Christian Marcotulli
Sapienza University of Rome
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Featured researches published by Christian Marcotulli.
Lancet Neurology | 2015
Silvia Romano; Giulia Coarelli; Christian Marcotulli; Luca Leonardi; Francesca Piccolo; Maria Spadaro; Marina Frontali; Michela Ferraldeschi; Maria Chiara Vulpiani; Federica Ponzelli; Marco Salvetti; Francesco Orzi; Antonio Petrucci; Nicola Vanacore; Carlo Casali; Giovanni Ristori
BACKGROUND Our previous study in patients with cerebellar ataxias of different causes showed significant benefit of riluzole after 8 weeks. We aimed to confirm these results in patients with spinocerebellar ataxia or Friedreichs ataxia in a 1-year trial. METHODS Patients with spinocerebellar ataxia or Friedreichs ataxia (2:1 ratio) from three Italian neurogenetic units were enrolled in this multicentre, double-blind, placebo-controlled trial, and randomly assigned to riluzole (50 mg orally, twice daily) or placebo for 12 months. The randomisation list was computer-generated and a centralised randomisation system was implemented. Participants and assessing neurologists were masked to treatment allocation. The primary endpoint was the proportion of patients with improved Scale for the Assessment and Rating of Ataxia (SARA) score (a drop of at least one point) at 12 months. An intention-to-treat analysis was done. This trial is registered at ClinicalTrials.gov, number NCT01104649. FINDINGS Between May 22, 2010, and Feb 25, 2013, 60 patients were enrolled. Two patients in the riluzole group and three in the placebo group withdrew their consent before receiving treatment, so the intention-to-treat analysis was done on 55 patients (19 with spinocerebellar ataxia and nine with Friedreichs ataxia in the riluzole group, and 19 with spinocerebellar ataxia and eight with Friedreichs ataxia in the placebo group). The proportion with decreased SARA score was 14 (50%) of 28 patients in the riluzole group versus three (11%) of 27 in the placebo group (OR 8·00, 95% CI 1·95-32·83; p=0·002). No severe adverse events were recorded. In the riluzole group, two patients had an increase in liver enzymes (less than two times above normal limits). In two participants in the riluzole group and two participants in the placebo group, sporadic mild adverse events were reported. INTERPRETATION Our findings lend support to the idea that riluzole could be a treatment for cerebellar ataxia. Longer studies and disease-specific trials are needed to confirm whether these findings can be applied in clinical practice. FUNDING Agenzia Italiana del Farmaco.
Journal of Neurology | 2016
Luca Leonardi; Lucia Ziccardi; Christian Marcotulli; Anna Rubegni; Antonino Longobardi; Mariano Serrao; Eugenia Storti; Francesco Pierelli; Alessandra Tessa; Vincenzo Parisi; Filippo M. Santorelli; Casali Carlo
SPG56 is an autosomal recessive form of hereditary spastic paraplegia (HSP) associated with mutations in CYP2U1. There is no clear documentation of visual impairment in the few reported cases of SPG56, although this form is complex on clinical ground and visual deficit are extremely frequent in complicated HSP. We report three patients in a consanguineous family harboring the novel homozygous c.1168C>T (p.R390*) in SPG56/CYP2U1, and showing a pigmentary degenerative maculopathy associated with progressive spastic paraplegia. Furthermore, we characterized precisely the ophthalmologic phenotype through indirect ophthalmoscopy, retinal optical coherence tomography and visual evoked potentials. This is the first formal report of pigmentary degenerative maculopathy associated with a CYP2U1 homozygous mutation.
Movement Disorders | 2016
Francesco Saccà; Giorgia Puorro; Angela Marsili; Antonella Antenora; Chiara Pane; Carlo Casali; Christian Marcotulli; Giovanni Defazio; Daniele Liuzzi; Chiara Tatillo; Donata Maria Cambriglia; Giuseppe Schiano di Cola; Luigi Giuliani; Vincenzo Guardasole; Andrea Salzano; Antonio Ruvolo; Anna De Rosa; Antonio Cittadini; Giuseppe De Michele; Alessandro Filla
Friedreich ataxia is an autosomal recessive disease with no available therapy. Clinical trials with erythropoietin in Friedreich ataxia patients have yielded conflicting results, and the long‐term effect of the drug remains unknown.
