Publications by authors named "Enrico Bertini"

527 Publications

A case of spastic paraplegia type 11 mimicking a GM2-gangliosidosis.

Neurol Sci 2022 Jan 23. Epub 2022 Jan 23.

Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.

Introduction: Spastic paraplegia type 11 (SPG11) is the most frequent autosomal recessive HSP. Studies on SPG11 patients' fibroblasts, post-mortem brains, and mouse models revealed endolysosomal system dysfunction and lipid accumulation, especially gangliosides. We report a patient with early clinical findings mimicking a GM2-gangliosidosis.

Methods: A clinical, biochemical, and metabolic characterization was performed. Electron microscopy analysis was completed on rectal mucosa and skin biopsy specimens. A NGS panel of genes associated to neuronal ceroid lipofuscinosis and HSP was analyzed.

Results: The patient presented with worsening walking difficulty and psychomotor slowdown since childhood; to exclude a neurometabolic storage disease, skin and rectal biopsies were performed: enteric neurons showed lipofuscin-like intracellular inclusions, thus suggesting a possible GM2-gangliosidosis. However, further analysis did not allow to confirm such hypothesis. In adulthood we detected flaccid paraplegia, nystagmus, axonal motor neuropathy, carpus callosum atrophy, and colon atony. Surprisingly, the NGS panel detected two already reported SPG11 mutations in compound heterozygosity.

Conclusions: We describe for the first time pathological hallmarks of SPG11 in enteric neuron from a rectal mucosa biopsy. The report illustrates the possible overlap between SPG11 and GM2-gangliosidosis, especially in the first disease phases and helps to improve our knowledge about SPG11 physiopathology.
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http://dx.doi.org/10.1007/s10072-021-05841-8DOI Listing
January 2022

Body mass index in type 2 spinal muscular atrophy: a longitudinal study.

Eur J Pediatr 2022 Jan 19. Epub 2022 Jan 19.

Pediatric Neurology, Università Cattolica del Sacro Cuore, Rome, Italy.

The aim of this retrospective study was to review body mass index (BMI) in a large cohort of Italian pediatric type 2 spinal muscular atrophy (SMA) patients, aged between 0 and 20 years and to establish possible differences in relation to a number of variables such as ventilation, motor function, and survival motor neuron 2 gene copies. Cross-sectional data were collected from 102 patients for a total of 344 visits. Standard growth charts for height and weight were used as reference, with age adjusted BMI calculated using the Center for Disease and Prevention Children's BMI Tool. In the 344 visits, weight ranged between 3.90 and 83 kg, and the BMI between 8.4 and 31.6 with a BMI/age z-scores <  - 2SD present in 28% and BMI/age z-scores >  + 2SD in 9% of the measurements. The BMI/age z-scores were relatively stable < 5 years of age with an increasing number of patients <  - 2SD after the age of 5, and a wider range of BMI/age z-scores after the age of 13. A difference on the BMI/age z-scores was found among the different age subgroups (< 5, 5-12, ≥ 13 years). A multivariate analysis in 58 patients with longitudinal assessments showed that baseline BMI/age z-scores and gender were significantly contributing to the changes while other variables were not.Conclusion: Our results confirm that careful surveillance of weight and BMI/age z-scores is needed in type 2 SMA. Further studies, including assessments of chewing and swallowing and of lean/fat body mass, will help to better understand the possible mechanisms underlying weight issues. What is Known: • Feeding difficulties have been reported in a few studies and were invariably found in patients with type 1 SMA. • Type 2 SMA patients often have low BMI with a relevant number of patients requiring tube feeding. What is New: • Reduction in BMI/age z-score overtime appeared to depend on baseline BMI/age z-score and gender. • Patients with a low BMI/age z-score were at higher risk of developing further reduction.
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http://dx.doi.org/10.1007/s00431-021-04325-3DOI Listing
January 2022

Correction to: Hepatobiliary disease in XLMTM: a common comorbidity with potential impact on treatment strategies.

Orphanet J Rare Dis 2022 Jan 17;17(1):18. Epub 2022 Jan 17.

Unit of Muscular and Neurodegenerative Disorders, Genetics and Rare Diseases Research Division, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, piazza S. Onofrio 4, 00165, Rome, Italy.

