Publications by authors named "Raffaella Zannolli"

25 Publications

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A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia.

Mov Disord 2012 Sep 23;27(10):1312-6. Epub 2012 Aug 23.

Child Neurology and Psychiatry Unit, Azienda Ospedaliera Universitaria Senese/University of Siena, Policlinico Le Scotte, Siena, Italy.

No controlled studies exist regarding the pharmaceutical reduction of ataxia symptoms in ataxia telangiectasia (A-T). In a multicenter, double-blind, randomized, placebo-controlled crossover trial, oral betamethasone (BETA) and placebo were compared in terms of their reduction of ataxia symptoms as assessed with the International Cooperative Ataxia Rating Scale (ICARS). In this study of 13 A-T children, betamethasone reduced the ICARS total score by a median of 13 points in the intent-to-treat population and 16 points in the per-protocol population (ie, median percent decreases of ataxia symptoms of 28% and 31%, respectively). In conclusion, Oral betamethasone could be a promising therapy to relieve ataxia symptoms in A-T patients; however, long-term effectiveness and safety must be established. (Current Controlled Trials, number ISRCTN08774933.)
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http://dx.doi.org/10.1002/mds.25126DOI Listing
September 2012

Silent increase of urinary ethylmalonic acid is an indicator of nonspecific brain dysfunction.

NMR Biomed 2010 May 25;23(4):353-8. Epub 2010 Feb 25.

Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, Siena, Italy.

Our aim was to compare urinary ethylmalonic acid (EMA) levels in subjects who had no apparent clinical reason to have increased levels of this substance but were suffering from non-specific CNS impairment, and healthy controls. Urinary EMA concentrations detected by (1)H-NMR spectroscopy were studied in 130 subjects with CNS impairment of unknown origin (with no definite diagnosis, no specific symptoms or signs, and normal common biochemical and metabolic screening results) and 130 age- and sex-matched healthy subjects. EMA levels exceeding two standard deviations (SD) above normal (i.e. 8.1 mmol/molCn) were found in a subgroup of CNS-impaired patients and healthy controls. EMA levels exceeding 2 SD above normal were fourfold prevalent in the urine of patients with non-specific CNS impairment compared to from the EMA levels in healthy controls. Moreover, we found that the level exceeding > 8.1 mmol/molCn (i.e. > + 2 SD) had sufficient discrimination accuracy in identifying subjects with non-specific CNS impairment; the level exceeding 12 mmol/molCn (i.e. > + 6 SD) reaches suitable accuracy (i.e. 100% specificity and 78.6% sensitivity). These observations are of importance, as we found that subtle increases in urinary EMA levels are frequent in patients with non-specific CNS impairment. The reasons for this association remain unknown.
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http://dx.doi.org/10.1002/nbm.1468DOI Listing
May 2010

EEG features and epilepsy in MECP2-mutated patients with the Zappella variant of Rett syndrome.

Clin Neurophysiol 2010 May 12;121(5):652-7. Epub 2010 Feb 12.

Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Child Neurology and Psychiatry Pediatrics, Azienda Ospedaliera Universitaria Senese, S. Maria alle Scotte Hospital, Siena, Italy.

Objective: To assess the presence/absence of peculiar EEG features and epilepsy in MECP2-mutated Rett patients with the Zappella-Rett variant (Z-RTT) also known as preserved speech variant.

Methods: Retrospective analysis of 16 (age 19.4+/-8.4years; range 8-38years) MECP2 mutated Z-RTT cases, including 11 high or intermediate performance (HIP), and five low-performance (LP) patients was performed. Peculiar EEG features were analyzed as a function of the HIP or LP Z-RTT categories: (1) centro-temporal spikes, (2) multifocal EEG activity, (3) EEG encephalopathy (i.e. multifocal EEG activity associated with the presence of background slowing and diffuse slow activity), (4) spindles and K-complex. Furthermore, we assessed the occurrence of epilepsy. Correlations between electroclinical features and category of Z-RTT genotype (missense or truncation mutation) were also tested.

Results: The Z-RTT HIP group showed a very abnormal EEG (presence of centro-temporal spikes: p=0.004808), although the cases studied were not epileptogenic and did not develop encephalopathy. The LP group showed multifocal EEG activity (p=0.000229), EEG encephalopathy (p=0.000229) and epilepsy (p=0.299451). No significant differences between the prevalence of centro-temporal spikes, multifocal EEG activity, EEG encephalopathy, and epilepsy between the patients with the truncation or missense mutation were observed.

Conclusions: EEG electrophysiological patterns and epileptogenic susceptibility differ in Z-RTT according to the level of performance (i.e. HIP or LP).