Clinical Neurophysiology | 2016
Claudio Babiloni; Claudio Del Percio; Paolo Capotosto; Giuseppe Noce; Francesco Infarinato; Chiara Muratori; Christian Marcotulli; Giovanni Bellagamba; Elena Righi; Andrea Soricelli; Paolo Onorati; Tommaso Lupattelli
OBJECTIVE Resting state electroencephalographic (EEG) rhythms are abnormal in multiple sclerosis (MS) patients, but it is unclear if they can reflect different neurophysiologic abnormalities in MS sub-types (phenotypes) such as relapsing-remitting (RR) and secondary progressive (SP). METHODS We tested whether cortical sources of resting state EEG rhythms are abnormal in MS patients and differ between MS phenotypes. Resting state eyes-closed EEG activity was recorded in 36 RR, 23 SP, and 41 matched healthy subjects. EEG bands of interest were individually identified based on Transition frequency (TF), Individual alpha frequency (IAF), and Individual beta frequency (IBF). LORETA freeware estimated cortical EEG sources. RESULTS Widespread TF -4Hz (delta) and IAF (alpha) cortical sources were abnormal in the MS sub-groups compared to the control group. Furthermore, TF -4Hz sources in central, parietal, and limbic regions were higher in amplitude in the SP compared to the RR sub-group. CONCLUSION Cortical sources of resting state EEG rhythms are abnormal in MS patients at group level and differ between RR and SP sub-groups. SIGNIFICANCE Future studies should test the utility of these EEG markers in the diagnosis and management of MS clinical phenotypes and in the therapy evaluation.
Neurological Sciences | 2014
Andrea Mignarri; Alessandra Tessa; Maria Alessandra Carluccio; Alessandra Rufa; Eugenia Storti; Giovanni Bonelli; Christian Marcotulli; Filippo M. Santorelli; Luca Leonardi; Carlo Casali; Antonio Federico; Maria Teresa Dotti
Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is a rare neurodegenerative disorder characterized by ataxia, spastic paraparesis, polyneuropathy, and evidence of superior cerebellar vermis atrophy at magnetic resonance imaging (MRI). Reports of atypical presentations and additional clinical or MRI findings have been recently published, but psychiatric disturbances have never been associated with ARSACS. We describe four ARSACS patients manifesting severe psychiatric symptoms including psychosis, panic disorder, and depression during the course of the disease. Our case reports further expand the ARSACS phenotype and add clinical data in favor of the hypothesized relationship between cerebellar dysfunction and psychiatric disorders.
Journal of Neurology | 2014
Luca Leonardi; Christian Marcotulli; Karen N. McFarland; Alessandra Tessa; Roberto DiFabio; Filippo M. Santorelli; Francesco Pierelli; Tetsuo Ashizawa; Carlo Casali
Abstract Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder manifested by ataxia with a variable presentation of epileptic seizures, which is caused by a large expansion of an intronic ATTCT pentanucleotide repeat in ATXN10 on 22q13.3. Herein, we report the first description of SCA10 in a Peruvian family, supporting the Amerindian origin of SCA10 and the Panamerican geographical distribution of the disease in North, Central and South America. Moreover, the presence of an interruption motif in the SCA10 expansion along with epileptic seizures in this family supports the correlation between the two, as seen in other families. Finally, this is the first SCA10 patient ever observed outside of America, specifically in Italy. Since this patient is a Peruvian immigrant of Amerindian ancestry, our case report highlights the growing need for awareness amongst clinicians of seemingly geographically restricted rare diseases.
Human Movement Science | 2017
Mariano Serrao; Giorgia Chini; Matteo Bergantino; Diego Sarnari; Carlo Casali; Carmela Conte; Alberto Ranavolo; Christian Marcotulli; Martina Rinaldi; Gianluca Coppola; Fabiano Bini; Francesco Pierelli; Franco Marinozzi
BACKGROUND Patients with degenerative neurological diseases such as cerebellar ataxia, spastic paraplegia, and Parkinsons disease often display progressive gait function decline that inexorably impacts their autonomy and quality of life. Therefore, considering the related social and economic costs, one of the most important areas of intervention in neurorehabilitation should be the treatment of gait abnormalities. This study aims to determine whether an entire dataset of gait parameters recorded in patients with degenerative neurological diseases can be clustered into homogeneous groups distinct from each other and from healthy subjects. Patients affected by three different types of primary degenerative neurological diseases were studied. These diseases were: i) cerebellar ataxia (28 patients), ii) hereditary spastic paraplegia (31 patients), and iii) Parkinsons disease (70 patients). Sixty-five gender-age-matched healthy subjects were enrolled as a control group. An optoelectronic motion analysis system was used to measure time-distance parameters and lower limb joint kinematics during gait in both patients and healthy controls. When clustering single parameters, step width and ankle joint range of motion (RoM) in the sagittal plane differentiated cerebellar ataxia group from the other groups. When clustering sets of two, three, or four parameters, several pairs, triples, and quadruples of clusters differentiated the cerebellar ataxia group from the other groups. Interestingly, the ankle joint RoM parameter was present in 100% of the clusters and the step width in approximately 50% of clusters. In addition, in almost all clusters, patients with cerebellar ataxia showed the lowest ankle joint RoM and the largest step width values compared to healthy controls, patients with hereditary spastic paraplegia, and Parkinsons disease subjects. This study identified several clusters reflecting specific gait patterns in patients with degenerative neurological diseases. In particular, the specific gait pattern formed by the increased step width, reduced ankle joint RoM, and increased gait variability, can differentiate patients with cerebellar ataxia from healthy subjects and patients with spastic paraplegia or Parkinsons disease. These abnormal parameters may be adopted as sensitive tools for evaluating the effect of pharmacological and rehabilitative treatments.