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http://dx.doi.org/10.1186/s13023-021-02171-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764784PMC
January 2022

Revised upper limb module in type II and III spinal muscular atrophy: 24-month changes.

Neuromuscul Disord 2021 Nov 7. Epub 2021 Nov 7.

Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital, London, United Kingdom; NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom.

The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches.
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http://dx.doi.org/10.1016/j.nmd.2021.10.009DOI Listing
November 2021

Movement disorders in MCT8 deficiency/Allan-Herndon-Dudley Syndrome.

Mol Genet Metab 2022 Jan 16;135(1):109-113. Epub 2021 Dec 16.

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:

Background And Objectives: MCT8 deficiency is a rare genetic leukoencephalopathy caused by a defect of thyroid hormone transport across cell membranes, particularly through blood brain barrier and into neural cells. It is characterized by a complex neurological presentation, signs of peripheral thyrotoxicosis and cerebral hypothyroidism. Movement disorders (MDs) have been frequently mentioned in this condition, but not systematically studied.

Methods: Each patient recruited was video-recorded during a routine outpatient visit according to a predefined protocol. The presence and the type of MDs were evaluated. The type of MD was blindly scored by two child neurologists experts in inherited white matter diseases and in MD. Dystonia was scored according to Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). When more than one MD was present, the predominant one was scored.

Results: 27 patients were included through a multicenter collaboration. In many cases we saw a combination of different MDs. Hypokinesia was present in 25/27 patients and was the predominant MD in 19. It was often associated with hypomimia and global hypotonia. Dystonia was observed in 25/27 patients, however, in a minority of cases (5) it was deemed the predominant MD. In eleven patients, exaggerated startle reactions and/or other paroxysmal non-epileptic events were observed.

Conclusion: MDs are frequent clinical features of MCT8 deficiency, possibly related to the important role of thyroid hormones in brain development and functioning of normal dopaminergic circuits of the basal ganglia. Dystonia is common, but usually mild to moderate in severity, while hypokinesia was the predominant MD in the majority of patients.
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http://dx.doi.org/10.1016/j.ymgme.2021.12.003DOI Listing
January 2022

Induced Pluripotent Stem Cells (iPSCs) and Gene Therapy: A New Era for the Treatment of Neurological Diseases.

Int J Mol Sci 2021 Dec 20;22(24). Epub 2021 Dec 20.

Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.

To date, gene therapy has employed viral vectors to deliver therapeutic genes. However, recent progress in molecular and cell biology has revolutionized the field of stem cells and gene therapy. A few years ago, clinical trials started using stem cell replacement therapy, and the induced pluripotent stem cells (iPSCs) technology combined with CRISPR-Cas9 gene editing has launched a new era in gene therapy for the treatment of neurological disorders. Here, we summarize the latest findings in this research field and discuss their clinical applications, emphasizing the relevance of recent studies in the development of innovative stem cell and gene editing therapeutic approaches. Even though tumorigenicity and immunogenicity are existing hurdles, we report how recent progress has tackled them, making engineered stem cell transplantation therapy a realistic option.
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http://dx.doi.org/10.3390/ijms222413674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8706293PMC
December 2021

Response to: Phenotypic heterogeneity of Leigh syndrome due to NDUFA12 variants is multicausal.

Hum Mutat 2022 01 9;43(1):99-100. Epub 2021 Dec 9.

Department of Neurosciences, Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù, Children's Hospital, IRCCS, Rome, Italy.

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http://dx.doi.org/10.1002/humu.24303DOI Listing
January 2022

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

Myocardial and Arrhythmic Spectrum of Neuromuscular Disorders in Children.

Biomolecules 2021 10 25;11(11). Epub 2021 Oct 25.

Division of Metabolism, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy.

