Publications by authors named "Davide Pareyson"

166 Publications

Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives.

Brain Sci 2021 Oct 29;11(11). Epub 2021 Oct 29.

Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.

There is still no effective drug treatment available for Charcot-Marie-Tooth neuropathies (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment of pain; fatigue and cramps are frequent complaints that are difficult to treat. The challenge is to find disease-modifying therapies. Several approaches, including gene silencing, to counteract the gene overexpression in the most frequent CMT1A type are under investigation. PXT3003 is the compound in the most advanced phase for CMT1A, as a second-phase III trial is ongoing. Gene therapy to substitute defective genes or insert novel ones and compounds acting on pathways important for different CMT types are being developed and tested in animal models. Modulation of the Neuregulin pathway determining myelin thickness is promising for both hypo-demyelinating and hypermyelinating neuropathies; intervention on Unfolded Protein Response seems effective for rescuing misfolded myelin proteins such as P0 in CMT1B. HDAC6 inhibitors improved axonal transport and ameliorated phenotypes in different CMT models. Other potential therapeutic strategies include targeting macrophages, lipid metabolism, and Nav1.8 sodium channel in demyelinating CMT and the P2X7 receptor, which regulates calcium influx into Schwann cells, in CMT1A. Further approaches are aimed at correcting metabolic abnormalities, including the accumulation of sorbitol caused by biallelic mutations in the sorbitol dehydrogenase () gene and of neurotoxic glycosphingolipids in HSN1.
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http://dx.doi.org/10.3390/brainsci11111447DOI Listing
October 2021

CMT2CC associated with mutations: a predominantly motor neuronopathy.

J Neurol Neurosurg Psychiatry 2021 Sep 13. Epub 2021 Sep 13.

Rare Neurodegenerative and Neurometabolic Diseases Unit, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy

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http://dx.doi.org/10.1136/jnnp-2021-327438DOI Listing
September 2021

Association Between Body Mass Index and Disability in Children With Charcot-Marie-Tooth Disease.

Neurology 2021 10 7;97(17):e1727-e1736. Epub 2021 Sep 7.

From the University of Sydney (G.A.D., S.P.G., M.P.M.), Faculty of Medicine and Health; Children's Hospital at Westmead (G.A.D., S.P.G., K.M.D.C., J.B., M.P.M.); University of Sydney (K.M.D.C., M.J.M., J.B.), School of Health Sciences; Faculty of Health and Medicine (J.N.B.), University of Newcastle, Australia; Departments of Pediatrics (R.R.S.) and Neurology (M.E.S.), Carver College of Medicine, University of Iowa, Iowa City; Division of Neurology (S.W.Y.) and Department of Occupational Therapy (T.E.), Children's Hospital of Philadelphia; Department of Neurology (S.W.Y., T.E.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Fondazione IRCCS Istituto Neurologico Carlo Besta (I.M., M.F., E.P., D.P.), Milan, Italy; Centre for Neuromuscular Diseases (M.L., M.M.R.), University College London, Queen Square; University College London Institute of Child Health & Great Ormond Street Hospital (T.B., F.M.), London, England; Translational Neurosciences (Pediatrics) (R.S.F.), St. Jude Children's Research Hospital, Memphis, TN; and Department of Neurology (J.E.S., K.J.E., D.N.H.), University of Rochester, NY.

Background And Objectives: This study examined the association between body mass index (BMI) and disability in children with Charcot-Marie-Tooth disease (CMT).

Methods: We conducted a cross-sectional analysis of 477 patients with CMT who were 3 to 20 years of age from the Inherited Neuropathy Consortium and 316 age- and sex-matched healthy children from the 1,000 Norms Project. BMI was categorized according to the International Obesity Task Force (IOTF) criteria, and BMI categorization was compared with healthy children. IOTF categories (adult equivalent BMI cut points) were severely underweight (BMI <17 kg/m), underweight (BMI ≥17-<18.5 kg/m), healthy weight (BMI ≥18.5-<25 kg/m), overweight (BMI ≥25-<30 kg/m), and obese (BMI ≥30 kg/m). Scores on the 0 to 44-point CMT Pediatric Scale (CMTPedS), a well-validated measure of disability, were examined in relation to BMI.

Results: There was a higher proportion of children with CMT categorized as severely underweight (5.7% vs 0.3%), underweight (10.3% vs 5.1%), and obese (7.3% vs 3.8%) ( < 0.05). Fewer children with CMT were categorized as healthy weight (61.8% vs 74.4%) ( < 0.05), and the proportion of overweight (14.9% vs 16.5%) between groups was similar. CMTPedS scores (mean ± SD) for weight categories were as follows: severely underweight 27 ± 9, underweight 20 ± 8, healthy weight 17 ± 9, overweight 17 ± 9, and obese 22 ± 10. Compared to children with a healthy weight with CMT, being severely underweight was associated with being more disabled ( < 0.001), as was being obese ( = 0.015).

