Publications by authors named "Roberta Battini"

149 Publications

Muscle "islands": An MRI signature distinguishing neurogenic from myopathic causes of early onset distal weakness.

Neuromuscul Disord 2021 Nov 18. Epub 2021 Nov 18.

Neuroradiological Academic Unit, Queen Square UCL Institute of Neurology and Lysholm Department of Neuroradiology, The National Hospital for Neurology and Neurosurgery, UCLH, London, UK.

Muscle MRI has an increasing role in diagnosis of inherited neuromuscular diseases, but no features are known which reliably differentiate myopathic and neurogenic conditions. Using patients presenting with early onset distal weakness, we aimed to identify an MRI signature to distinguish myopathic and neurogenic conditions. We identified lower limb MRI scans from patients with either genetically (n = 24) or clinically (n = 13) confirmed diagnoses of childhood onset distal myopathy or distal spinal muscular atrophy. An initial exploratory phase reviewed 11 scans from genetically confirmed patients identifying a single potential discriminatory marker concerning the pattern of fat replacement within muscle, coined "islands". This pattern comprised small areas of muscle tissue with normal signal intensity completely surrounded by areas with similar intensity to subcutaneous fat. In the subsequent validation phase, islands correctly classified scans from all 12 remaining genetically confirmed patients, and 12/13 clinically classified patients. In the genetically confirmed patients MRI classification of neurogenic/myopathic aetiology had 100% accuracy (24/24) compared with 65% accuracy (15/23) for EMG, and 79% accuracy (15/19) for muscle biopsy. Future studies are needed in other clinical contexts, however the presence of islands appears to highly suggestive of a neurogenic aetiology in patients presenting with early onset distal motor weakness.
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http://dx.doi.org/10.1016/j.nmd.2021.11.003DOI Listing
November 2021

Alexander disease evolution over time: data from an Italian cohort of pediatric-onset patients.

Mol Genet Metab 2021 12 24;134(4):353-358. Epub 2021 Nov 24.

Unit of Pediatric Neurology, V. Buzzi Children's Hospital, Milan, Italy; C.O.A.L.A (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children's Hospital, Milan, Italy. Electronic address:

Alexander disease (AxD) is a leukodystrophy that primarily affects astrocytes and is caused by dominant variants in the Glial Fibrillary Acidic Protein gene. Three main classifications are currently used, the traditional one defined by the age of onset, and two more recent ones based on both clinical features at onset and brain MRI findings. In this study, we retrospectively included patients with genetically confirmed pediatric-onset AxD. Twenty-one Italian patients were enrolled, and we revised all their clinical and radiological data. Participants were divided according to the current classification systems. We qualitatively analyzed data on neurodevelopment and neurologic decline in order to identify the possible trajectories of the evolution of the disease over time. One patient suffered from a Neonatal presentation and showed a rapidly evolving course which led to death within the second year of life (Type Ia). 16 patients suffered from the Infantile presentation: 5 of them (here defined Type Ib) presented developmental delay and began to deteriorate by the age of 5. A second group (Type Ic) included patients who presented a delay in neuromotor development and started deteriorating after 6 years of age. A third group (Type Id) included patients who presented developmental delay and remained clinically stable beyond adolescence. In 4 patients, the age at last evaluation made it not possible to ascertain whether they belonged to Type Ic or Id, as they were too young to evaluate their neurologic decline. 4 patients suffered from the Juvenile presentation: they had normal neuromotor development with no or only mild cognitive impairment; the subsequent clinical evolution was similar to Type Ic AxD in 2 patients, to Id group in the other 2. In conclusion, our results confirm previously described findings about clinical features at onset; based on follow-up data we might classify patients with Type I AxD into four subgroups (Ia, Ib, Ic, Id). Further studies will be needed to confirm our results and to better highlight the existence of clinical and neuroradiological prognostic factors able to predict disease progression.
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http://dx.doi.org/10.1016/j.ymgme.2021.11.009DOI Listing
December 2021

A Rare Case of Perrault Syndrome with Auditory Neuropathy Spectrum Disorder: Cochlear Implantation Treatment and Literature Review.

Audiol Res 2021 Nov 13;11(4):609-617. Epub 2021 Nov 13.

Otolaryngology, Audiology and Phoniatrics Unit, University of Pisa, 56100 Pisa, Italy.

Perrault syndrome (PRLTS) is a rare autosomal recessive disorder characterised by ovarian failure in females and sensorineural hearing loss (SNHL) in both genders. In the present paper we describe a child affected by PRLTS3, due to CLPP homozygous mutations, presenting auditory neuropathy spectrum disorder (ANSD) with bilateral progressive SNHL. This is the first case reported in the literature of an ANSD in PRLTS3. CLPP is a nuclear encoded mitochondrial protease directed at the mitochondrial matrix. It is encoded on chromosome 19. This protease participates in mitochondrial protein quality control by degrading misfolded or damaged proteins, thus maintaining the normal metabolic function of the cell. In PRLTS3, the peptidase activity of CLPP is suppressed. Neurological impairments involved in PRLTS3 suggest that the pathogenic mutations in CLPP might trigger a mitochondrial dysfunction. A comprehensive description of the clinical and audiological presentation, as well as the issues related to cochlear implant (CI) procedure and the results, are addressed and discussed. A brief review of the literature on this topic is also provided.
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http://dx.doi.org/10.3390/audiolres11040055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8628573PMC
November 2021

17q12 Recurrent Deletions and Duplications: Description of a Case Series with Neuropsychiatric Phenotype.