Neuromuscular disorders (NMDs) are highly heterogenous from both an etiological and clinical point of view. Their signs and symptoms are often multisystemic, with frequent cardiac involvement. In fact, childhood onset forms can predispose a person to various progressive cardiac abnormalities including cardiomyopathies (CMPs), valvulopathies, atrioventricular conduction defects (AVCD), supraventricular tachycardia (SVT) and ventricular arrhythmias (VA). In this review, we selected and described five specific NMDs: Friedreich's Ataxia (FRDA), congenital and childhood forms of Myotonic Dystrophy type 1 (DM1), Kearns Sayre Syndrome (KSS), Ryanodine receptor type 1-related myopathies (-RM) and Laminopathies. These changes are widely investigated in adults but less researched in children. We focused on these specific topics due their relative frequency and their potential unexpected cardiac manifestations in children. Moreover these conditions present different inheritance patterns and mechanisms of action. We decided not to discuss Duchenne and Becker muscular dystrophies due to extensive work regarding the cardiac aspects in children. For each described NMD, we focused on the possible cardiac manifestations such as different types of CMPs (dilated-DCM, hypertrophic-HCM, restrictive-RCM or left ventricular non compaction-LVNC), structural heart abnormalities (including valvulopathies), and progressive heart rhythm changes (AVCD, SVT, VA). We describe the current management strategies for these conditions. We underline the importance, especially for children, of a serial multidisciplinary personalized approach and the need for periodic surveillance by a dedicated heart team. This is largely due to the fact that in children, the diagnosis of certain NMDs might be overlooked and the cardiac aspect can provide signs of their presence even prior to overt neurological diagnosis.
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http://dx.doi.org/10.3390/biom11111578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615674PMC
October 2021

Clinical variability at the mild end of BRAT1-related spectrum: Evidence from two families with genotype-phenotype discordance.

Hum Mutat 2022 01 15;43(1):67-73. Epub 2021 Nov 15.

Department of Human Neuroscience, Sapienza University of Rome, Roma, Italy.

Biallelic mutations in the BRAT1 gene, encoding BRCA1-associated ATM activator 1, result in variable phenotypes, from rigidity and multifocal seizure syndrome, lethal neonatal to neurodevelopmental disorder, and cerebellar atrophy with or without seizures, without obvious genotype-phenotype associations. We describe two families at the mildest end of the spectrum, differing in clinical presentation despite a common genotype at the BRAT1 locus. Two siblings displayed nonprogressive congenital ataxia and shrunken cerebellum on magnetic resonance imaging. A third unrelated patient showed normal neurodevelopment, adolescence-onset seizures, and ataxia, shrunken cerebellum, and ultrastructural abnormalities on skin biopsy, representing the mildest form of NEDCAS hitherto described. Exome sequencing identified the c.638dup and the novel c.1395G>A BRAT1 variants, the latter causing exon 10 skippings. The p53-MCL test revealed normal ATM kinase activity. Our findings broaden the allelic and clinical spectrum of BRAT1-related disease, which should be suspected in presence of nonprogressive cerebellar signs, even without a neurodevelopmental disorder.
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http://dx.doi.org/10.1002/humu.24293DOI Listing
January 2022

Long-term efficacy of T3 analogue Triac in children and adults with MCT8 deficiency: a real-life retrospective cohort study.

J Clin Endocrinol Metab 2021 Oct 22. Epub 2021 Oct 22.

Department of Pediatrics, Hematology and Oncology, Medical University of Gdańsk, Gdańsk, Poland.

Context: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. Our previous trial showed improvement of key clinical and biochemical features during one year of treatment with the T3-analogue Triac. Long-term follow-up data are lacking.

Methods: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8 deficient patients in 33 sites. The primary endpoint was the change in serum T3 concentrations from baseline to last-available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action.

Results: Between 15-Oct-2014 and 1-Jan-2021, sixty-seven patients with a median baseline age of 4.6 years (range:0.5-66 years) were treated up to 6 years, with a median of 2.2 years (range 0.2-6.2 years). Mean T3 concentrations decreased from 4.58 (SD:1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L, 95%CI:2.61-3.23, p<0.0001; target:1.4-2.5 nmol/L). Body weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SDs, 95%CI:0.36-1.09, p=0.0002). Heart rate-for-age decreased (mean difference 0.64 SDs, 95%CI:0.29-0.98, p=0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L, 95%CI:16-57, p=0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L, 95%CI:6-9, p<0.0001). Mean CK concentrations did not significantly change. No drug-related severe adverse events were reported.