Discussion: The proportion of children with CMT who are underweight or obese is higher compared to age- and sex-matched healthy children. In children with CMT, being underweight or obese is associated with greater disability, when compared to children with CMT of healthy weight.
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http://dx.doi.org/10.1212/WNL.0000000000012725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605613PMC
October 2021

Progressive brachial plexus enlargement in hereditary transthyretin amyloidosis.

J Neurol 2021 Aug 19. Epub 2021 Aug 19.

Department of Neurosciences, University of Padova, Via Giustiniani 5, 35128, Padova, Italy.

Axonal polyneuropathy is the main feature of hereditary transthyretin amyloidosis (ATTRv). Nerve morphological abnormalities have been reported, but longitudinal changes have never been assessed. We performed a prospective widespread nerve ultrasound evaluation and nerve cross-sectional area (CSA) was compared with baseline data in both ATTRv patients and pre-symptomatic carriers. Thirty-eight subjects were evaluated (mean follow-up 17.1 months), among them 21 had polyneuropathy while 17 were pre-symptomatic carriers. CSA significantly increased at brachial plexus in both groups (p = 0.008 and p = 0.012) pointing to progressive brachial plexus enlargement as a longitudinal biomarker of both disease progression and disease occurrence in pre-symptomatic carriers.
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http://dx.doi.org/10.1007/s00415-021-10754-9DOI Listing
August 2021

Novel deep intronic mutation in PLA2G6 causing early-onset Parkinson's disease with brain iron accumulation through pseudo-exon activation.

Neurogenetics 2021 10 13;22(4):347-351. Epub 2021 Aug 13.

Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

PLA2G6 is the causative gene for a group of autosomal recessive neurodegenerative disorders known as PLA2G6-associated neurodegeneration (PLAN). We present a case with early-onset parkinsonism, ataxia, cognitive decline, cerebellar atrophy, and brain iron accumulation. Sequencing of PLA2G6 coding regions identified only a heterozygous nonsense variant, but mRNA analysis revealed the presence of an aberrant transcript isoform due to a novel deep intronic variant (c.2035-274G > A) leading to activation of an intronic pseudo-exon. These results expand the genotypic spectrum of PLAN, showing the paramount importance of detecting possible pathogenic variants in deep intronic regions in undiagnosed patients.
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http://dx.doi.org/10.1007/s10048-021-00667-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426226PMC
October 2021

Dysregulation of Muscle-Specific MicroRNAs as Common Pathogenic Feature Associated with Muscle Atrophy in ALS, SMA and SBMA: Evidence from Animal Models and Human Patients.

Int J Mol Sci 2021 May 26;22(11). Epub 2021 May 26.

Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.

Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of -mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients' sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.
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http://dx.doi.org/10.3390/ijms22115673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198536PMC
May 2021

Updated review of therapeutic strategies for Charcot-Marie-Tooth disease and related neuropathies.

Expert Rev Neurother 2021 Jun 7;21(6):701-713. Epub 2021 Jun 7.

Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

: Charcot-Marie-Tooth disease (CMT) and related neuropathies represent the most prevalent inherited neuromuscular disorders. Nonetheless, there is still no pharmacological treatment available for any CMT type. However, the landscape is rapidly evolving and several novel approaches are providing encouraging results in preclinical studies and leading to clinical trials.: The authors review the most promising therapies under study and the ongoing/planned clinical trials. Several approaches to address PMP22 overexpression underlying CMT1A, the most frequent subtype, are being tested. Gene silencing, targeting PMP22, and gene therapy, to introduce specific genes or to substitute or modulate defective ones, are being experimented in animal models. Compounds acting on ER stress, unfolded protein response, neuregulin pathways, phosphoinositides metabolism, axonal transport and degeneration, inflammation, polyol pathway, deoxysphingolipid metabolism, purine nucleotide pool are potential therapeutic candidates for different forms of CMT and related neuropathies.: We are getting closer to find effective therapies for CMT, but are far behind the exciting examples of other genetic neuromuscular disorders. The authors analyze the possible reasons for this gap and the way to fill it. Preclinical and clinical research is ongoing with coordinated efforts and they are confident that in the next few years we will see the first effective treatments.
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http://dx.doi.org/10.1080/14737175.2021.1935242DOI Listing
June 2021

Charcot-Marie-Tooth disease type 2F associated with biallelic HSPB1 mutations.

Ann Clin Transl Neurol 2021 05 4;8(5):1158-1164. Epub 2021 May 4.

Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, Neuroscience Section, University of Milan, Milan, Italy.

Objective: This work aims to expand knowledge regarding the genetic spectrum of HSPB1-related diseases. HSPB1 is a gene encoding heat shock protein 27, and mutations in HSPB1 have been identified as the cause of axonal Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy (dHMN).

