Francesca Magrinelli

UCL Queen Square Institute of Neurology - University College London · Clinical and Movement Neurosciences

The 2018 consensus statement on the classification of tremors proposes a two-axis categorization scheme based on clinical features and etiology. It also defines “isolated” and “combined” tremor syndromes depending on whether tremor is the sole clinical manifestation or is associated with other neurological or systemic signs. This syndromic approach...

Background: Progress in genetics - particularly the advent of next-generation sequencing (NGS) - has enabled an unparalleled gene discovery and revealed unmatched complexity of genotype-phenotype correlations in movement disorders. Among other things, it has emerged that mutations in one and the same gene can cause multiple, often markedly differe...

Background: Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration. Objectives: The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported. Methods: We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic l...

Background: Biallelic loss-of-function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only. Objectives: To fully characterize, both phenotypically and genotypically, NDUFA12-related mitochondrial disease. Methods: We collected data...

We report the results of a comprehensive copy number variant (CNV) reanalysis of 9171 exome sequencing datasets from 5757 families affected by a rare disease (RD). The data reanalysed was extremely heterogeneous, having been generated using 28 different enrichment kits by 42 different research groups across Europe partnering in the Solve-RD project...

Background Progressive supranuclear palsy (PSP) is a progressive atypical parkinsonian condition that results in severe disability. There are few studies of PSP in patients of non‐white European ancestry. Objectives We aim to perform deep phenotyping in a South Asian PSP cohort to uncover possible ethnic differences in disease characteristics. Me...

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neu...

Biallelic expansions of the AAGGG repeat in the replication factor C subunit 1 (RFC1) have recently been described to be responsible for the cerebellar ataxia, peripheral neuropathy and vestibular areflexia syndrome. This genetic alteration has also allowed genetic classification in up to one third of cases with idiopathic sensory neuropathy. Here...

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN -PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN -PD was also assessed. Am...

Mobile element insertions (MEIs) are a known cause of genetic disease but have been underexplored due to technical limitations of genetic testing methods. Various bioinformatic tools have been developed to identify MEIs in Next Generation Sequencing data. However, most tools have been developed specifically for genome sequencing (GS) data rather th...

TUBB4A pathogenic variants are associated with a spectrum of neurologic impairments including movement disorders and leukodystrophy. With the development of targeted therapies, there is an urgent unmet need for validated tools to measure mobility impairment. Our aim is to explore gross motor function in a pediatric-onset TUBB4A-related leukodystrop...

In patients with movement disorders, voluntary movements can sometimes be accompanied by unintentional muscle contractions in other body regions. In this review, we discuss clinical and pathophysiological aspects of several motor phenomena including mirror movements, dystonic overflow, synkinesia, entrainment and mirror dystonia, focusing on their...

Paroxysmal movement disorders have traditionally been classified into paroxysmal dyskinesia (PxD), which consists in attacks of involuntary movements (mainly dystonia and/or chorea) without loss of consciousness, and episodic ataxia (EA), which features spells of cerebellar dysfunction with or without interictal neurological manifestations. In this...

Background: Cerebral toxoplasmosis (CTx) is a central nervous system opportunistic infection with variable neurological manifestations. Although tropism of Toxoplasma gondii for the basal ganglia is well known, movement disorders (MDs) represent only a small percentage of CTx-related neurological complications. CTx-associated MDs are usually hyper...

Background: Heterozygous NKX2-1 loss-of-function variants cause combinations of hyperkinetic movement disorders (MDs, particularly childhood-onset chorea), pulmonary dysfunction, and hypothyroidism. Mobile element insertions (MEIs) are potential disease-causing structural variants whose detection in routine diagnostics remains challenging. Object...

Purpose The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated famil...

Background: Biallelic variants in HPCA were linked to isolated dystonia (formerly DYT2) in 2015. Since then, the clinical spectrum of HPCA-related disorder has expanded up to including a complex syndrome encompassing neurodevelopmental delay, generalized dystonia with bulbar involvement, and infantile seizures. Cases: We report four individuals...

Biallelic variants of the gene encoding for the zinc‐finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among...

Background Non-genetic risk factors play a relevant role in Parkinson's disease (PD) development but the relationship between these factors and PD clinical features is unknown. Objective The aim of the present multicenter study was to investigate possible relationship between risk factors and clinical motor and non-motor features in a large sample...

