-orphan disease.

Funding: European Commission, US Food and Drug Administration, and ApoPharma Inc.
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http://dx.doi.org/10.1016/S1474-4422(19)30142-5DOI Listing
July 2019

Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review.

J Clin Med 2019 05 26;8(5). Epub 2019 May 26.

Molecular medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy.

Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes () have been associated with an AGS phenotype. Next Generation Sequencing (NGS) analysis was performed on 51 AGS patients and interferon signature (IS) was investigated in 18 AGS patients and 31 healthy controls. NGS identified mutations in 48 of 51 subjects, with three patients demonstrating a typical AGS phenotype but not carrying mutations in known AGS-related genes. Five mutations, in , and gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS > 2.216). This work presents, for the first time, the genetic data of an Italian cohort of AGS patients, with a higher percentage of mutations in and a lower frequency of mutations in than those seen in international series. mutated patients showed a prevalence of negative IS consistent with data reported in the literature. We also identified five novel pathogenic mutations that warrant further functional investigation. Exome/genome sequencing will be performed in future studies in patients without a mutation in AGS-related genes.
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http://dx.doi.org/10.3390/jcm8050750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572054PMC
May 2019

Spontaneous MRI improvement and absence of cerebral calcification in Aicardi-Goutières syndrome: Diagnostic and disease-monitoring implications.

Mol Genet Metab 2019 04 25;126(4):489-494. Epub 2019 Feb 25.

Department of Pediatric Radiology and Neuroradiology, V. Buzzi Children's Hospital, Milan, Italy.

Background: Aicardi-Goutières syndrome (AGS) is a rare genetic leukoencephalopathy related to inappropriate activation of type I interferon. Neuroradiological findings are typically characterized by white matter abnormalities, cerebral atrophy and cerebral calcification. The disease usually manifests itself during the first year of life in the form of an initial "encephalitic-like" phase followed by a chronic phase of stabilization of the neurological signs. Recently new therapeutic strategies have been proposed aimed at blocking the abnormal activation of the interferon cascade.

Materials And Methods: We reviewed clinical and MRI findings in three young RNASEH2B-mutated patients studied with serial CT and MRI studies.

Results: All three patients presented clinical and MRI features consistent with AGS but, very unexpectedly, an improving neuroradiological course. In patient 1, the MRI improvement was noted some months after treatment with high-dose steroid and IVIg treatment; in patients 2 and 3 it occurred spontaneously. Patient 2 did not show cerebral calcification on CT images.

Conclusions: Our series highlights the possibility of spontaneous neuroradiological improvement in AGS2 patients, as well as the possibility of absence of cerebral calcification in AGS. The study underlines the need for extreme caution when using MRI as an outcome measure in therapeutic trials specific for this disease. MRI follow-up studies in larger series are necessary to describe the natural course of AGS.
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http://dx.doi.org/10.1016/j.ymgme.2019.02.006DOI Listing
April 2019

Substantia Nigra Swelling and Dentate Nucleus T2 Hyperintensity May Be Early Magnetic Resonance Imaging Signs of β-Propeller Protein-Associated Neurodegeneration.

Mov Disord Clin Pract 2019 Jan 9;6(1):51-56. Epub 2018 Nov 9.

Neuroradiology Department, Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy.

Background And Methods: Mutations in cause β-propeller protein-associated neurodegeneration (BPAN), a type of neurodegeneration with brain iron accumulation (NBIA). We reviewed clinical and MRI findings in 4 patients with de novo mutations.

Results: Psychomotor delay and movement disorders were present in all cases; early-onset epileptic encephalopathy was present in 3. In all cases, first MRI showed: prominent bilateral SN enlargement, bilateral dentate nuclei T2-hyperintensity, and corpus callosum thinning. Iron deposition in the SN and globus pallidus (GP) only became evident later. Diffuse cerebral atrophy was present in 3 cases.

Conclusions: In this series, SN swelling and dentate nucleus T2 hyperintensity were early signs of BPAN, later followed by progressive iron deposition in the SN and GP. When clinical suspicion is raised, MRI is crucial for identifying early features suggesting this type of NBIA.
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http://dx.doi.org/10.1002/mdc3.12693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335537PMC
January 2019

The noncoding RNA AK127244 in 2p16.3 locus: A new susceptibility region for neuropsychiatric disorders.