Methods: Two patients with axonal sensorimotor neuropathy underwent detailed clinical examinations, neurophysiological studies, and next-generation sequencing with subsequent bioinformatic prioritization of genetic variants and in silico analysis of the likely causal mutation.

Results: The HSPB1 p.S135F and p.R136L mutations were identified in homozygosis in the two affected individuals. Both mutations affect the highly conserved alpha-crystallin domain and have been previously described as the cause of severe CMT2F/dHMN, showing a strictly dominant inheritance pattern.

Interpretation: Thus, we report for the first time two cases of biallelic HSPB1 p.S135F and p.R136L mutations in two families.
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http://dx.doi.org/10.1002/acn3.51364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108422PMC
May 2021

Neuro-telehealth for fragile patients in a tertiary referral neurological institute during the COVID-19 pandemic in Milan, Lombardy.

Neurol Sci 2021 Jul 30;42(7):2637-2644. Epub 2021 Apr 30.

Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Background: Lombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced.

Methods: At the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children.

Results: After a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March-September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high.

Conclusions: During the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.
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http://dx.doi.org/10.1007/s10072-021-05252-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086222PMC
July 2021

Psychosocial burden and professional and social support in patients with hereditary transthyretin amyloidosis (ATTRv) and their relatives in Italy.

Orphanet J Rare Dis 2021 04 7;16(1):163. Epub 2021 Apr 7.

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Background: Hereditary transthyretin amyloidosis (hATTR), alias ATTR variant (ATTRv) is a severe and disabling disease causing sensory and motor neuropathy, autonomic dysfunction, and cardiomyopathy. The progressive decline of patient's functional autonomy negatively affects the patient's quality of life and requires increasing involvement of relatives in the patient's daily life. Family caregiving may become particularly demanding when the patient is no longer able to move independently. This study is focused on the psychosocial aspects of ATTRv from the patient and relative perspectives. In particular, it explored: the practical and psychological burdens experienced by symptomatic patients with ATTRv and their key relatives and the professional and social network support they may rely on; whether burden varied in relation to patients' and relatives' socio-demographic variables, patients' clinical variables, and perceived professional and social network support; and, any difference in burden and support between patients and their matched relatives.

Methods: The study was carried out on symptomatic patients included in the ATTRv Italian national registry and living with at least one adult relative not suffering from severe illness and being free from ATTRv symptoms. Patients and relatives' assessments were performed using validated self-reported tools.

Results: Overall, 141 patients and 69 relatives were evaluated. Constraints of leisure activities, feelings of loss and worries for the future were the consequences of ATTRv most frequently reported by patients and relatives. Both in patients and their relatives, the burden increased with the duration of symptoms and the level of help in daily activities needed by the patient. In the 69 matched patient-relative pairs, the practical burden was significantly higher among the patients than among their relatives, while the psychological burden was similar in the two groups. Moreover, compared to their relatives, patients with ATTRv reported higher levels of professional and social network support.

Conclusions: These results show that ATTRv is a disease affecting quality of life of both patients and their families. Supporting interventions should be guaranteed to patients, to facilitate their adaptation to the disease, and to their families, to cope as best as possible with the difficulties that this pathology may involve.
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http://dx.doi.org/10.1186/s13023-021-01812-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028211PMC
April 2021

Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy.

Proc Natl Acad Sci U S A 2021 03;118(10)

Human Inherited Neuropathies Unit, Institute of Experimental Neurology (INSPE) and Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132 Milan, Italy;

Charcot-Marie-Tooth type 4B1 (CMT4B1) is a severe autosomal recessive demyelinating neuropathy with childhood onset, caused by loss-of-function mutations in the myotubularin-related 2 () gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3 and PtdIns(3,5) , with a preference for PtdIns(3,5) A hallmark of CMT4B1 neuropathy are redundant loops of myelin in the nerve termed myelin outfoldings, which can be considered the consequence of altered growth of myelinated fibers during postnatal development. How MTMR2 loss and the resulting imbalance of 3'-phosphoinositides cause CMT4B1 is unknown. Here we show that MTMR2 by regulating PtdIns(3,5) levels coordinates mTORC1-dependent myelin synthesis and RhoA/myosin II-dependent cytoskeletal dynamics to promote myelin membrane expansion and longitudinal myelin growth. Consistent with this, pharmacological inhibition of PtdIns(3,5) synthesis or mTORC1/RhoA signaling ameliorates CMT4B1 phenotypes. Our data reveal a crucial role for MTMR2-regulated lipid turnover to titrate mTORC1 and RhoA signaling thereby controlling myelin growth.
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http://dx.doi.org/10.1073/pnas.2009469118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958260PMC
March 2021

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study.