Conclusions: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages and highlight the potential of Triac for MCT8 deficiency in real-life.
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http://dx.doi.org/10.1210/clinem/dgab750DOI Listing
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

Hepatobiliary disease in XLMTM: a common comorbidity with potential impact on treatment strategies.

Orphanet J Rare Dis 2021 10 12;16(1):425. Epub 2021 Oct 12.

Unit of Muscular and Neurodegenerative Disorders, Genetics and Rare Diseases Research Division, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, piazza S. Onofrio 4, 00165, Rome, Italy.

Background: X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy resulting from pathogenic variants in the MTM1 gene. Affected male subjects typically present with severe hypotonia and respiratory distress at birth and they often require intensive supportive care. Long-term survivors are often non-ambulant, ventilator and feeding tube-dependent and they generally show additional organ manifestations, indicating that myotubularin does play a vital role in tissues other than muscle. For XLMTM several therapeutic strategies are under investigation. For XLMTM several therapeutic strategies are under investigation including a study of intravenous MTM1 gene transfer using a recombinant AAV8 vector of which has some concerns arises due to hepatotoxicity.

Results: We report prospective and retrospective clinical data of 12 XLMTM patients collected over a period of up to 10 years. In particular, we carried out a thorough review of the data about incidence and the course of hepatobiliary disease in our case series.

Conclusions: We demonstrate that hepatobiliary disease represents a common comorbidity of XLMTM that seems irrespective to age and diseases severity. We recommend to carefully explore and monitor the hepatobiliary function in XLMTM patients. We believe that a better understanding of the pathogenic mechanisms that induce hepatobiliary damage is essential to understand the fatal events that may occur in the gene therapy program.
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http://dx.doi.org/10.1186/s13023-021-02055-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513353PMC
October 2021

Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases.

Orphanet J Rare Dis 2021 10 9;16(1):413. Epub 2021 Oct 9.

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

Background: Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with primary or secondary dysfunction of mitochondrial oxidative phosphorylation and is the most common mitochondrial disease in childhood. Numerous reports on the biochemical and molecular profiles of LS have been published, but there are limited studies on genetically confirmed large series. We reviewed the clinical, imaging, biochemical and molecular data of 122 patients with a diagnosis of LS collected in the Italian Collaborative Network of Mitochondrial Diseases database.

Results: Clinical picture was characterized by early onset of several neurological signs dominated by central nervous system involvement associated with both supra- and sub-tentorial grey matter at MRI in the majority of cases. Extraneurological organ involvement is less frequent in LS than expected for a mitochondrial disorder. Complex I and IV deficiencies were the most common biochemical diagnoses, mostly associated with mutations in SURF1 or mitochondrial-DNA genes encoding complex I subunits. Our data showed SURF1 as the genotype with the most unfavorable prognosis, differently from other cohorts reported to date.

Conclusion: We report on a large genetically defined LS cohort, adding new data on phenotype-genotype correlation, prognostic factors and possible suggestions to diagnostic workup.
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http://dx.doi.org/10.1186/s13023-021-02029-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501644PMC
October 2021

SMA-miRs (miR-181a-5p, -324-5p, and -451a) are overexpressed in spinal muscular atrophy skeletal muscle and serum samples.

Elife 2021 09 20;10. Epub 2021 Sep 20.

Department of Life Sciences and Public Health, Section of Genomic Medicine, Università cattolica del Sacro Cuore, Roma, Italy.

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of the second motor neuron. The phenotype ranges from very severe to very mild forms. All patients have the homozygous loss of the gene and a variable number of (generally 2-4 copies), inversely related to the severity. The amazing results of the available treatments have made compelling the need of prognostic biomarkers to predict the progression trajectories of patients. Besides the products, few other biomarkers have been evaluated so far, including some miRs.

Methods: We performed whole miRNome analysis of muscle samples of patients and controls (14 biopsies and 9 cultures). The levels of muscle differentially expressed miRs were evaluated in serum samples (51 patients and 37 controls) and integrated with copies, full-length transcript levels in blood and age (SMA-score).

Results: Over 100 miRs were differentially expressed in SMA muscle; 3 of them (hsa-miR-181a-5p, -324-5p, -451a; SMA-miRs) were significantly upregulated in the serum of patients. The severity predicted by the SMA-score was related to that of the clinical classification at a correlation coefficient of 0.87 (p<10).