Genes (Basel) 2021 10 21;12(11). Epub 2021 Oct 21.

Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Calambrone, 56128 Pisa, Italy.

Syndromic neurodevelopmental disorders are usually investigated through genetics technologies, within which array comparative genomic hybridization (Array-CGH) is still considered the first-tier clinical diagnostic test. Among recurrent syndromic imbalances, 17q12 deletions and duplications are characterized by neurodevelopmental disorders associated with visceral developmental disorders, although expressive variability is common. Here we describe a case series of 12 patients with 17q12 chromosomal imbalances, in order to expand the phenotypic characterization of these recurrent syndromes whose diagnosis is often underestimated, especially if only mild traits are present. Gene content and genotype-phenotype correlations have been discussed, with special regard to neuropsychiatric features, whose impact often requires etiologic analysis.
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http://dx.doi.org/10.3390/genes12111660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620923PMC
October 2021

haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum.

J Med Genet 2021 Oct 21. Epub 2021 Oct 21.

Unit of Neurorehabilitation, Department of Neurosciences, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.

Background: Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the gene in two families with mild JS. Recently, heterozygous truncating variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies.

Methods: We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.

Results: Heterozygous truncating and splice-site variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents.

Conclusion: Heterozygous truncating or splice-site variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.
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http://dx.doi.org/10.1136/jmedgenet-2021-108114DOI Listing
October 2021

Hyperkinetic stereotyped movements in a boy with biallelic CNTNAP2 variants.

Ital J Pediatr 2021 Oct 12;47(1):208. Epub 2021 Oct 12.

Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Background: Heterozygous variants in CNTNAP2 have been implicated in a wide range of neurological phenotypes, including intellectual disability (ID), epilepsy, autistic spectrum disorder (ASD), and impaired language. However, heterozygous variants can also be found in unaffected individuals. Biallelic CNTNAP2 variants are rarer and cause a well-defined genetic syndrome known as CASPR2 deficiency disorder, a condition characterised by ID, early-onset refractory epilepsy, language impairment, and autistic features.

Case-report: A 7-year-old boy presented with hyperkinetic stereotyped movements that started during early infancy and persisted over childhood. Abnormal movements consisted of rhythmic and repetitive shaking of the four limbs, with evident stereotypic features. Additional clinical features included ID, attention deficit-hyperactivity disorder (ADHD), ASD, and speech impairment, consistent with CASPR2 deficiency disorder. Whole-genome array comparative genomic hybridization detected a maternally inherited 0.402 Mb duplication, which involved intron 1, exon 2, and intron 2 of CNTNAP2 (c.97 +?_209-?dup). The affected region in intron 1 contains a binding site for the transcription factor FOXP2, potentially leading to abnormal CNTNAP2 expression regulation. Sanger sequencing of the coding region of CNTNAP2 also identified a paternally-inherited missense variant c.2752C > T, p.(Leu918Phe).

Conclusion: This case expands the molecular and phenotypic spectrum of CASPR2 deficiency disorder, suggesting that Hyperkinetic stereotyped movements may be a rare, yet significant, clinical feature of this complex neurological disorder. Furthermore, the identification of an in-frame, largely non-coding duplication in CNTNAP2 points to a sophisticated underlying molecular mechanism, likely involving impaired FOXP2 binding.
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http://dx.doi.org/10.1186/s13052-021-01162-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507175PMC
October 2021

Monoallelic KIF1A-related disorders: a multicenter cross sectional study and systematic literature review.

J Neurol 2022 Jan 6;269(1):437-450. Epub 2021 Sep 6.

Neurofisiopathology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168, Rome, Italy.

Background: Monoallelic variants in the KIF1A gene are associated with a large set of clinical phenotypes including neurodevelopmental and neurodegenerative disorders, underpinned by a broad spectrum of central and peripheral nervous system involvement.

Methods: In a multicenter study conducted in patients presenting spastic gait or complex neurodevelopmental disorders, we analyzed the clinical, genetic and neuroradiological features of 28 index cases harboring heterozygous variants in KIF1A. We conducted a literature systematic review with the aim to comparing our findings with previously reported KIF1A-related phenotypes.

Results: Among 28 patients, we identified nine novel monoallelic variants, and one a copy number variation encompassing KIF1A. Mutations arose de novo in most patients and were prevalently located in the motor domain. Most patients presented features of a continuum ataxia-spasticity spectrum with only five cases showing a prevalently pure spastic phenotype and six presenting congenital ataxias. Seventeen mutations occurred in the motor domain of the Kinesin-1A protein, but location of mutation did not correlate with neurological and imaging presentations. When tested in 15 patients, muscle biopsy showed oxidative metabolism alterations (6 cases), impaired respiratory chain complexes II + III activity (3/6) and low CoQ10 levels (6/9). Ubiquinol supplementation (1gr/die) was used in 6 patients with subjective benefit.

Conclusions: This study broadened our clinical, genetic, and neuroimaging knowledge of KIF1A-related disorders. Although highly heterogeneous, it seems that manifestations of ataxia-spasticity spectrum disorders seem to occur in most patients. Some patients also present secondary impairment of oxidative metabolism; in this subset, ubiquinol supplementation therapy might be appropriate.
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http://dx.doi.org/10.1007/s00415-021-10792-3DOI Listing
January 2022

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

Int J Mol Sci 2021 Aug 6;22(16). Epub 2021 Aug 6.