Brain 2020 12;143(12):3589-3602

Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.
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http://dx.doi.org/10.1093/brain/awaa323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805791PMC
December 2020

Hypomyelinating leukodystrophies in adults: Clinical and genetic features.

Eur J Neurol 2021 03 3;28(3):934-944. Epub 2020 Dec 3.

Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Background And Purpose: Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among undefined leukoencephalopathies in adulthood.

Methods: We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near-normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy-targeted next generation sequencing panel.

Results: We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early-onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early-onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early-onset diseases with central hypomyelination/dysmyelination.

Conclusions: A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease-causing genes, including genes associated with severe early-onset HLDs, and genes causing peroxisome biogenesis disorders.
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http://dx.doi.org/10.1111/ene.14646DOI Listing
March 2021

Hereditary transthyretin amyloidosis overview.

Neurol Sci 2020 Nov 14. Epub 2020 Nov 14.

Rare Neurodegenerative and Neurometabolic Diseases Unit, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis is a rare autosomal dominantly inherited disorder caused by mutations in the transthyretin (TTR) gene. The pathogenetic model of ATTRv amyloidosis indicates that amyloidogenic, usually missense, mutations destabilize the native TTR favouring the dissociation of the tetramer into partially unfolded species that self-assemble into amyloid fibrils. Amyloid deposits and monomer-oligomer toxicity are the basis of multisystemic ATTRv clinical involvement. Peripheral nervous system (autonomic and somatic) and heart are the most affected sites. In the last decades, a better knowledge of pathomechanisms underlying the disease led to develop novel and promising drugs that are rapidly changing the natural history of ATTRv amyloidosis. Thus, clinicians face the challenge of timely diagnosis for addressing patients to appropriate treatment. As well, the progressive nature of ATTRv raises the issue of presymptomatic testing and risk management of carriers. The main aim of this review was to focus on what we know about ATTRv so far, from pathogenesis to clinical manifestations, diagnosis and hence patient's monitoring and treatment, and from presymptomatic testing to management of carriers.
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http://dx.doi.org/10.1007/s10072-020-04889-2DOI Listing
November 2020

hATTR Pathology: Nerve Biopsy Results from Italian Referral Centers.

Brain Sci 2020 Oct 26;10(11). Epub 2020 Oct 26.

Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, 00168 Roma, Italy.

Pathological evidence of amyloid on nerve biopsy has been the gold standard for diagnosis in hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN) for a long time. In this article, we reviewed the pathological findings of a large series of sural nerve biopsies from a cohort of hATTR-PN patients, collected by different Italian referral centers. We reviewed clinical and pathological data from hATTR-PN patients, diagnosed and followed in five Italian referral centers for peripheral neuropathies. Diagnosis was formulated after a positive genetic test for transthyretin () mutations. Sural nerve biopsy was performed according to standard protocols. Sixty-nine sural nerve biopsies from hATTR-PN patients were examined. Congo red positive deposits were found in 73% of cases. Only the Phe64Leu mutation failed to show amyloid deposits in a high percentage of biopsies (54%), as already described. Unusual pathological findings, such as myelin abnormalities or inflammatory infiltrates, were detected in occasional cases. Even if no longer indicated to confirm hATTR-PN clinical suspicion, nerve biopsy remains, in expert hands, a rapid and inexpensive tool to detect amyloid deposition. In Italy, clinicians should be aware that a negative biopsy does not exclude hATTR-PN, particularly for Phe64Leu, one of the most frequent mutations in this country.
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http://dx.doi.org/10.3390/brainsci10110780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692609PMC
October 2020

Pregnancy in Charcot-Marie-Tooth disease: Data from the Italian CMT national registry.

Neurology 2020 12 14;95(24):e3180-e3189. Epub 2020 Sep 14.

From the Fondazione IRCCS Istituto Neurologico Carlo Besta (C. Pisciotta, D.C., I.T., P.S., D.P.), Milan; Department of Neurosciences, Reproductive Sciences and Odontostomatology (L.S., F.M., S.T.), Federico II University of Naples; Department of Neuroscience, Biomedicine and Movement Sciences (G.M.F., T.C.), University of Verona; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal Infantile Sciences (A.S., M.G.), University of Genoa; IRCCS Ospedale Policlinico San Martino (A.S., M.G.), Genoa; Division of Neuroscience and INSPE (S.C.P.), IRCCS Ospedale San Raffaele, Milan; A.O. di Parma (I.A., M.C.T.), U.O. Neurologia; Università Cattolica del Sacro Cuore (L.P.); Fondazione Policlinico Universitario A. Gemelli IRCCS (L.P., C. Pazzaglia), Rome; Neuroscience Centre (A.Q.), Magna Graecia University and Neuroimaging Research Unit, IBFM-CNR, Germaneto, Catanzaro; Department of Medical Sciences (P.V.), Magna Graecia University, Catanzaro; Unit of Neurology and Neuromuscular Diseases (L.G., M.R., A.M., G.V.), Department of Clinical and Experimental Medicine, University of Messina; and Department of Woman, Newborn and Child (F.P.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, and University of Milan, Italy.