Conclusions: miRNome analyses suggest the primary involvement of skeletal muscle in SMA pathogenesis. The SMA-miRs are likely actively released in the blood flow; their function and target cells require to be elucidated. The accuracy of the SMA-score needs to be verified in replicative studies: if confirmed, its use could be crucial for the routine prognostic assessment, also in presymptomatic patients.

Funding: Telethon Italia (grant #GGP12116).
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http://dx.doi.org/10.7554/eLife.68054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486378PMC
September 2021

Growth patterns in children with spinal muscular atrophy.

Orphanet J Rare Dis 2021 09 4;16(1):375. Epub 2021 Sep 4.

International Center for the Assessment of Nutritional Status (ICANS), Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Sandro Botticelli 21, 20133, Milan, Italy.

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy and weakness. SMA type 1 (SMA1) is the most severe form: affected infants are unable to sit unaided; SMA type 2 (SMA2) children can sit, but are not able to walk independently. The Standards of Care has improved quality of life and the increasing availability of disease-modifying treatments is progressively changing the natural history; so, the clinical assessment of nutritional status has become even more crucial. Aims of this multicenter study were to present the growth pattern of treatment-naïve SMA1 and SMA2, and to compare it with the general growth standards.

Results: Body Weight (BW, kg) and Supine Length (SL, cm) were collected using a published standardized procedure. SMA-specific growth percentiles curves were developed and compared to the WHO reference data. We recruited 133 SMA1 and 82 SMA2 (48.8% females). Mean ages were 0.6 (0.4-1.6) and 4.1 (2.1-6.7) years, respectively. We present here a set of disease-specific percentiles curves of BW, SL, and BMI-for-age for girls and boys with SMA1 and SMA2. These curves show that BW is significantly lower in SMA than healthy peers, while SL is more variable. BMI is also typically lower in both sexes and at all ages.

Conclusions: These data on treatment-naïve patients point toward a better understanding of growth in SMA and could be useful to improve the clinical management and to assess the efficacy of the available and forthcoming therapies not only on motor function, but also on growth.
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http://dx.doi.org/10.1186/s13023-021-02015-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418717PMC
September 2021

Expanded phenotype of AARS1-related white matter disease.

Genet Med 2021 Dec 27;23(12):2352-2359. Epub 2021 Aug 27.

Department of Neuropediatrics, Jena University Hospital, Jena, Germany.

Purpose: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease.

Methods: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts.

Results: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes.

Conclusion: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.
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http://dx.doi.org/10.1038/s41436-021-01286-8DOI Listing
December 2021

Imbalance of Systemic Redox Biomarkers in Children with Epilepsy: Role of Ferroptosis.

Antioxidants (Basel) 2021 Aug 9;10(8). Epub 2021 Aug 9.

Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Viale San Paolo 15, 00146 Rome, Italy.

To assess if ferroptosis, a new type of programmed cell death accompanied by iron accumulation, lipid peroxidation, and glutathione depletion, occurs in children with epilepsy, and in order to identify a panel of biomarkers useful for patient stratification and innovative-targeted therapies, we measured ferroptosis biomarkers in blood from 83 unrelated children with a clinical diagnosis of epilepsy and 44 age-matched controls. We found a marked dysregulation of three ferroptosis key markers: a consistent increase of 4-hydroxy-2-nonenal (4-HNE), the main by-product of lipid peroxidation, a significant decrease of glutathione (GSH) levels, and a partial inactivation of the enzyme glutathione peroxidase 4 (GPX4), the mediator of lipid peroxides detoxification. Furthermore, we found a significant increase of NAPDH oxidase 2 (NOX2) in the blood of children, supporting this enzyme as a primary source of reactive oxygen species (ROS) in epilepsy. Additionally, since the nuclear factor erythroid 2-related factor 2 (NRF2) induction protects the brain from epileptic seizure damage, we also evaluated the NRF2 expression in the blood of children. The antioxidant and anti-inflammatory transcription factor was activated in patients, although not enough to re-establish a correct redox homeostasis for counteracting ferroptosis. Ferroptosis-mediated oxidative damage has been proposed as an emergent mechanism underlying the pathogenesis of epilepsy. Overall, our study confirms a crucial role for ferroptosis in epilepsy, leading to the identification of a panel of biomarkers useful to find new therapeutic targets. Developing innovative drugs, which act by inhibiting the ferroptosis signaling axis, may represent a promising strategy for new anti-seizure medications.
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http://dx.doi.org/10.3390/antiox10081267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389337PMC
August 2021

Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?