Neurological Sciences | 2015
Luca Leonardi; Christian Marcotulli; Filippo M. Santorelli; Alessandra Tessa; Carlo Casali
Hereditary spastic paraplegias (HSPs) are genetically determined neurodegenerative disorders presenting with spasticity and progressive weakness predominantly affecting the lower limbs due to a length-dependent, retrograde axonopathy of corticospinal motor neurons. Traditionally, HSPs can be divided into pure (uncomplicated) and complicated forms, depending on the presence of additional neurological and non-neurological features [1]. To date, about 70 HSPs gene loci have been mapped and all patterns of inheritance have been described [2]. Mutations in SPG3A/ATL1, encoding atlastin-1, cause both pure and complicated forms and represent the most common autosomal dominant (AD) HSP with onset before age 10 years [2]. The rate of progression is usually slow; wheelchair dependency or need for a support to walk is relatively rare [3]. Herein, we describe three patients with infantile onset HSP harbouring de novo mutations, including a new variant, in SPG3A/ATL1. Patient 1 is a 50-year-old man, born to healthy nonconsanguineous parents, with a clinically pure slowly progressive form of HSP diagnosed in his early childhood as ‘‘infantile cerebral palsy’’. Subsequently, he fathered a similarly affected daughter, now aged 17. Both patients sought expert neurological evaluation and counselling last year. At examination, Patient 1 showed moderate to marked spastic scissor gait, brisk lower limb reflexes, bilateral foot clonus and Babinski sign. He was still able to walk unsupported. He complained also of urinary urgency. His ‘Spastic Paraplegia Rating Scale’ (SPRS) score was 17/52. Both his parents were examined and their neurological condition was unremarkable. His daughter developed walking difficulties after age 3 years. At neurological examination, she had mild spastic gait, brisk lower limb reflexes and bilateral Babinski sign. She has no urinary complaints. Her SPRS score was 9/52. Brain and spinal cord MRI showed no relevant abnormalities in both Patient 1 and his daughter. Both patients harboured the heterozygous c.859C[T/p.R239C in SPG3A/ATL1 mutation. In contrast both Patient 1’s parents did not harbour any SPG3A/ATL1 mutation. Patient 2 is a 3-year-old boy, born to healthy non-consanguineous parents, who presented with delay of motor milestones acquisition in childhood. He was able to stand at 15 months and walk unsupported at 23 months of age. He was the product of full-term, uncomplicated gestation, labour and delivery. At examination, he showed moderate lower limb spasticity, brisk lower limb reflexes and bilateral Babinski sign. His SPRS score was 7/52. Brain and spinal cord MRI as well as EMG and nerve conduction velocities (NCV) were normal. SPG3A/ATL1 analyses disclosed a novel heterozygous c.1308T[A/p.N436K mutation that was absent in his healthy parents. The p.N436K mutation was absent in 400 healthy control chromosomes and predicted to be deleterious in silico (Polyphen2, genetics.bwh.harvard.edu/pph2/). Patient 3 is a 15-year-old boy with a moderately severe form of HSP since his early childhood. His neurological examination showed moderate stiffness while walking, mild spasticity and brisk tendon reflexes over his lower limbs and bilateral foot clonus (SPRS score 9/52). EMG and NCV studies showed mild axonal motor and sensory neuropathy. Mutation analyses disclosed a heterozygous L. Leonardi C. Marcotulli C. Casali (&) Department of Medical-Surgical Sciences and Biotechnologies, Polo Pontino-Sapienza University of Rome, Latina, Italy e-mail: [email protected]
Journal of Neurology | 2014
Christian Marcotulli; Luca Leonardi; Alessandra Tessa; Anna Maria De Negris; Riccardo Cornia; Alberto Pierallini; Shalom Haggiag; Francesco Pierelli; Filippo M. Santorelli; Carlo Casali
Mutations in SPG7-Paraplegin (MIM 602783) have first been associated with a rare autosomal recessive form of hereditary spastic paraparesis (HSP) [1]. Over the past 15 years, dominant and recessive mutations in SPG7 have been increasingly recognized and associated with cerebellar involvement and subtentorial atrophy at MRI [2, 3], optic neuropathy [4], progressive external ophthalmoplegia and ptosis [5], and supranuclear palsy [6]. In the vast majority of cases, the age at onset of motor symptoms ranges from 10 to 45 years [3] and ancillary features usually occur later. We report a 43-year-old man, born to healthy non consanguineous parents, who presented severe visual problems since childhood, diagnosed as congenital optic atrophy. His visual acuity slowly worsened over several years but remained his only complaint. He first sought neurological expert consultation after age 30, when he started