Objective: To collect information on frequency of pregnancy and delivery complications in Charcot-Marie-Tooth (CMT) disease and on CMT course during pregnancy.

Methods: Through an ad hoc online questionnaire, we investigated pregnancy and neuropathy course in women with CMT adhering to the Italian CMT Registry. Data were compared to those of controls (recruited among friends and unaffected relatives) and the Italian (or other reference) population.

Results: We collected data on 193 pregnancies from 86 women with CMT (age 20-73 years) with 157 deliveries (81.4%) after a mean of 38.6 gestational weeks. In women with CMT, there were no differences compared to controls (59 pregnancies and 46 deliveries from 24 controls) and the reference population for miscarriages (11.4%) and planned (21.0%) and emergency (14.0%) cesarean sections. We found a significantly higher frequency of placenta previa (1.6% vs 0.4%), abnormal fetal presentations (8.4% vs 4.5%), and preterm deliveries (20.3% vs 6.9%; most in week 34-36 of gestation) compared to reference populations. Excluding twins, newborn weight did not differ from the reference population. Postpartum bleeding rate in patients with CMT (2.1%) was similar to that of the general population (2.4%). CMT status worsened during 18 of 193 pregnancies (9.3%) with no recovery in 16 of them and with similar figures in the CMT1A and non-CMT1A subtypes.

Conclusions: We observed higher rates of placenta previa, abnormal presentations, and preterm deliveries in CMT, but pregnancy outcome and newborn weight and health were similar to those of the reference populations. Worsening of CMT is not infrequent and occurs not only in CMT1A. Pregnant women with CMT should be monitored with particular care.
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http://dx.doi.org/10.1212/WNL.0000000000010860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836663PMC
December 2020

Reliability of the Charcot-Marie-Tooth functional outcome measure.

J Peripher Nerv Syst 2020 09 26;25(3):288-291. Epub 2020 Aug 26.

Department of Neurology, University of Rochester, Rochester, New York, USA.

The CMT-FOM is a 13-item clinical outcome assessment (COA) that measures physical ability in adults with Charcot-Marie-Tooth disease (CMT). Test-retest reliability, internal consistency and convergent validity have been established for the CMT-FOM. This current study sought to establish inter-rater reliability. Following an in-person training of six international clinical evaluators we recruited 10 participants with genetically diagnosed CMT1A, (aged 18-74 years, 6 female). Participants were evaluated using the CMT-FOM over 2 days. Participants were given at least a 3 hour rest between evaluations, and were assessed twice each day. Following the provision of training by master trainers, all 13 items of the CMT-FOM exhibited excellent inter-rater reliability for raw scores (ICC 0.825-0.989) and z-scores (ICC 0.762-0.969). Reliability of the CMT-FOM total score was excellent (ICC 0.983, 95% CI 0.958-0.995). The CMT-FOM is a reliable COA used by clinical evaluators internationally. The next steps are to establish further validation through psychometric evaluation of the CMT-FOM in the Accelerate Clinical Trials in CMT (ACT-CMT) study.
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http://dx.doi.org/10.1111/jns.12406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520097PMC
September 2020

Myelin protein zero gene dose dependent axonal ion-channel dysfunction in a family with Charcot-Marie-Tooth disease.

Clin Neurophysiol 2020 10 6;131(10):2440-2451. Epub 2020 Aug 6.

Department of Neuroscience, University of Copenhagen, Denmark; Department of Clinical Neurophysiology, Rigshospitalet, Copenhagen, Denmark. Electronic address:

Objective: The myelin impairment in demyelinating Charcot-Marie-Tooth (CMT) disease leads to various degrees of axonal degeneration, the ultimate cause of disability. We aimed to assess the pathophysiological changes in axonal function related to the neuropathy severity in hypo-/demyelinating CMT patients associated with myelin protein zero gene (MPZ) deficiency.

Methods: We investigated four family members (two parents and two sons) harboring a frameshift mutation (c.306delA, p.Asp104ThrfsTer14) in the MPZ gene, predicted to result in a nonfunctional P, by conventional conduction studies and multiple measures of motor axon excitability. In addition to the conventional excitability studies of the median nerve at the wrist, we tested the spinal accessory nerves. Control measures were obtained from 14 healthy volunteers.

Results: The heterozygous parents (aged 56 and 63) had a mild CMT1B whereas their two homozygous sons (aged 31 and 39 years) had a severe Dejerine-Sottas disease phenotype. The spinal accessory nerve excitability could be measured in all patients. The sons showed reduced deviations during depolarizing threshold electrotonus and other depolarizing features which were not apparent in the accessory and median nerve studies of the parents. Mathematical modeling indicated impairment in voltage-gated sodium channels. This interpretation was supported by comparative modeling of excitability measurements in MPZ deficient mice.