Am J Med Genet B Neuropsychiatr Genet 2018 09 14;177(6):557-562. Epub 2018 Aug 14.

Laboratory of Clinical Pathology and Medical Genetics, Foundation IRCCS C. Besta Neurological Institute, Milan, Italy.

The presence of redundant copy number variants (CNVs) in groups of patients with neurological diseases suggests that these variants could have pathogenic effect. We have collected array comparative genomic hybridization (CGH) data of about 2,500 patients affected by neurocognitive disorders and we observed that CNVs in 2p16.3 locus were as frequent as those in 15q11.2, being both the most frequent unbalances in our cohort of patients. Focusing to 2p16.3 region, unbalances involving NRXN1 coding region have been already associated with neuropsychiatric disorders, although with incomplete penetrance, but little is known about CNVs located proximal to the gene, in the long noncoding RNA AK127244. We found that, in our cohort of patients with neuropsychiatric disorders, the frequency of CNVs involving AK127244 was comparable to that of NRXN1 gene. Patients carrying 2p16.3 unbalances shared some common clinical characteristics regardless NRXN1 and AK127244 CNVs localization, suggesting that the AK127244 long noncoding RNA could be involved in neurocognitive disease with the same effect of NRXN1 unbalances. AK127244 as well as NRXN1 unbalances seem to have a particular influence on language development, behavior or mood, according with the topographic correlation between NRXN1 expression and prefrontal cortex functions.
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http://dx.doi.org/10.1002/ajmg.b.32649DOI Listing
September 2018

Benign hereditary chorea and deletions outside NKX2-1: What's the role of MBIP?

Eur J Med Genet 2018 Oct 3;61(10):581-584. Epub 2018 Apr 3.

Molecular Neurogenetics, Foundation IRCCS Neurological Institute Besta, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. Electronic address:

Heterozygous point mutations or deletions of the NKX2-1 gene cause benign hereditary chorea (BHC) or a various combinations of primary hypothyroidism, respiratory distress and neurological disorders. Deletions proximal to, but not encompassing, NKX2-1 have been described in few subjects with brain-lung-thyroid syndrome. We report on a three-generation Italian family, with 6 subjects presenting BHC and harboring a genomic deletion adjacent to NKX2-1 and including the gene MBIP, recently proposed to be relevant for the pathogenesis of brain-lung-thyroid syndrome. We observed a clear reduction of NKX2-1 transcript levels in fibroblasts from our patients compared to controls; this finding suggests that MBIP deletion affects NKX2-1 expression, mimicking haploinsufficiency caused by classical NKX2-1 related mutations.
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http://dx.doi.org/10.1016/j.ejmg.2018.03.011DOI Listing
October 2018

CANS: Childhood acute neuropsychiatric syndromes.

Eur J Paediatr Neurol 2018 03;22(2):316-320

Fondazione IRCSS Istituto Neurologico Carlo Besta, Milan, Italy. Electronic address:

The terms Pediatric Autoimmune Neuropsychiatric disorders associated with streptococcal infections (PANDAS), Pediatric acute-onset neuropsychiatric Syndrome (PANS), and Childhood Acute Neuropsychiatric Symptoms (CANS) have been used to describe certain acute onset neuropsychiatric pediatric disorders. This clinical characteristic was unusually abrupt onset of obsessive compulsive symptoms and/or severe eating restrictions and concomitant cognitive, behavioral or neurological symptoms. Because the CANS/PANS criteria define a broad spectrum of neuropsychiatric conditions, the syndrome is presumed to result from a variety of disease mechanisms and to have multiple etiologies, ranging from postinfectious autoimmune and neuroinflammatory disorders to toxic, endocrine or metabolic disorders. We suggest a diagnostic flow-chart in case of acute onset neuropsychiatric syndrome to better define diagnostic criteria, identify possible subtypes and delineate treatment.
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http://dx.doi.org/10.1016/j.ejpn.2018.01.011DOI Listing
March 2018

Diagnosis and treatment of pediatric onset isolated dystonia.

Eur J Paediatr Neurol 2018 Mar 17;22(2):238-244. Epub 2018 Jan 17.

Department of Paediatric Neurology, IRCCS Fondazione C. Besta, Milan, Italy.