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, 56128 Pisa, Italy.

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. , , and were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.
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http://dx.doi.org/10.3390/ijms22168490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395181PMC
August 2021

The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development.

Genes (Basel) 2021 07 24;12(8). Epub 2021 Jul 24.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, I-56128 Pisa, Italy.

Creatine (Cr) Transporter Deficiency (CTD) is an X-linked metabolic disorder, mostly caused by missense mutations in the gene and presenting with intellectual disability, autistic behavior, and epilepsy. There is no effective treatment for CTD and patients need lifelong assistance. Thus, the research of novel intervention strategies is a major scientific challenge. Animal models are an excellent tool to dissect the disease pathogenetic mechanisms and drive the preclinical development of therapeutics. This review illustrates the current knowledge about Cr metabolism and CTD clinical aspects, with a focus on mainstay diagnostic and therapeutic options. Then, we discuss the rodent models of CTD characterized in the last decade, comparing the phenotypes expressed within clinically relevant domains and the timeline of symptom development. This analysis highlights that animals with the ubiquitous deletion/mutation of genes well recapitulate the early onset and the complex pathological phenotype of the human condition. Thus, they should represent the preferred model for preclinical efficacy studies. On the other hand, brain- and cell-specific conditional mutants are ideal for understanding the basis of CTD at a cellular and molecular level. Finally, we explain how CTD models might provide novel insight about the pathogenesis of other disorders, including cancer.
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http://dx.doi.org/10.3390/genes12081123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392480PMC
July 2021

The Diagnostic Approach to Mitochondrial Disorders in Children in the Era of Next-Generation Sequencing: A 4-Year Cohort Study.

J Clin Med 2021 Jul 22;10(15). Epub 2021 Jul 22.

Department of Molecular Medicine, IRCCS Stella Maris Foundation, 56128 Pisa, Italy.

Mitochondrial diseases (MDs) are a large group of genetically determined multisystem disorders, characterized by extreme phenotypic heterogeneity, attributable in part to the dual genomic control (nuclear and mitochondrial DNA) of the mitochondrial proteome. Advances in next-generation sequencing technologies over the past two decades have presented clinicians with a challenge: to select the candidate disease-causing variants among the huge number of data provided. Unfortunately, the clinical tools available to support genetic interpretations still lack specificity and sensitivity. For this reason, the diagnosis of MDs continues to be difficult, with the new "genotype first" approach still failing to diagnose a large group of patients. With the aim of investigating possible relationships between clinical and/or biochemical phenotypes and definitive molecular diagnoses, we performed a retrospective multicenter study of 111 pediatric patients with clinical suspicion of MD. In this cohort, the strongest predictor of a molecular (in particular an mtDNA-related) diagnosis of MD was neuroimaging evidence of basal ganglia (BG) involvement. Regression analysis confirmed that normal BG imaging predicted negative genetic studies for MD. Psychomotor regression was confirmed as an independent predictor of a definitive diagnosis of MD. The findings of this study corroborate previous data supporting a role for neuroimaging in the diagnostic approach to MDs and reinforce the idea that mtDNA sequencing should be considered for first-line testing, at least in specific groups of children.
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http://dx.doi.org/10.3390/jcm10153222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348083PMC
July 2021

Parental Distress in the Time of COVID-19: A Cross-Sectional Study on Pediatric Patients with Neuropsychiatric Conditions during Lockdown.

Int J Environ Res Public Health 2021 Jul 26;18(15). Epub 2021 Jul 26.

Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.

The lockdown due to the COVID-19 pandemic has had adverse psychological effects on children and parents. While parenting is essential for positive development, increased parental distress has interfered with children's wellbeing. In our study, we aimed to identify the predictors of parental distress in families of children with neuropsychiatric disorders during lockdown. Seventy-seven parents of children with neuropsychiatric disorders were asked to fill three online questionnaires (a socio-demographic questionnaire, the Child Behavior Checklist (CBCL) and Parental-Stress-Index (PSI-4-SF) to explore the relationship between parental distress, emotional/behavioral problems in children and quarantine-related factors through univariate analyses and multiple mediation models. Significant positive associations between CBCL-internalizing-problems and all PSI-4-SF subscales, and between CBCL-externalizing-problems and "Difficult Child" subscales were found. "Parent-Child Dysfunctional Interaction" subscale and teachers-child relationship quality resulted negatively associated, as well as the "Difficult Child" subscale and peers-child relationship quality. The effect of teachers-child relationship quality on "Parent-Child Dysfunctional Interaction" was mediated by children internalizing problems, while the effect of peers-child relationship quality on "Difficult Child" by the child internalizing/externalizing problems. Internalizing problems in children with neuropsychiatric disorders were among the strongest predictors of parental stress during lockdown, mediating the indirect effects of quarantine-related factors, thus suggesting the importance of their detection during and after emergency situations to provide assistance and reduce parenting pressure.
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http://dx.doi.org/10.3390/ijerph18157902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345642PMC
July 2021

Clinical, molecular and glycophenotype insights in SLC39A8-CDG.

Orphanet J Rare Dis 2021 07 10;16(1):307. Epub 2021 Jul 10.

Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Viale del Tirreno 331, Calambrone, 56128, Pisa, Italy.