Conclusion: Our data suggest that axonal depolarization in the context of abnormal voltage-gated sodium channels precedes axonal degeneration in severely hypo-/demyelinating CMT as previously reported in the mouse models.

Significance: Measures of the accessory nerve excitability could provide pathophysiological markers of neurotoxicity in severe demyelinating neuropathies.
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http://dx.doi.org/10.1016/j.clinph.2020.06.034DOI Listing
October 2020

Refining clinical trial inclusion criteria to optimize the standardized response mean of the CMTPedS.

Ann Clin Transl Neurol 2020 09 6;7(9):1713-1715. Epub 2020 Aug 6.

School of Health Sciences, University of Sydney, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

The CMT Pediatric Scale (CMTPedS) is a reliable, valid, and responsive clinical outcome measure of disability in children with CMT. The aim of this study was to identify the most responsive patient subset(s), based on the standardized response mean (SRM), to optimize the CMTPedS as a primary outcome measure for upcoming clinical trials. Analysis was based on a 2-year natural history data from 187 children aged 3-20 years with a range of CMT genetic subtypes. Subsets based on age (3-8 years), disability level (CMTPedS score 0-14), and CMT type (CMT1A) increased the SRM of the CMTPedS considerably. Refining the inclusion criteria in clinical trials to younger, mildly affected cases of CMT1A optimizes the responsiveness of the CMTPedS.
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http://dx.doi.org/10.1002/acn3.51145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480902PMC
September 2020

ATTRv amyloidosis Italian Registry: clinical and epidemiological data.

Amyloid 2020 Dec 22;27(4):259-265. Epub 2020 Jul 22.

Fatebenefratelli Foundation-'San Giovanni Calibita' Fatebenefratelli Hospital, Clinical Pathophysiology Center, Rome, Italy.

Introduction: ATTRv amyloidosis is worldwide spread with endemic foci in Portugal and Sweden, Japan, Brazil, Maiorca, and Cyprus. A national Registry was developed to characterise the epidemiology and genotype-phenotype correlation of ATTRv amyloidosis in Italy and to allow a better planning of diagnostic and therapeutic services.

Methods: Fifteen Italian referral centres for amyloidosis spread all over the country have contributed to the Registry.

Results: Four-hundred-forty-seven subjects were enrolled, 187 asymptomatic carriers and 260 affected patients. Thirty-one different mutations were recorded. The seven most represented genetic variants were significantly different in terms of age at onset, clinical features and geographical distribution. National prevalence is 4.33/million with higher values in Southern Italy. Overall symptoms of polyneuropathy were present at disease onset in about half of the patients, symptoms of cardiomyopathy in a quarter of patients, the rest referring carpal tunnel syndrome, dysautonomia or lumbar spinal stenosis. 52.6% of patients were in FAP stage 1, 20.4% in stage 2 and 13.5% in stage 3, while 13.5% patients had no neuropathy, presenting only cardiological symptoms.

Conclusions: We presented an epidemiological study based on collaboration among referral centres for ATTRv amyloidosis spread in all the Italian territory, using web-based Registry. It provided a detailed map of the regional distribution of the disease. The increased awareness of the disease among general practitioners and medical specialists has contributed to reduce the diagnostic delay and the rate of misdiagnosis. The Registry will allow to collect also future information about clinical and instrumental follow-up.
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http://dx.doi.org/10.1080/13506129.2020.1794807DOI Listing
December 2020

Optical coherence tomography in adult adrenoleukodystrophy: a cross-sectional and longitudinal study.

Neurol Sci 2021 Jan 6;42(1):235-241. Epub 2020 Jul 6.

Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133, Milan, Italy.

Background: Adrenoleukodystrophy (ALD) encompasses different neurological phenotypes, ranging from the most severe cerebral forms (C-ALD) to the less severe adrenomyeloneuropathy (AMN). As visual system can be varyingly involved, we aimed at exploring whether optical coherence tomography (OCT) may detect retinal abnormalities and their longitudinal changes in adult ALD patients.

Methods: In this cross-sectional and longitudinal study, we measured the thicknesses of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell complex (mGCC), and segmented inner and outer macula at baseline and their changes over time in 11 symptomatic adult ALD males and 10 age- and sex-matched healthy controls. Statistical analyses were performed for the patients as complete group, and splitting them into two subgroups, one (C-ALD) with and the other (AMN) without cerebral parieto-occipital white matter (WM) lesions.