Orphanet J Rare Dis 2021 08 11;16(1):360. Epub 2021 Aug 11.

Department of Neurology and Neurosurgery, Federal University of São Paulo (UNIFESP), Embaú Street, 67, Vila Clementino, São Paulo, SP, 04039-060, Brazil.

Background: Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and fatal neurodegenerative disease due to upper and lower motor neuron involvement with symptoms classically occurring in adulthood with an increasing recognition of juvenile presentations and childhood neurodegenerative disorders caused by genetic variants in genes related to Amyotrophic Lateral Sclerosis. The main objective of this study is detail clinical, radiological, neurophysiological, and genetic findings of a Brazilian cohort of patients with a recent described condition known as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency and compare with other cases described in the literature and discuss whether the clinical picture related to SOD1 protein deficiency is a new entity or may be represent a very early-onset form of Amyotrophic Lateral Sclerosis.

Methods: We conducted a case series report which included retrospective data from five Brazilian patients with SOD1 protein deficiency of a Brazilian reference center for Neuromuscular Disorders. Clinical data were obtained from a review of the medical records and descriptive statistics and variables were summarized using counts and percentages of the total population.

Results: All 5 patients presented with a childhood-onset neurodegenerative disorders characterized by spastic tetraplegia with axial hypotonia in all cases, with gestational history showing polyhydramnios in 4/5 and intrauterine growth restriction in 3/5 patients, with most patients initially presenting a normal motor development until the six month of life or during the first year followed by a rapidly progressive motor decline with severe dysphagia and respiratory insufficiency in all patients accompanied by cognitive impairment in 3/5 patients. All patients were homozygous for the c.335dupG (p.Cys112Trpfs*11) mutation in the SOD1 gene with completely decreased enzyme activity.

Conclusions: This case series is the biggest data collection of the new recent clinical entity described as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency.
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http://dx.doi.org/10.1186/s13023-021-01993-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359534PMC
August 2021

Age-related sensory neuropathy in patients with spinal muscular atrophy type 1.

Muscle Nerve 2021 Nov 23;64(5):599-603. Epub 2021 Aug 23.

Neurology Ward Unit, Bambino Gesù Hospital, Rome, Italy.

Introduction/aims: Spinal muscular atrophy type 1 (SMA 1) is a devastating motor neuron disorder that leads to progressive muscle weakness, respiratory failure and premature death. Although sensory electrophysiological changes have been anecdotally found in pediatric SMA 1 patients, the age of onset of sensory neuropathy remains unknown.

Methods: Sensory nerve conduction studies of the median and sural nerves were performed in 28 consecutive SMA 1 patients of different ages. Sensory nerve conduction velocities and sensory nerve action potential (SNAP) amplitudes recorded in these patients were compared with those obtained from 93 healthy subjects stratified by age.

Results: SNAP amplitudes decreased with increasing age in the sural and median nerves, without any significant difference between upper and lower limbs.

Discussion: Our data suggest that sural and median nerve SNAP amplitudes are normal in younger patients, while an axonal neuropathy appears in older ones.
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http://dx.doi.org/10.1002/mus.27389DOI Listing
November 2021

Different trajectories in upper limb and gross motor function in spinal muscular atrophy.

Muscle Nerve 2021 Nov 9;64(5):552-559. Epub 2021 Aug 9.

Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital, London, UK.

Introduction: The Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM) have been widely used in natural history studies and clinical trials. Our aim was to establish how the scales relate to each other at different age points in spinal muscular atrophy (SMA) type 2 and 3, and to describe their coherence over 12 mo.

Methods: The study was performed by cross-sectional and longitudinal reanalysis of previously published natural history data. The longitudinal analysis of the 12-mo changes also included the analysis of concordance between scales with changes grouped as stable (±2 points), improved (>+2) or declined (>-2).