Background: SLC39A8, a gene located on chromosome 4q24, encodes for the manganese (Mn) transporter ZIP8 and its detrimental variants cause a type 2 congenital disorder of glycosylation (CDG). The common SLC39A8 missense variant A391T is associated with increased risk for multiple neurological and systemic disorders and with decreased serum Mn. Patients with SLC39A8-CDG present with different clinical and neuroradiological features linked to variable transferrin glycosylation profile. Galactose and Mn supplementation therapy results in the biochemical and clinical amelioration of treated patients.

Results: Here, we report clinical manifestations, neuroradiological features and glycophenotypes associated with novel SLC39A8 variants (c.1048G > A; p.Gly350Arg and c.131C > G; p.Ser44Trp) in two siblings of the same Italian family. Furthermore, we describe a third patient with overlapping clinical features harbouring the homozygous missense variant A391T. The clinical phenotype of the three patients was characterized by severe developmental disability, dystonic postural pattern and dyskinesia with a more severe progression of the disease in the two affected siblings. Neuroimaging showed a Leigh syndrome-like pattern involving the basal ganglia, thalami and white matter. In the two siblings, atrophic cerebral and cerebellum changes consistent with SLC39A8-CDG were detected as well. Serum transferrin isoelectric focusing (IEF) yielded variable results with slight increase of trisialotransferrin isoforms or even normal pattern. MALDI-MS showed the presence of hypogalactosylated transferrin N-glycans, spontaneously decreasing during the disease course, only in one affected sibling. Total serum N-glycome depicted a distinct pattern for the three patients, with increased levels of undergalactosylated and undersialylated precursors of fully sialylated biantennary glycans, including the monosialo-monogalacto-biantennary species A2G1S1.

Conclusions: Clinical, MRI and glycosylation features of patients are consistent with SLC39A8-CDG. We document two novel variants associated with Leigh syndrome-like disease presentation of SLC39A8-CDG. We show, for the first time, a severe neurological phenotype overlapping with that described for SLC39A8-CDG in association with the homozygous A391T missense variant. We observed a spontaneous amelioration of transferrin N-glycome, highlighting the efficacy of MS-based serum glycomics as auxiliary tool for the diagnosis and clinical management of therapy response in patients with SLC39A8-CDG. Further studies are needed to analyse more in depth the influence of SLC39A8 variants, including the common missense variant, on the expression and function of ZIP8 protein, and their impact on clinical, biochemical and neuroradiological features.
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http://dx.doi.org/10.1186/s13023-021-01941-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272319PMC
July 2021

North Star Ambulatory Assessment changes in ambulant Duchenne boys amenable to skip exons 44, 45, 51, and 53: A 3 year follow up.

PLoS One 2021 25;16(6):e0253882. Epub 2021 Jun 25.

Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, Rome, Italy.

Introduction: The aim of this study was to report 36-month longitudinal changes using the North Star Ambulatory Assessment (NSAA) in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53.

Materials And Methods: We included 101 patients, 34 had deletions amenable to skip exon 44, 25 exon 45, 19 exon 51, and 28 exon 53, not recruited in any ongoing clinical trials. Five patients were counted to skip exon 51 and 53 since they had a single deletion of exon 52.

Results: The difference between subgroups (skip 44, 45, 51 and 53) was significant at 12 (p = 0.043), 24 (p = 0.005) and 36 months (p≤0.001).

Discussion: Mutations amenable to skip exons 53 and 51 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had higher scores both at baseline and at follow up.

Conclusion: Our results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253882PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232423PMC
November 2021

Broadening the spectrum phenotype of TBCE-related neuron neurodegeneration.

Brain Dev 2021 Oct 13;43(9):939-944. Epub 2021 Jun 13.

Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Ospedale Bambino Gesù Research Children's Hospital, IRCCS, Rome, Italy.

Background: Severe loss of TBCE function has been related to two well-known dysmorphic syndromes, while TBCE hypomorphic variants have been linked to neurodegenerative conditions due to perturbed microtubule dynamics and homeostasis, with signs of central and peripheral nervous system involvement.

Method: We report on an Italian female originating from Southern Italy who presented early-onset regression and neurodegeneration, with neurological features of tetraparesis and signs of peripheral nervous system involvement. Her brain MRI revealed white matter involvement.

Results: Analyzing all known hypomyelination leukodystrophies related genes, two mutations in TBCE (NM_001079515) were detected: the missense variant c.464 T > A; p. (Ile155Asn) and the frameshift variant c.924del; p. (Leu309Ter), in compound heterozygosity, already reported in the literature in patients coming from the same geographical area. The clinical phenotype of the proposita was more severe and with an earlier onset than the majority of the patients reported so far.

Conclusions: Next Generation Sequencing is becoming increasingly necessary to assess unusual phenotypes, with the opportunity to establish prognosis and disease mechanisms, and facilitating differential diagnosis.
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http://dx.doi.org/10.1016/j.braindev.2021.05.015DOI Listing
October 2021

Refining the mutational spectrum and gene-phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study.

J Med Genet 2021 Mar 5. Epub 2021 Mar 5.

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

Background: Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes.

Methods: We performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters.

Results: A genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was , which accounted for nearly half cases (45%) and was mutated in females and occasionally in males. The European founder mutation p.Ala307Ser in and pathogenic variants in accounted for 18% and 9% of cases, respectively. , and were mutated in single patients. We were able to confirm only few previously reported associations, including jitteriness and clonus with and lower motor neuron signs with . When considering multiple features simultaneously, a clear association with a phenotypic cluster only emerged for .