Results: In the complete ALD group and in the C-ALD subgroup, the average pRNFL, mGCC, and inner macula were significantly thinner than in controls (p ≤ 0.01), whereas in the AMN subgroup, they were constantly, though non-significantly, thinner. Significant outer macula thinning was also observed (p < 0.01). In the complete ALD group, follow-up assessment (mean 26.8 months, range 8-48) showed mildly progressive thinning of inferior pRNFL, average mGCC, and inner macula.

Conclusions: In adult ALD patients, OCT can reveal retinal abnormalities which are prominent in the more compromised patients, namely those with parieto-occipital WM lesions. The inferior pRNFL, average mGCC and inner macula thicknesses might be sensitive-to-change OCT parameters, but their utility and consistency for short-term longitudinal studies deserve further investigations.
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http://dx.doi.org/10.1007/s10072-020-04576-2DOI Listing
January 2021

Validation of the Italian version of the Charcot-Marie-Tooth Health Index.

J Peripher Nerv Syst 2020 09 24;25(3):292-296. Epub 2020 Jun 24.

Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

The Charcot-Marie-Tooth Health Index (CMT-HI) is a disease-specific patient-reported outcome measure measuring overall disease burden in Charcot-Marie-Tooth (CMT) patients, designed for natural history studies and clinical trials in English-speaking affected individuals. We developed and validated its Italian Charcot-Marie-Tooth Health Index (I-CMT-HI) version. The questionnaire was translated and culturally adapted from source into Italian by two neurologists experienced in CMT and neuromuscular disorders (NMDs). The two translations were reviewed by a panel of seven experts in CMT and NMD. The provisional version was back-translated into English by a professional translator. The definitive Italian version was developed during a consensus teleconference by the panel and a patient representative from ACMT-Rete. A series of clinically and genetically characterized CMT patients completed the final questionnaire; 11 participated in a test-retest reliability assessment of the instrument. The I-CMT-HI was administered to 30 CMT patients (13 CMT1A, eight CMTX1, two CMT1B, two CMT1E, two CMT2I, one CMT2A, one CMT2N, one distal Hereditary Motor Neuropathy), with test-rest in 11:14 females and 16 males, aged (mean ± SD) 48.0 ± 16.4 years (range 18-81), with CMT Examination Score (CMTES) = 10.0 ± 4.4 (range 2-18). The I-CMT-HI mean total score was 29.4 ± 21.2 (range 0.1-60.3). The I-CMT-HI showed a high test-retest reliability: intraclass correlation coefficient = 0.95 (95% confidence interval, 0.84-0.99). No patient had difficulty in completing the questionnaire and none reported any problem with the questions' formulation. The total CMT-HI score was positively correlated with age and CMTES, with higher disease burden with increasing age and disease severity according to the CMTES. The I-CMT-HI is now ready for use in clinical studies in the Italian population.
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http://dx.doi.org/10.1111/jns.12397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484132PMC
September 2020

Validation of the Italian version of the Charcot-Marie-Tooth disease Pediatric Scale.

J Peripher Nerv Syst 2020 06 26;25(2):138-142. Epub 2020 May 26.

University of Sydney School of Health Sciences & Children's Hospital at Westmead, Sydney, New South Wales, Australia.

The Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS) is a Rasch-built clinical outcome measure of disease severity. It is valid, reliable, and responsive to change for children and adolescents aged 3 to 20 years. The aim of this study was to translate and validate an Italian version of the CMTPedS using a validated framework of transcultural adaptation. The CMTPedS (Italian) was translated and culturally adapted from source into Italian by two experts in CMT with good English language proficiency. The two translations were reviewed by a panel of experts in CMT. The agreed provisional version was back translated into English by a professional translator. The definitive Italian version was developed during a consensus teleconference by the same panel. CMT patients were assessed with the final version of the outcome measure and a subset had a second assessment after 2 weeks to evaluate test-retest reliability. Seventeen patients with CMT aged 5 to 20 years (eight female) were evaluated with the CMTPedS (Italian), and test-retest was performed in three patients. The CMTPedS (Italian) showed a high test-retest reliability. No patient had difficulty in completing the scale. The instructions for the different items were clearly understood by clinicians and therefore the administration of the outcome measure was straight forward and easily understood by the children assessed. The CMTPedS (Italian) will be used for clinical follow-up and in clinical research studies in the Italian population. The data is fully comparable to that obtained from the English language version.
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http://dx.doi.org/10.1111/jns.12383DOI Listing
June 2020

Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.

Nat Genet 2020 05 4;52(5):473-481. Epub 2020 May 4.

Istituiti Clinici Scientifici Maugeri IRCCS, Environmental Research Center, Pavia, Italy.

Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy. In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol. Furthermore, the serum fasting sorbitol levels in patients were dramatically increased. In Drosophila, loss of SORD orthologs caused synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a novel and potentially treatable cause of neuropathy and may contribute to a better understanding of the pathophysiology of diabetes.
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http://dx.doi.org/10.1038/s41588-020-0615-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353599PMC
May 2020

Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel Mutation and Inhibited EGFR Degradation.