Parkinson’s disease (PD) is the neurological disorder showing the greatest rise in prevalence from 1990 to 2016. Despite clinical definition criteria and a tremendous effort to develop objective biomarkers, precise diagnosis of PD is still unavailable at early stage. In recent years, an increasing number of studies have used omic methods to unveil...

Although restless legs syndrome (RLS) is a common neurological disorder, it remains poorly understood from both clinical and pathophysiological perspectives. RLS is classified among sleep-related movement disorders, namely, conditions characterized by simple, often stereotyped movements occurring during sleep. However, several clinical, neurophysio...

A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within th...

A 58‐year‐old male with B‐cell chronic lymphocytic leukemia presented with fever, chest pain, and acute‐onset neurological deficits suggestive of multiple strokes (A). Brain autopsy revealed softening areas in the brain parenchyma (B, C) corresponding to extensive necrosis (D) caused by neuroinvasion by Aspergillus hyphae (E, F) necrosis (D) caused...

After extensive evaluation, one-third of patients affected by polyneuropathy remain undiagnosed and are labelled as having chronic idiopathic axonal polyneuropathy, which refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy of unknown origin. Since a sensory neuropathy/neuronopathy is identified in all patients with genetical...

X-linked parkinsonism encompasses rare heterogeneous disorders mainly inherited as a recessive trait, therefore being more prevalent in males. Recent developments have revealed a complex underlying panorama, including a spectrum of disorders in which parkinsonism is variably associated with additional neurological and non-neurological signs. In par...

The association of movement disorders with structural or functional hepatic disease occurs in three principal scenarios: a) combined involvement of both organ systems from a single disease entity, b) nervous system dysfunction resulting from exposure to toxic compounds in the setting of defective hepatic clearance, or c) hepatic or neurological inj...

Objective Hexanucleotide repeat expansions (HREs) in C9orf72 are a major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We aimed to determine the frequency and phenomenology of movement disorders (MD) in carriers of HRE in C9orf72 through a retrospective review of patients' medical records. Methods We retrospective...

Advanced age is the major risk factor for idiopathic Parkinson’s disease (PD), but to date the biological relationship between PD and ageing remains elusive. Here we describe the rationale and the design of the H2020 funded project “PROPAG-AGEING”, whose aim is to characterize the contribution of the ageing process to PD development. We summarize c...

Somatic mutations in JAK2 are associated with chronic myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis (PMF). The most common variant, Val617Phe (JAK2V617F), accounts for >95% of polycythemia vera and 50%–60% of essential thrombocythemia and PMF cases.1, 2 Chorea is a well‐descri...

Objective: To perform a simultaneous evaluation of potential risk/protective factors of Parkinson's disease (PD) in order to identify independent risk/protective factors, assess interaction among factors and determine whether identified risk factors predict etiological subtypes of PD. Methods: We designed a large case-control study assessing 31...

The pathophysiology of essential tremor (ET) is controversial and might be further elucidated by advanced neuroimaging. Focusing on homogenous ET patients diagnosed according to the 2018 consensus criteria, this study aimed to: (1) investigate whether task functional MRI (fMRI) can identify networks of activated and deactivated brain areas, (2) cha...

Background Biallelic mutations in ATP13A2 were identified as the cause of Kufor‐Rakeb disease, a pallido‐pyramidal syndrome characterised by young‐onset dystonia‐parkinsonism with vertical supranuclear gaze palsy, spasticity and cognitive decline. The phenotypic spectrum has broadened since, but predominantly psychiatric or behavioural manifestatio...

Cortical tremor is a fine rhythmic oscillation involving distal upper limbs, linked to increased sensorimotor cortex excitability, as seen in cortical myoclonus. Cortical tremor is the hallmark feature of autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE), a syndrome not yet officially recognized and characterized by clinica...

Background: Disease-modifying pharmacological agents for transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on their efficacy and safety is limited. This review focuses on disease-modifying pharmacological treatment for TTR-related and other FAPs, encompassing amyloid kinetic st...

Background: Camptocormia is a disabling complication of Parkinson's disease (PD), but its pathophysiology is poorly elucidated. Depending on the fulcrum of forward trunk flexion, two subtypes have been defined, upper (UCC) and lower camptocormia, the former being much more frequent. The aim of the study was to explore possible pathophysiological m...

Introduction: Pathological forward trunk flexion is a disabling and drug-refractory motor complication of Parkinson's disease (PD) leading to imbalance, pain, and fall-related injuries. Since it might be reversible, early and multidisciplinary management is emphasised. The primary aim was to compare the effects of a four-week trunk-specific rehabi...