Conclusion: represents the major PCH causative gene in Italy. Phenotypic variability associated with the most common genetic causes of PCH is wider than previously thought, with marked overlap between and -associated disorders.
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http://dx.doi.org/10.1136/jmedgenet-2020-107497DOI Listing
March 2021

Focusing on Autism Spectrum Disorder in Xia-Gibbs Syndrome: Description of a Female with High Functioning Autism and Literature Review.

Children (Basel) 2021 May 26;8(6). Epub 2021 May 26.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, 56128 Calambrone, Italy.

Background: Xia-Gibbs syndrome (XGS) is a rare disorder caused by de novo mutations in the AT-Hook DNA binding motif Containing 1 () gene, which is characterised by a wide spectrum of clinical manifestations, including global developmental delay, intellectual disability, structural abnormalities of the brain, global hypotonia, feeding problems, sleep difficulties and apnoea, facial dysmorphisms, and short stature.

Methods: Here, we report on a girl patient who shows a peculiar cognitive and behavioural profile including high-functioning autism spectrum disorder (ASD) without intellectual disability and provide information on her developmental trajectory with the aim of expanding knowledge of the XGS clinical spectrum. On the basis of the current clinical case and the literature review, we also attempt to deepen understanding of behavioural and psychiatric manifestations associated with XGS.

Results: In addition to the patient we described, a considerable rate of individuals with XGS display autistic symptoms or have been diagnosed with an autistic spectrum disorder. Moreover, the analysis of the few psychopathological profiles of patients with XGS described in the literature shows a frequent presence of aggressive and self-injurious behaviours that could be either an expression of autistic functioning or an additional symptom of the ASD evolution. A careful investigation of the abovementioned symptoms is therefore required, since they could represent a "red flag" for ASD.
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http://dx.doi.org/10.3390/children8060450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227570PMC
May 2021

Movement Disorders in Children with a Mitochondrial Disease: A Cross-Sectional Survey from the Nationwide Italian Collaborative Network of Mitochondrial Diseases.

J Clin Med 2021 May 12;10(10). Epub 2021 May 12.

IRCCS Fondazione Stella Maris, 56018 Pisa, Italy.

Movement 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.
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http://dx.doi.org/10.3390/jcm10102063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151313PMC
May 2021

Challenges and resources in adult life with Joubert syndrome: issues from an international classification of functioning (ICF) perspective.

Disabil Rehabil 2021 May 19:1-8. Epub 2021 May 19.

Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy.

Background: Joubert Syndrome (JS) is a rare inherited neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation (i.e. the molar tooth sign) and variable organ involvement. The aim of the present study was to describe functional limitations and disabilities in a large sample of adult patients with a diagnosis of JS.

Methods: We administered the International Classification of Functioning (ICF) checklist to thirty-six adult Italian patients with JS or their caregivers through telephone calls.

Results: None-to-mild impairment was documented for basic cognitive and mental functions, whereas severe deficit emerged for higher-order skills and language. A mismatch between individuals' capacity for daily activity and social participation and the actual performance in these fields emerged, suggesting that adults with JS may greatly benefit from external support from the caring environment. Indeed, specific facilitators were highlighted, including communication technologies as well as family members, healthcare professionals and peers support. Mild-to-severe barriers have been identified by adult patients with JS in the domains of services, systems and policies.

Conclusions: These findings highlight challenges and barriers for adults with JS in areas of daily functioning that may be improved by investing in rehabilitation care models that embed social support programs and policies into clinical interventions.IMPLICATIONS FOR REHABILITATIONChildren with Joubert Syndrome, a child-onset rare inherited neurodevelopmental condition, are growing up and becoming adults; a life course approach in rehabilitation is needed;There is a substantial lack of information on the long-term adaptive daily functioning of children with a diagnosis of Joubert Syndrome;In this paper, the International Classification of Functioning (ICF) was applied to assess the daily functioning in people with JS;Severe deficits emerged for high-order skills and language, whereas the use of communication technologies and the engagement of family members were highlighted as key facilitators;These findings highlight the need for a change of paradigm in the care model of subjects with JS, with the embedding of social support in rehabilitation programs.
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http://dx.doi.org/10.1080/09638288.2021.1922516DOI Listing
May 2021

Neural substrates of neuropsychological profiles in dystrophynopathies: A pilot study of diffusion tractography imaging.

PLoS One 2021 3;16(5):e0250420. Epub 2021 May 3.

Department of Developmental Neuroscience, IRCCS Stella Maris, Calambrone, Pisa, Italy.

Introduction: Cognitive difficulties and neuropsychological alterations in Duchenne and Becker muscular dystrophy (DMD, BMD) boys are not yet sufficiently explored, although this topic could have a relevant impact, finding novel biomarkers of disease both at genetics and neuroimaging point of view. The current study aims to: 1) analyze the neuropsychological profile of a group of DMD and BMD boys without cognitive impairment with an assessment of their executive functions; 2) explore the structural connectivity in DMD, BMD, and age-matched controls focusing on cortico-subcortical tracts that connect frontal cortex, basal ganglia, and cerebellum via the thalamus; 3) explore possible correlations between altered structural connectivity and clinical neuropsychological measures.