Results: Three hundred sixty-four patients were included in the cross-sectional analysis, showing different trends in score and point of slope change for the two scales. For type 2, the point of slope change was 4.1 y for the HFMSE and 5.8 for the RULM, while for type 3, it was 6 y for the HFMSE and 7.3 for the RULM. One-hundred-twenty-one patients had at least two assessments at 12 mo. Full concordance was found in 57.3% of the assessments, and in 40.4% one scale remained stable and the other changed. Each scale appeared to be more sensitive to specific age or functional subgroups.

Discussion: The two scales, when used in combination, may increase the sensitivity to detect clinically meaningful changes in motor function in patients with SMA types 2 and 3.
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http://dx.doi.org/10.1002/mus.27384DOI Listing
November 2021

Circadian Genes as Exploratory Biomarkers in DMD: Results From Both the Mouse Model and Patients.

Front Physiol 2021 8;12:678974. Epub 2021 Jul 8.

Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Duchenne muscular dystrophy (DMD) is a rare genetic disease due to dystrophin gene mutations which cause progressive weakness and muscle wasting. Circadian rhythm coordinates biological processes with the 24-h cycle and it plays a key role in maintaining muscle functions, both in animal models and in humans. We explored expression profiles of circadian circuit master genes both in Duchenne muscular dystrophy skeletal muscle and in its animal model, the mdx mouse. We designed a customized, mouse-specific Fluidic-Card-TaqMan-based assay (Fluid-CIRC) containing thirty-two genes related to circadian rhythm and muscle regeneration and analyzed gastrocnemius and tibialis anterior muscles from both unexercised and exercised mice. Based on this first analysis, we prioritized the 7 most deregulated genes in mdx mice and tested their expression in skeletal muscle biopsies from 10 Duchenne patients. We found that , and are upregulated in DMD patient biopsies, consistent with the mdx data. We also demonstrated that their proteins are detectable and measurable in the DMD patients' plasma. We suggest that , and might represent exploratory circadian biomarkers in DMD.
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http://dx.doi.org/10.3389/fphys.2021.678974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300012PMC
July 2021

Personalized profiles of antioxidant signaling pathway in patients with tuberculosis.

J Microbiol Immunol Infect 2021 Jul 17. Epub 2021 Jul 17.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience, Children's Hospital Bambino Gesù, IRCCS, Rome, Italy. Electronic address:

Background/purpose: The non-protein thiol glutathione is protective against infection by Mycobacterium tuberculosis (MTB) and, together with the transcription factor NRF2 (the nuclear factor erythroid 2-related factor 2), plays a crucial role in counteracting MTB-induced redox imbalance. Many genes implicated in the antioxidant response belong to the NRF2-signalling pathway, whose central role in the pathogenesis of tuberculosis (TB) has been recently proposed.

Methods: In this study, we measured GSH levels in blood of patients with active TB and analysed the individual NRF2-mediated redox profile, in order to provide additional tools for discriminating the pathologic TB state and addressing therapeutic interventions.

Results: Our findings show a systemic individual modulation of GSH and NRF2 signaling pathway in patients with TB, with a "personalized" induction of NRF2-target genes.

Conclusion: This study can provide useful tools to monitor the course of the infection and address patients' treatment.
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http://dx.doi.org/10.1016/j.jmii.2021.07.004DOI Listing
July 2021

The ARCA Registry: A Collaborative Global Platform for Advancing Trial Readiness in Autosomal Recessive Cerebellar Ataxias.

Front Neurol 2021 25;12:677551. Epub 2021 Jun 25.