Isolated dystonia refers to a genetic heterogeneous group of progressive conditions with onset of symptoms during childhood or adolescence, progressive course with frequent generalization and marked functional impairment. There are well-known monogenic forms of isolated dystonia with pediatric onset such as DYT1 and DYT6 transmitted with autosomal dominant inheritance and low penetrance. Genetic findings of the past years have widened the etiological spectrum and the phenotype. The recently discovered genes (GNAL, ANO-3, KTM2B) or variant of already known diseases, such as Ataxia-Teleangectasia, are emerging as another causes of pediatric onset dystonia, sometimes with a more complex phenotype, but their incidence is unknown and still a considerable number of cases remains genetically undetermined. Due to the severe disability of pediatric onset dystonia treatment remains unsatisfactory and still mainly based upon oral pharmacological agents. However, deep brain stimulation is now extensively applied with good to excellent results especially when patients are treated early during the course of the disease.
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http://dx.doi.org/10.1016/j.ejpn.2018.01.006DOI Listing
March 2018

Deep brain stimulation for dystonia due to cerebral palsy: A review.

Eur J Paediatr Neurol 2018 Mar 14;22(2):308-315. Epub 2017 Dec 14.

Department of Neurology - Movement Disorders, IRCCS Fondazione C. Besta, Milan, Italy. Electronic address:

Cerebral palsy (CP) is a heterogeneous group of syndromes that cause a non-progressive disorder of early onset, with abnormal control of movement and posture. Various aetiologies can cause the CP clinical spectrum, but all have a disruption of motor control in common. CP can be divided into four major types based on the motor disability: predominant spastic, dyskinetic, ataxic and mixed form. Dyskinetic CP (DCP) is the most common cause of acquired dystonia in children. The treatment of DCP is challenging because most individuals have mixed degrees of chorea, athetosis and dystonia. Pharmacological treatment is often unsatisfactory. Functional neurosurgery, in particular deep brain stimulation targeting the basal ganglia or the cerebellum, is emerging as a promising therapeutic approach in selected patients with DCP. We evaluated herein the effects of DBS on patients with DCP in a review of published patient data in the largest available studies.
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http://dx.doi.org/10.1016/j.ejpn.2017.12.002DOI Listing
March 2018

ATP1A3-related disorders: An update.

Eur J Paediatr Neurol 2018 Mar 21;22(2):257-263. Epub 2017 Dec 21.

Department of Pediatric Neurology, IRCCS Foundation Carlo Besta Neurological Institute, Via Celoria 11, 20131 Milan, Italy. Electronic address:

Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) are three distinct, yet partially overlapping clinical syndromes that have long been thought to be allelic disorders. From 2004 to 2012, both autosomal dominant and de novo mutations in ATP1A3 have been detected in patients affected by these three conditions. Growing evidence suggests that AHC, RDP and CAPOS syndrome are part of a large and continuously expanding clinical spectrum and share some recurrent clinical features, such as abrupt-onset, asymmetric anatomical distribution and the presence of triggering factors, which are highly suggestive of ATP1A3 mutations. In this review, we will highlight the main clinical and genetic features of ATP1A3-related disorders focussing on shared and distinct features that can be helpful in clinical practice to individuate mutation carriers.
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http://dx.doi.org/10.1016/j.ejpn.2017.12.009DOI Listing
March 2018

SLC19A3 related disorder: Treatment implication and clinical outcome of 2 new patients.

Eur J Paediatr Neurol 2018 Mar 16;22(2):332-335. Epub 2017 Dec 16.

Child Neurology Unit, IRCCS-Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.

Encephalopathies with neostriatal involvement constitute a heterogeneous group of acquired and genetically inherited conditions that include Bilateral Striatal Necrosis (BSN) and other Striatal Lesions (SL) (Tonduti et al). We describe two new patients suffering from BSN due to biallelic SLC19A3 mutations. In the first patient vitamin supplementation was started early on, resulting in the remission of the clinical picture, and an almost complete normalization of the neuroradiological findings. In the second one treatment was started late, compliance was irregular and the resulting clinical outcome was poor. The clinical outcome of our two patients confirms and further stresses the importance of the early administration of vitamin supplementation in all patients presenting with neostriatal lesions, or clear bilateral striatal necrosis. Patient 2 didn't present any additional episode of acute decompensation after the age of 20 years despite having completely stopped treatment. This suggests the existence of an age dependency of thiamin requirement in humans.
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http://dx.doi.org/10.1016/j.ejpn.2017.11.012DOI Listing
March 2018

A PDE10A de novo mutation causes childhood-onset chorea with diurnal fluctuations.