Materials And Methods: This pilot study included 15 boys (5 DMD subjects, 5 BMD subjects, and 5 age-matched typically developing, TD). They were assessed using a neuropsychological assessment protocol including cognitive and executive functioning assessment and performed a 1.5T MRI brain exam including advance Diffusion Weighted Imaging (DWI) method for tractography. Structural connectivity measurements were extracted along three specific tracts: Cortico-Ponto-Cerebellar Tract (CPCT), Cerebellar-Thalamic Tract (CTT), and Superior Longitudinal Fasciculus (SLF). Cortical-Spinal Tract (CST) was selected for reference, as control tract.

Results: Regarding intellectual functioning, a major impairment in executive functions compared to the general intellectual functioning was observed both for DMD (mean score = 86.20; SD = 11.54) and for BMD children (mean score = 88; SD = 3.67). Mean FA resulted tendentially always lower in DMD compared to both BMD and TD groups for all the examined tracts. The differences in FA were statistically significant for the right CTT (DMD vs BMD, p = 0.002, and DMD vs TD, p = 0.0015) and the right CPCT (DMD vs TD, p = 0.008). Concerning DMD, significant correlations emerged between FA-R-CTT and intellectual quotients (FIQ, p = 0.044; ρs = 0.821), and executive functions (Denomination Total, p = 0.044, ρs = 0.821; Inhibition Total, p = 0.019, ρs = 0.900). BMD showed a significant correlation between FA-R-CPCT and working memory index (p = 0.007; ρs = 0.949).

Discussion And Conclusion: In this pilot study, despite the limitation of sample size, the findings support the hypothesis of the involvement of a cerebellar-thalamo-cortical loop for the neuropsychological profile of DMD, as the CTT and the CPCT are involved in the network and the related brain structures are known to be implied in executive functions. Our results suggest that altered WM connectivity and reduced fibre organization in cerebellar tracts, probably due to the lack of dystrophin in the brain, may render less efficient some neuropsychological functions in children affected by dystrophinopathies. The wider multicentric study could help to better establish the role of cerebellar connectivity in neuropsychological profile for dystrophinopathies, identifying possible novel diagnostic and prognostic biomarkers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250420PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092766PMC
October 2021

Neuroimaging patterns in paediatric onset hereditary spastic paraplegias.

J Neurol Sci 2021 06 10;425:117441. Epub 2021 Apr 10.

IRCCS Stella Maris Foundation, Calambrone, 56128 Pisa, Italy; Department of Clinical and Experimental Medicine, University of Pisa, 56125 Pisa, Italy. Electronic address:

Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness of the lower limbs with a notable phenotypic variation and an autosomal recessive (AR), autosomal dominant (AD), and X-linked inheritance pattern. The recent clinical use of next generation sequencing methods has facilitated the diagnostic approach to HSPs, but the diagnosis remains quite challenging considering its wide clinical and genetic heterogeneity. In this scenario, magnetic resonance imaging (MRI) emerges as a valuable tool in helping to exclude mimicking disorders and to guide genetic testing. The aim of this study is to investigate the presence of possible patterns of morphostructural MRI findings that may provide relevant clues for a specific genetic HSP subtype. In our cohort, for example, white matter abnormalities were the most common finding followed by the thinning of the corpus callosum, which, interestingly, presented different thinning characteristics depending on the HSP subtype.
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http://dx.doi.org/10.1016/j.jns.2021.117441DOI Listing
June 2021

De Novo 1q21.3q22 Duplication Revaluation in a "Cold" Complex Neuropsychiatric Case with Syndromic Intellectual Disability.

Genes (Basel) 2021 03 31;12(4). Epub 2021 Mar 31.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Calambrone, 56128 Pisa, Italy.

Syndromic intellectual disability often obtains a genetic diagnosis due to the combination of first and next generation sequencing techniques, although their interpretation may require revaluation over the years. Here we report on a composite neuropsychiatric case whose phenotype includes moderate intellectual disability, spastic paraparesis, movement disorder, and bipolar disorder, harboring a 1.802 Mb de novo 1q21.3q22 duplication. The role of this duplication has been reconsidered in the light of negativity of many other genetic exams, and of the possible pathogenic role of many genes included in this duplication, potentially configuring a contiguous gene-duplication syndrome.
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http://dx.doi.org/10.3390/genes12040511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066010PMC
March 2021

The nonsense mutation stop+4 model correlates with motor changes in Duchenne muscular dystrophy.

Neuromuscul Disord 2021 06 21;31(6):479-488. Epub 2021 Feb 21.

Pediatric Neurology, Università Cattolica del Sacro Cuore, Rome, Italy; Centro Clinico Nemo, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, Rome 00152, Italy. Electronic address:

The aim was to assess 3-year longitudinal data using 6MWT in 26 ambulant boys affected by DMD carrying nonsense mutations and to compare their results to other small mutations. We also wished to establish, within the nonsense mutations group, patterns of change according to several variables. Patients with nonsense mutations were categorized according to the stop codon type newly created by the mutation and also including the adjacent 5' (upstream) and 3' (downstream) nucleotides. No significant difference was found between nonsense mutations and other small mutations (p > 0.05) on the 6MWT. Within the nonsense mutations group, there was no difference in 6MWT when the patients were subdivided according to: Type of stop codon, frame status of exons involved, protein domain affected. In contrast, there was a difference when the stop codon together with the 3' adjacent nucleotide ("stop+4 model") was considered (p < 0.05) with patients with stop codon TGA and 3' adjacent nucleotide G (TGAG) having a more rapid decline. Our finding suggest that the stop+4 model may help in predicting functional changes. This data will be useful at the time of interpreting the long term follow up of patients treated with Ataluren that are becoming increasingly available.
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http://dx.doi.org/10.1016/j.nmd.2021.02.015DOI Listing
June 2021

A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine.