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

Autosomal recessive cerebellar ataxias (ARCAs) form an ultrarare yet expanding group of neurodegenerative multisystemic diseases affecting the cerebellum and other neurological or non-neurological systems. With the advent of targeted therapies for ARCAs, disease registries have become a precious source of real-world quantitative and qualitative data complementing knowledge from preclinical studies and clinical trials. Here, we review the , a global collaborative multicenter platform (>15 countries, >30 sites) with the overarching goal to advance trial readiness in ARCAs. It presents a good clinical practice (GCP)- and general data protection regulation (GDPR)-compliant professional-reported registry for multicenter web-based capture of cross-center standardized longitudinal data. Modular electronic case report forms (eCRFs) with core, extended, and optional datasets allow data capture tailored to the participating site's variable interests and resources. The eCRFs cover all key data elements required by regulatory authorities [European Medicines Agency (EMA)] and the European Rare Disease (ERD) platform. They capture genotype, phenotype, and progression and include demographic data, biomarkers, comorbidity, medication, magnetic resonance imaging (MRI), and longitudinal clinician- or patient-reported ratings of ataxia severity, non-ataxia features, disease stage, activities of daily living, and (mental) health status. Moreover, they are aligned to major autosomal-dominant spinocerebellar ataxia (SCA) and sporadic ataxia (SPORTAX) registries in the field, thus allowing for joint and comparative analyses not only across ARCAs but also with SCAs and sporadic ataxias. The registry is at the core of a systematic multi-component ARCA database cluster with a linked biobank and an evolving study database for digital outcome measures. Currently, the registry contains more than 800 patients with almost 1,500 visits representing all ages and disease stages; 65% of patients with established genetic diagnoses capture all the main ARCA genes, and 35% with unsolved diagnoses are targets for advanced next-generation sequencing. The ARCA Registry serves as the backbone of many major European and transatlantic consortia, such as PREPARE, PROSPAX, and the Ataxia Global Initiative, with additional data input from SPORTAX. It has thus become the largest global trial-readiness registry in the ARCA field.
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http://dx.doi.org/10.3389/fneur.2021.677551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267795PMC
June 2021

Asymmetrical anterior thigh muscle atrophy as an atypical presentation of RYR1-core myopathy.

Neuromuscul Disord 2021 08 24;31(8):798-799. Epub 2021 May 24.

UOC Neurofisiopatologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, Rome 00168, Italy; Dipartimento Universitario di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy.

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http://dx.doi.org/10.1016/j.nmd.2021.05.003DOI Listing
August 2021

Dissecting the Role of PCDH19 in Clustering Epilepsy by Exploiting Patient-Specific Models of Neurogenesis.

J Clin Med 2021 Jun 23;10(13). Epub 2021 Jun 23.

Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.

PCDH19-related epilepsy is a rare genetic disease caused by defective function of PCDH19, a calcium-dependent cell-cell adhesion protein of the cadherin superfamily. This disorder is characterized by a heterogeneous phenotypic spectrum, with partial and generalized febrile convulsions that are gradually increasing in frequency. Developmental regression may occur during disease progression. Patients may present with intellectual disability (ID), behavioral problems, motor and language delay, and a low motor tone. In most cases, seizures are resistant to treatment, but their frequency decreases with age, and some patients may even become seizure-free. ID generally persists after seizure remission, making neurological abnormalities the main clinical issue in affected individuals. An effective treatment is lacking. In vitro studies using patient-derived induced pluripotent stem cells (iPSCs) reported accelerated neural differentiation as a major endophenotype associated with PCDH19 mutations. By using this in vitro model system, we show that accelerated in vitro neurogenesis is associated with a defect in the cell division plane at the neural progenitors stage. We also provide evidence that altered PCDH19 function affects proper mitotic spindle orientation. Our findings identify an altered equilibrium between symmetric versus asymmetric cell division as a previously unrecognized mechanism contributing to the pathogenesis of this rare epileptic encephalopathy.
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http://dx.doi.org/10.3390/jcm10132754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268119PMC
June 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

Nusinersen in pediatric and adult patients with type III spinal muscular atrophy.

Ann Clin Transl Neurol 2021 08 24;8(8):1622-1634. Epub 2021 Jun 24.

Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital, London, United Kingdom.

Objective: We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort.

Methods: Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83 years after nusinersen treatment.

Results: Over 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT.

Interpretation: Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.
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http://dx.doi.org/10.1002/acn3.51411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351459PMC
August 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

Age related treatment effect in type II Spinal Muscular Atrophy pediatric patients treated with nusinersen.

Neuromuscul Disord 2021 07 2;31(7):596-602. Epub 2021 Apr 2.

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

Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p < 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p < 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p < 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study.
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http://dx.doi.org/10.1016/j.nmd.2021.03.012DOI Listing
July 2021
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