Mov Disord 2017 11 26;32(11):1646-1647. Epub 2017 Sep 26.

Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

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http://dx.doi.org/10.1002/mds.27175DOI Listing
November 2017

Clinical rating scale for pantothenate kinase-associated neurodegeneration: A pilot study.

Mov Disord 2017 Nov 28;32(11):1620-1630. Epub 2017 Aug 28.

Neurology Department, Hospital de Santo Espirito, Ilha Terceira, Portugal.

Background: Pantothenate kinase-associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot-test a disease-specific clinical rating scale for the assessment of patients with pantothenate kinase-associated neurodegeneration.

Methods: In this international cross-sectional study, patients were examined at the referral centers following a standardized protocol. The motor examination was filmed, allowing 3 independent specialists in movement disorders to analyze 28 patients for interrater reliability assessment. The scale included 34 items (maximal score, 135) encompassing 6 subscales for cognition, behavior, disability, parkinsonism, dystonia, and other neurological signs.

Results: Forty-seven genetically confirmed patients (30 ± 17 years; range, 6-77 years) were examined with the scale (mean score, 62 ± 21; range, 20-106). Dystonia with prominent cranial involvement and atypical parkinsonian features were present in all patients. Other common signs were cognitive impairment, psychiatric features, and slow and hypometric saccades. Dystonia, parkinsonism, and other neurological features had a moderate to strong correlation with disability. The scale showed good internal consistency for the total scale (Cronbach's α = 0.87). On interrater analysis, weighted kappa values (0.30-0.93) showed substantial or excellent agreement in 85% of the items. The scale also discriminated a subgroup of homozygous c.1583C>T patients with lower scores, supporting construct validity for the scale.

Conclusions: The proposed scale seems to be a reliable and valid instrument for the assessment of pediatric and adult patients with pantothenate kinase-associated neurodegeneration. Additional validation studies with a larger sample size will be required to confirm the present results and to complete the scale validation testing. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27129DOI Listing
November 2017

ADCY5-related movement disorders: Frequency, disease course and phenotypic variability in a cohort of paediatric patients.

Parkinsonism Relat Disord 2017 Aug 10;41:37-43. Epub 2017 May 10.

Department of Pediatric Neurology, IRCCS Foundation Neurological Institute C. Besta, Via Celoria 11, 20133 Milan, Italy.

Introduction: ADCY5 mutations have been recently identified as an important cause of early-onset hyperkinetic movement disorders. The phenotypic spectrum associated with mutations in this gene is expanding. However, the ADCY5 mutational frequency in cohorts of paediatric patients with hyperkinetic movement disorders has not been evaluated.

Methods: We performed a screening of the entire ADCY5 coding sequence in 44 unrelated subjects with genetically undiagnosed childhood-onset hyperkinetic movement disorders, featuring chorea alone or in combination with myoclonus and dystonia. All patients had normal CSF analysis and brain imaging and were regularly followed-up in tertiary centers for paediatric movement disorders.

Results: We identified five unrelated subjects with ADCY5 mutations (11% of the cohort). Three carried the p. R418W mutation, one the p. R418Q and one the p. R418G mutation. Mutations arose de novo in four cases, while one patient inherited the mutation from his similarly affected father. All patients had delayed motor and/or language milestones with or without axial hypotonia and showed generalized chorea and dystonia, with prominent myoclonic jerks in one case. Episodic exacerbations of the baseline movement disorder were observed in most cases, being the first disease manifestation in two patients. The disease course was variable, from stability to spontaneous improvement during adolescence.

Conclusion: Mutations in ADCY5 are responsible for a hyperkinetic movement disorder that can be preceded by episodic attacks before the movement disorder becomes persistent and is frequently misdiagnosed as dyskinetic cerebral palsy. A residual degree of neck hypotonia and a myopathy-like facial appearance are frequently observed in patients with ADCY5 mutations.
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http://dx.doi.org/10.1016/j.parkreldis.2017.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549507PMC
August 2017
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