Significance: These results indicate that HIP and LP Z-RTT should be considered as distinct entities, not only on a clinical basis, but also as it concerns EEG features and epileptogenic susceptibility. These results could offer support in the practical management of patients and family counseling.
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http://dx.doi.org/10.1016/j.clinph.2010.01.003DOI Listing
May 2010

Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling.

Hum Mutat 2009 Dec;30(12):1667-75

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid and CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.

Autosomal recessive Ellis-van Creveld syndrome and autosomal dominant Weyer acrodental dysostosis are allelic conditions caused by mutations in EVC or EVC2. We performed a mutation screening study in 36 EvC cases and 3 cases of Weyer acrodental dysostosis, and identified pathogenic changes either in EVC or in EVC2 in all cases. We detected 40 independent EVC/EVC2 mutations of which 29 were novel changes in Ellis-van Creveld cases and 2 were novel mutations identified in Weyer pedigrees. Of interest one EvC patient had a T>G nucleotide substitution in intron 7 of EVC (c.940-150T>G), which creates a new donor splice site and results in the inclusion of a new exon. The T>G substitution is at nucleotide +5 of the novel 5' splice site. The three Weyer mutations occurred in the final exon of EVC2 (exon 22), suggesting that specific residues encoded by this exon are a key part of the protein. Using murine versions of EVC2 exon 22 mutations we demonstrate that the expression of a Weyer variant, but not the expression of a truncated protein that mimics an Ellis-van Creveld syndrome mutation, impairs Hedgehog signal transduction in NIH 3T3 cells in keeping with its dominant effect.
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http://dx.doi.org/10.1002/humu.21117DOI Listing
December 2009

[(1)H] magnetic resonance spectroscopy of urine: diagnosis of a guanidinoacetate methyl transferase deficiency case.

J Child Neurol 2010 Jan 21;25(1):98-101. Epub 2009 May 21.

The NMR Center University of Siena, Siena, Italy.

For the first time, the use of urine [(1)H] magnetic resonance spectroscopy has allowed the detection of 1 case of guanidinoacetate methyl transferase in a database sample of 1500 pediatric patients with a diagnosis of central nervous system impairment of unknown origin. The urine [(1)H] magnetic resonance spectroscopy of a 9-year-old child, having severe epilepsy and nonprogressive mental and motor retardation with no apparent cause, revealed a possible guanidinoacetic acid increase. The definitive assignment of guanidinoacetic acid was checked by addition of pure substance to the urine sample and by measuring [(1)H]-[(1)H] correlation spectroscopy. Diagnosis of guanidinoacetate methyl transferase deficiency was further confirmed by liquid chromatography-mass spectrometry, brain [(1)H] magnetic resonance spectroscopy, and mutational analysis of the guanidinoacetate methyl transferase gene. The replacement therapy was promptly started and, after 1 year, the child was seizure free. We conclude that for this case, urine [(1)H] magnetic resonance spectroscopy screening was able to diagnose guanidinoacetate methyl transferase deficiency.
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http://dx.doi.org/10.1177/0883073809336120DOI Listing
January 2010

Guanidinoacetate methyltransferase (GAMT) deficiency diagnosed by proton NMR spectroscopy of body fluids.

NMR Biomed 2009 Jun;22(5):538-44

Laboratory of Pediatrics and Neurology, Nijmegen Medical Center, Radboud University, Nijmegen, The Netherlands.

In patients with guanidinoacetate methyltransferase (GAMT) deficiency several parameters may point towards the diagnosis of GAMT deficiency. These include the low levels of creatine and creatinine in urine, the high concentration of guanidinoacetic acid (GAA) in urine and the low levels of creatine and creatinine in the cerebrospinal fluid (CSF). In this study, body fluids from 10 GAMT deficient patients were analysed using (1)H NMR spectroscopy. The urine 1D (1)H NMR spectra of all the patients showed a doublet resonance at 3.98 ppm (pH 2.50) derived from GAA present in high concentration. For this compound, a good recovery and good correlation was found between an LC-MS/MS method and (1)H NMR spectroscopy. In CSF NMR spectra of these patients, the singlet resonances of creatine and creatinine (3.05 and 3.13 ppm, respectively) were absent (normally always present in (1)H NMR spectra of CSF). Due to overlap by other resonances, the doublet of GAA could not be observed. Our data demonstrate that (1)H NMR spectroscopy of urine and CSF can be used to diagnose patients with GAMT deficiency.
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http://dx.doi.org/10.1002/nbm.1367DOI Listing
June 2009

Quantitative Real-Time PCR detection of TRPV1-4 gene expression in human leukocytes from healthy and hyposensitive subjects.