Background A heterozygous mutation in the TOR1A gene (DYT1) accounts for an isolated dystonia typically presenting during childhood or adolescence with initial involvement of a limb, rapid spreading to other limbs and trunk, and sparing of craniocervical muscles. However, atypical phenotypes in terms of age at onset, site of presentation, and sprea...

Introduction: Tremor is the most frequent and disabling neurological side effect under Calcineurin inhibitor-induced immunosuppression, but no studies have defined its phenomenology, severity, distribution, the impact on quality of life, as well as of other neurological symptoms associated. Methods: 126 consecutive kidney-transplanted patients,...

Objective: Nerve ultrasound (US) data on myelin protein zero (MPZ)-related Charcot-Marie-Tooth disease (CMT) are lacking. To offer a comprehensive perspective on MPZ-related CMTs, we combined nerve US with clinics, electrodiagnosis and histopathology. Methods: We recruited 36 patients (12 MPZ mutations), and correlated nerve US to clinical, elec...

Introduction: Adult-onset neuronal ceroid lipofuscinoses (ANCL) are a group of rare inherited neurodegenerative diseases of early adulthood, named after the presence of intralysosomal autofluorescent lipopigment with characteristic ultrastructural features in neurons and other cell types. Over the last decade, six ANCL genes have been identified, t...

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess and compare the efficacy, acceptability, and tolerability of pharmacologic disease-modifying agents for familial amyloid neuropathy (FAP). © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Background: Pain is an important non-motor symptom in several neurological diseases, such as Parkinson's disease, cervical dystonia, amyotrophic lateral sclerosis, severe acquired brain injury, disorders of consciousness and dementia, as well as in oncology and neuroinfectivology. Aims: To overcome the lack of evidence-based data on pain managem...

Pain is very common in neurorehabilitation, where it may be a target for treatment and have a negative effect on rehabilitation procedures and outcomes. Promising preliminary preclinical data support some therapeutic approaches to pain, but there is a strong need of adequate preclinical models, experimental settings, outcome measures, and biomarker...

Cardinal motor features of Parkinson’s disease (PD) include bradykinesia, rest tremor, and rigidity, which appear in the early stages of the disease and largely depend on dopaminergic nigrostriatal denervation. Intermediate and advanced PD stages are characterized by motor fluctuations and dyskinesia, which depend on complex mechanisms secondary to...

Pain is very common in the neurorehabilitation setting, where it may not only represent a target for treatment but can also negatively influence rehabilitation procedures directly or through the side effects of painkillers. To date, there are neither guidelines nor consensus on how to assess and treat pain in neurorehabilitation. Because of the ver...

Diabetic peripheral neuropathy (DPN) is a frequent complication of type 2 diabetes mellitus (DM) and may involve small and large peripheral nerve fibers. Recent evidence suggests a role of cytokines in DPN. The paper is aimed at exploring whether the serum concentration of cytokines is associated with small and large nerve fiber function and with n...

Objective: Trigeminal neuralgia (TN) is a neuropathic pain condition affecting one or more branches of the trigeminal nerve. It is characterized by unilateral, sudden, shock-like, and brief painful attacks, which follow the distribution of trigeminal nerve branches, and with no other accompanying sensorimotor or autonomic signs and symptoms. Curre...

The treatment of chronic pain is still unsatisfactory. Despite the availability of different drugs, most patients with chronic pain do not receive satisfactory pain relief or report side effects. Converging evidence implicates involvement of the immune system in the pathogenesis of different types of nociceptive and neuropathic chronic pain. At a w...

Diabetic lumbosacral radiculoplexus neuropathy ( DLRPN ) is a rare painful peripheral neuropathic complication of diabetes mellitus. The clinical features of DLRPN include severe neuropathic pain, weakness, atrophy, and sensory loss in the lower limbs with asymmetrical distribution. Nerve ischemia due to inflammation and microvasculitis has been su...

Neuropathic pain (NP) develops as a consequence of a lesion or disease affecting the somatosensory pathways in the peripheral or central nervous system, and occurs in many neurological diseases (eg, peripheral neuropathy, radiculopathy, spinal cord injury, stroke and multiple sclerosis). It affects 6%-8% of the general population and its impact on...

Neuropathic pain (NP) is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system and represents a severe and debilitating chronic pain condition. Peripheral and central sensitization phenomena have long been known as the key pathogenetic mechanisms in NP and its chronicization. Current therapies for...