Cells 2020 04 21;9(4). Epub 2020 Apr 21.

Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.

The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A>G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family.
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http://dx.doi.org/10.3390/cells9041028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226405PMC
April 2020

Asymptomatic adrenoleukodystrophy in elderly males.

J Neurol 2020 Jun 20;267(6):1849-1851. Epub 2020 Apr 20.

Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133, Milan, Italy.

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http://dx.doi.org/10.1007/s00415-020-09834-zDOI Listing
June 2020

Severe worsening of adult-onset Alexander disease after minor head trauma: Report of two patients and review of the literature.

J Clin Neurosci 2020 May 26;75:221-223. Epub 2020 Mar 26.

Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy; Neuroscience PhD Program, University of Milano-Bicocca, Monza, Italy. Electronic address:

Alexander disease (ALXDRD) is a rare astrocytic leukodystrophy caused by GFAP mutations. The adult-onset (AO) variant is usually characterized by gradual onset of spastic ataxia and bulbar symptoms with slowly progressive course. We report two AO-ALXDRD cases with rapid worsening after minor head trauma. In one of them, the only post-traumatic neuroimaging change was revealed by diffusion tensor imaging study. Our observations support the link between head trauma and ALXDRD progression, and suggest that this progression may be ascribed to microstructural changes. Clinicians should inform ALXDRD patients to minimize the risk of head trauma.
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http://dx.doi.org/10.1016/j.jocn.2020.03.033DOI Listing
May 2020

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy.

Ann Neurol 2020 07 21;88(1):18-32. Epub 2020 Apr 21.

IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy.

Objective: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed.

Methods: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts.

Results: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells.

Interpretation: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.
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http://dx.doi.org/10.1002/ana.25723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383914PMC
July 2020

-related disease is associated with central pontine calcifications and atypical parkinsonism.

Neurol Genet 2020 Apr 20;6(2):e399. Epub 2020 Feb 20.

Department of Neuromuscular Diseases (V.C., S.E., L.S., J.V., V.S., N.W.W., H.H.), UCL Queen Square Institute of Neurology; National Hospital for Neurology and Neurosurgery (V.C., S.E., L.S., J.V., V.S., N.W.W., H.H.), Queen Square, London, UK; Department of Neurology and Neurosurgery (V.C., S.G.), Institute of Emergency Medicine, Chisinau, Republic of Moldova; Department of Neuroscience (M.C.), University of Padua, Italy; Northern Ireland Regional Genetics Service (G.R., P.J.M.), Belfast City Hospital, UK; Department of Neuroscience (A.B.), Interdisciplinary Center (IDC) Herzliya, Israel; Department of Paediatrics & Child Health (S.K., F.J., S.I., F.K., Z.Q.), Aga Khan University, Karachi, Pakistan; Department of Neurology (L.M.), Eastern Piedmont University, Novara, Italy; Department of Neurology (E.S., D.P.) and Department of Neuroradiology (L.C.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Department of Clinical Neurology (N.B.), University of Nottingham, UK; Department of Clinical and Movement Neurosciences (B.B., K.P.B., N.W.W.), UCL Queen Square Institute of Neurology, London, UK; Department of Neurology (B.B.), Heidelberg University Hospital, Germany; Reta Lila Weston Institute (A.L.), UCL Queen Square Institute of Neurology, London, UK; and Medical Genetics and Neurogenetics Unit (B.G.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Objective: To identify the phenotypic, neuroimaging, and genotype-phenotype expression of mutations.

Methods: Using next-generation sequencing, we screened 86 patients with primary familial brain calcification (PFBC) from 60 families with autosomal recessive or absent family history that were negative for mutations in , , , and . In-depth phenotyping and neuroimaging investigations were performed in all cases reported here.

Results: We identified 12 distinct deleterious variants in 7 of the 60 families with PFBC. Overall, biallelic mutations accounted for 11.6% of PFBC families in our cohort. A heterogeneous phenotypic expression was identified within and between families with a median age at onset of 56.4 years, a variable combination of parkinsonism, cerebellar signs, and cognitive decline. Psychiatric disturbances were not a prominent feature. Cognitive assessment showed impaired cognitive function in 62.5% of cases. Parkinsonism associated with vertical nuclear gaze palsy was the initial clinical presentation in 1/3 of cases and was associated with central pontine calcifications. Cerebral cortical atrophy was present in 37% of cases.

Conclusions: This large, multicentric study shows that biallelic mutations represent a significant proportion of autosomal recessive PFBC. We recommend screening mutations in all patients with primary brain calcifications and autosomal recessive or negative family history, especially when presenting clinically as atypical parkinsonism and with pontine calcification on brain CT.
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http://dx.doi.org/10.1212/NXG.0000000000000399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073457PMC
April 2020
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