Front Neurol 2021 26;12:612429. Epub 2021 Feb 26.

Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy.

Tetrabenazine has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of tetrabenazine in children with dyskinetic cerebral palsy (DCP). The purpose of this study was to evaluate the efficacy of tetrabenazine in a sample of children with DCP using the Movement Disorders-Childhood Rating Scale 4-18 Revised (MD-CRS 4-18 R). The study is a multicenter retrospective longitudinal study in which the participants were selected from the databases of each Center involved, according to detailed inclusion criteria. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP having been evaluated before starting the treatment (baseline), after 6 and 12 months of treatment and in a sub-cohort after >2 years follow-up. A linear mixed model was used to evaluate the effects of the different timings on each MD-CRS 4-18 R Index (Index I, Index II, and Global Index) adding age and type of movement disorder as random effect. A significant clinical improvement related to a reduction of MD-CRS 4-18 R Indexes was detected between the baseline and after 6 and 12 months of treatment. Findings support the efficacy of tetrabenazine in children with DCP through a standardized outcome measure (MD-CRS 4-18 R) and confirm the use of this scale as a suitable tool to detect changes in further randomized clinical trials.
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http://dx.doi.org/10.3389/fneur.2021.612429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953156PMC
February 2021

New pathogenic variants in COQ4 cause ataxia and neurodevelopmental disorder without detectable CoQ deficiency in muscle or skin fibroblasts.

J Neurol 2021 Sep 11;268(9):3381-3389. Epub 2021 Mar 11.

IRCCS Fondazione Stella Maris, Pisa, Italy.

COQ4 is a component of an enzyme complex involved in the biosynthesis of coenzyme Q (CoQ), a molecule with primary importance in cell metabolism. Mutations in the COQ4 gene are responsible for mitochondrial diseases showing heterogeneous age at onset, clinical presentations and association with CoQ deficiency. We herein expand the phenotypic and genetic spectrum of COQ4-related diseases, by reporting two patients harboring bi-allelic variants but not showing CoQ deficiency. One patient was found to harbor compound heterozygous mutations (specifically, c.577C>T/p.Pro193Ser and the previously reported c.718C>T/p.Arg240Cys) associated with progressive spasticity, while the other harbored two novel missense (c.284G>A/p.Gly95Asp and c.305G>A/p.Arg102His) associated with a neurodevelopmental disorder. Both patients presented motor impairment and ataxia. To further understand the role of COQ4, we performed functional studies in patient-derived fibroblasts, yeast and "crispant" zebrafish larvae. Micro-oxygraphy showed impaired oxygen consumption rates in one patient, while yeast complementation assays showed that all the mutations were presumably disease related. Moreover, characterization of the coq4 F0 CRISPR zebrafish line showed motor defects and cell reduction in a specific area of the hindbrain, a region reminiscent of the human cerebellum. Our expanded phenotype associated with COQ4 mutations allowed us to investigate, for the first time, the role of COQ4 in brain development in vivo.
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http://dx.doi.org/10.1007/s00415-021-10509-6DOI Listing
September 2021

CASK related disorder: Epilepsy and developmental outcome.

Eur J Paediatr Neurol 2021 Mar 19;31:61-69. Epub 2021 Feb 19.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genova, Italy; Unit of Child Neuropsychiatry, ASST Fatebenefratelli Sacco, Milano, Italy.

Objective: CASK pathogenic variants are associated with variable features, as intellectual disability, optic atrophy, brainstem/cerebellar hypoplasia, and epileptic encephalopathy. Few studies describe the electroclinical features of epilepsy in patients with CASK pathogenic variants and their relationship with developmental delay.

Methods: this national multicentre cohort included genetically confirmed patients with different CASK pathogenic variants. Our findings were compared with cohorts reported in the literature.

Results: we collected 34 patients (29 females) showing from moderate (4 patients) to severe (22) and profound (8) developmental delay; all showed pontine and cerebellar hypoplasia, all except three with microcephaly. Seventeen out of 34 patients (50%) suffered from epileptic seizures, including spasms (11 patients, 32.3%), generalized (5) or focal seizures (1). In 8/17 individuals (47.1%), epilepsy started at or beyond the age of 24 months. Seven (3 males) out of the 11 children with spasms showed EEG features and a course supporting the diagnosis of a developmental and epileptic encephalopathy (DEE). Drug resistance was frequent in our cohort (52.9% of patients with epilepsy). EEG abnormalities included poorly organized background activity with diffuse or multifocal epileptiform abnormalities and sleep-activation, with possible appearance over the follow-up period. Developmental delay degree was not statistically different among patients with or without seizures but feeding difficulties were more frequent in patients with epilepsy.