complaining of slowly progressive walking difficulties and urinary urgency. At the age of 43, neurological examination showed moderate spastic paraparesis (SPRS score was 14 [7]), brisk reflexes as well as some difficulties in tandem walking, gaze-evoked nystagmus, slight intentional hand tremor but no sensory disturbance. Visual acuity was 1/100 bilaterally; at fundus examination, pale optic disks were observed. Optical Coherence Tomography (OCT) scan showed bilateral reduction of macular thickness, due to selective depletion of ganglionic cells, diffuse and severe reduction of papillar nervous fibers. Brain MRI showed marked optic nerves and chiasm as well as mild cerebellar atrophy (Fig. 1). After obtaining written informed consent, molecular studies identified the c.538[A/p.V180M in compound heterozygosity with the c.1045[A/p.G349S in SPG7, while failed to show any change in OPA1, MFN2 and AFG3L2. Both mutations have been previously reported as disease-causative [4]. MtDNA mutations usually associated with Leber Hereditary Optic Neuropathy (LHON) were also excluded. Interestingly, the patient’s sister, aged 42 years, who carries the heterozygous c.538[A/p.V180M mutation, shows signs of mild cerebellar involvement and bilateral mild depletion of ganglionic cells at OCT scan. Moreover, the patient’s father, also carrying the same mutation, was found to have mild signs of cerebellar involvement but no changes at the OCT scan. This raises the possibility of a partially dominant pattern of transmission of the c.538[A/p.V180M mutation as reported already for the c.1232A[C/p.D411A [4]. Optic neuropathy is a relatively frequent clinical finding associated with SPG7 mutations, usually presenting C. Marcotulli L. Leonardi C. Casali (&) Department of SBMC, Sapienza University Rome, Rome, Italy e-mail: [email protected]
Clinical Genetics | 2014
R. Di Fabio; Alessandra Tessa; Christian Marcotulli; Luca Leonardi; Francesco Pierelli; Filippo M. Santorelli; Carlo Casali
To the Editor : Significant clinical overlap between the genetically heterogeneous hereditary spastic paraplegias (HSPs) and the high degree of inter/intra-familial variability characterizing this group of diseases makes it difficult to predict HSP genotype on the basis of clinical findings alone (1). HSPs typically progress slowly and awareness of motor dysfunction can differ significantly between patients. Consequently, medical attention may not be sought until a functional impairment is clearly perceived. It is therefore crucial, when apparently isolated cases of progressive paraparesis are detected, to extend neurological evaluation to the patient’s relatives, in order to clarify the pattern of inheritance in the pedigree and disclose minor signs of disease in other family members. We describe a family with a pure form of autosomal dominant HSP (AD-HSP) in which the 16-year-old proband (IV-7) is affected by cerebral palsy, diagnosed in infancy (Fig. 1). His 47-year-old mother (III-5) had been at risk of preterm delivery at 34 weeks and had also had three previous miscarriages. The patient took first steps at the age of 16 months and experienced slight difficulty in walking and running during childhood. He complained of urinary urgency in cold weather conditions. Direct sequencing of common AD-HSP genes (SPG3A/ATL1 , SPG4/SPAST , SPG31/REEP1 ) in peripheral blood DNA disclosed an already described heterozygous mutation (c.1243C>T/p.R415W) in SPG3A/ATL1, the gene encoding atlastin 1. The parents reported no neurological complaints, although case III-5 revealed that she had long experienced urinary urgency in cold weather and leg stiffness after long walks. Her neurological examination was significant for brisk tendon reflexes in the lower limbs and pes cavus . Surprisingly, she did not carry the mutation detected in her son and further investigations disclosed a novel heterozygous mutation (c.751insA) in SPG4/SPAST , the gene encoding spastin. The same SPG4/SPAST mutation was also found in seven maternal relatives (III-1, III-2, III-3, III-4, IV-1, IV-2, and IV-3 in Fig. 1), all of whom were unaware of their disease status. Neurological assessment of the family revealed moderate gait impairment in some members consisting of difficulties in walking on heels or stiff gait, variable degrees of spasticity, brisk reflexes and inconstant Babinski sign (Table 1). Upon direct interview, case III6, the proband’s 49-year-old father, who had initially been reluctant to be assessed because he was convinced he was healthy, admitted experiencing stiffness after Fig. 1. The family pedigree. Filled symbols indicate subjects carrying mutations SPG4/SPAST whereas dashed symbols with red frames indicate cases harbouring mutations in SPG3A/ATL1 .