Conclusions: epilepsy is a frequent comorbidity with a high incidence of spasms and drug resistance. Overall developmental disability does not seem to be more severe in the group of patients with epilepsy nor to be linked to specific epilepsy/EEG characteristics. A childhood onset of epilepsy is frequent, with possible worsening over time, so that serial and systematic monitoring is mandatory.
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http://dx.doi.org/10.1016/j.ejpn.2021.02.006DOI Listing
March 2021

Clinical and radiological correlates of activities of daily living in cerebellar atrophy caused by PMM2 mutations (PMM2-CDG).

Cerebellum 2021 Aug 22;20(4):596-605. Epub 2021 Feb 22.

Child Neurology and Psychiatry Section, Department of Clinical and Experimental Medicine, University of Catania, Policlinico, Via Santa Sofia 78, 95123, Catania, Italy.

We aimed to identify clinical, molecular and radiological correlates of activities of daily living (ADL) in patients with cerebellar atrophy caused by PMM2 mutations (PMM2-CDG), the most frequent congenital disorder of glycosylation. Twenty-six PMM2-CDG patients (12 males; mean age 13 ± 11.1 years) underwent a standardized assessment to measure ADL, ataxia (brief ataxia rating scale, BARS) and phenotype severity (Nijmegen CDG rating scale, NCRS). MRI biometry of the cerebellum and the brainstem were performed in 23 patients (11 males; aged 5 months-18 years) and 19 control subjects with equal gender and age distributions. The average total ADL score was 15.3 ± 8.5 (range 3-32 out of 36 indicating severe functional disability), representing variable functional outcome in PMM2-CDG patients. Total ADL scores were significantly correlated with NCRS (r = 0.55, p < 0.001) and BARS scores (r = 0.764; p < 0.001). Severe intellectual disability, peripheral neuropathy, and severe PMM2 variants were all significantly associated with worse functional outcome. Higher ADL scores were significantly associated with decreased diameters of cerebellar vermis (r = 0.347; p = 0.004), hemispheres (r = 0.436; p = 0.005), and brainstem, particularly the mid-pons (r = 0.64; p < 0.001) representing the major radiological predictor of functional disability score in multivariate regression analysis. We show that cerebellar syndrome severity, cognitive level, peripheral neuropathy, and genotype correlate with ADL used to quantify disease-related deficits in PMM2-CDG. Brainstem involvement should be regarded among functional outcome predictors in patients with cerebellar atrophy caused by PMM2-CDG.
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http://dx.doi.org/10.1007/s12311-021-01242-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360885PMC
August 2021

Aromatic L-amino Acid Decarboxylase (AADC) deficiency: results from an Italian modified Delphi consensus.

Ital J Pediatr 2021 Jan 21;47(1):13. Epub 2021 Jan 21.

Child Neurology and Psychiatric Unit-Presidio Ospedaliero Santa Maria Nuova -AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

Background: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare and underdiagnosed neurometabolic disorder resulting in a complex neurological and non-neurological phenotype, posing diagnostic challenges resulting in diagnostic delay. Due to the low number of patients, gathering high-quality scientific evidence on diagnosis and treatment is difficult. Additionally, based on the estimated prevalence, the number of undiagnosed patients is likely to be high.

Methods: Italian experts in AADC deficiency formed a steering committee to engage clinicians in a modified Delphi consensus to promote discussion, and support research, dissemination and awareness on this disorder. Five experts in the field elaborated six main topics, each subdivided into 4 statements and invited 13 clinicians to give their anonymous feedback.

Results: 100% of the statements were answered and a consensus was reached at the first round. This enabled the steering committee to acknowledge high rates of agreement between experts on clinical presentation, phenotypes, diagnostic work-up and treatment strategies. A research gap was identified in the lack of standardized cognitive and motor outcome data. The need for setting up an Italian working group and a patients' association, together with the dissemination of knowledge inside and outside scientific societies in multiple medical disciplines were recognized as critical lines of intervention.

Conclusions: The panel expressed consensus with high rates of agreement on a series of statements paving the way to disseminate clear messages concerning disease presentation, diagnosis and treatment and strategic interventions to disseminate knowledge at different levels. Future lines of research were also identified.
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http://dx.doi.org/10.1186/s13052-021-00954-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819234PMC
January 2021

Post-Traumatic Stress Reactions in Caregivers of Children and Adolescents/Young Adults with Severe Diseases: A Systematic Review of Risk and Protective Factors.

Int J Environ Res Public Health 2020 12 29;18(1). Epub 2020 Dec 29.

Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.

Severe illnesses in children and adolescents/young adults (AYAs) may represent a complex burden for patients and their caregivers, including a wide range of mental disorders, particularly post-traumatic stress disorder (PTSD). Few events are as potentially traumatizing as having a son or a daughter diagnosed with a severe, life-threatening, or disabling disease. The presence of PTSD symptoms in caregivers may compromise their efficacy as caregivers and negatively affect the child's well-being. This systematic review aims at outlining potential risk and protective factors for the development of PTSD symptoms in caregivers of children and AYAs affected by severe acute or chronic illnesses. Thirty-one studies on caregivers of children and AYAs affected by severe, acute, or chronic diseases were included. Socio-demographic and socio-economic characteristics, illness-related distress, psychiatric symptoms, support, and coping styles were found as potential risk/protective factors across studies. It is crucial to consider risk factors affecting caregivers of severely ill young patients, in order to plan focused interventions aimed at preventing an adverse clinical outcome in caregivers and at enhancing caregivers' coping skills, in order to ultimately improve their quality of life.
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http://dx.doi.org/10.3390/ijerph18010189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796025PMC
December 2020
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