Mol Pain 2008 Nov 4;4:51. Epub 2008 Nov 4.

Department of Evolutionary Biology, University of Siena, Siena, Italy.

Background: Besides functioning as chemosensors for a broad range of endogenous and synthetic ligands, transient receptor potential vanilloid (TRPV) 1-4 channels have also been related to capsaicin (TRPV1), pain, and thermal stimuli perception, and itching sensation (TRPV1-4). While the expression of the TRPV1-4 genes has been adequately proved in skin, sensory fibres and keratinocytes, less is known about TRPV3 and TRPV4 expression in human blood cells.

Results: To study the gene expression of TRPV1-4 genes in human leukocytes, a quantitative Real-Time PCR (qRT-PCR) method, based on the calculation of their relative expression, has been developed and validated. The four commonly used house-keeping genes (HKGs), beta-Actin (Act-B), glyceraldehyde-3P-dehydrogenase (GAPDH), hypoxanthine ribosyltransferase (HPRT1), and cyclophilin B (hCyPB), were tested for the stability of their expression in several human leukocyte samples, and used in the normalization procedure to determine the mRNA levels of the TRPV 1-4 genes in 30 healthy subjects. cDNAs belonging to all the TRPV1-4 genes were detected in leukocytes but the genes appear to be expressed at different levels. Our analysis did not show significant sex differences in TRPV1-4 cDNA levels in the 30 healthy subjects. The same qRT-PCR assay was used to compare TRPV1-4 expression between healthy controls and patients hyposensitive to capsaicin, pain and thermal stimuli: an almost doubled up-regulation of the TRPV1 gene was found in the pathological subjects.

Conclusion: The qRT-PCR assay developed and tested in this study allowed us to determine the relative expression of TRPV1-4 genes in human leukocytes: TRPV3 is the least expressed gene of this pool, followed by TRPV4, TRPV1 and TRPV2. The comparison of TRPV1-4 gene expression between two groups of healthy and hyposensitive subjects highlighted the evident up-regulation of TRPV1, which was almost doubly expressed (1.9x normalized fold induction) in the latter group. All the four house-keeping genes tested in this work (Act-B, GAPDH, hCyPB, HPRT1) were classified as optimal controls and showed a constant expression in human leukocytes samples. We recommend the use of these genes in similar qRT-PCR studies on human blood cells.
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http://dx.doi.org/10.1186/1744-8069-4-51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588574PMC
November 2008

Drug-resistant epilepsy and epileptic phenotype-EEG association in MECP2 mutated Rett syndrome.

Clin Neurophysiol 2008 Nov 7;119(11):2455-8. Epub 2008 Oct 7.

Pediatrics Neuropsychiatric Unit, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, Siena, Italy.

Objective: To determine in MECP2-mutated Rett syndrome (RTT [MIM 312750]): (1) the prevalence of drug-resistant epilepsy (DRE); (2) whether the presence of DRE is related to the abnormal EEG patterns or to the particular MECP2 mutant genotype.

Methods: Retrospective survey of a large population of patients (n=154) evaluated between 1978 to 2007 (May) at the Child Psychiatry and Neurology Unit of Siena (Italy) with both clinical and genetic (i.e. MECP2 mutated) diagnoses of RTT. Some subjects were followed for up to 20 years. Among those, cases with epilepsy were first selected for study; within that group, cases with DRE were identified and studied. The association between clinical severity of their epilepsy and quantitative or qualitative scores of EEG severity was tested using rank coefficients (Spearman's rho values). The relationship between DRE and RTT genotype category (i.e. gene deletion, gene duplication, early truncating mutation, late truncating mutation, and missense mutation) or a specific MECP2 genotype was tested using the chi-square test. A p-value <0.05 (two sided) was considered to indicate statistical significance.

Results: Prevalence of DRE was 16% (i.e. 16 DRE out of 100 MECP2-mutated RTT epileptic patients). No significant relationship was found between clinical severity of DRE and quantitative (p=0.9190) or qualitative EEG scores (p=0.1511). In addition, no significant relationship was found between the DRE and the RTT genotype category (chi-square=1.147, DF=4, p=0.8867), or a specific MECP2 genotype (chi-square=30.958, DF=39, p=0.8173).

Conclusions: Although RTT MECP2-mutated patients suffer from a serious and progressive encephalopathy, it is "epileptogenic" but not "DREgenic" as they have a decreased risk (16%) for DRE compared to the general epileptic population (DRE: 20-40%). The presence of DRE is not related to abnormal EEG findings or a particular MECP2 mutant genotype.

Significance: These observations could be of help in the practical management and family counseling.
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http://dx.doi.org/10.1016/j.clinph.2008.08.015DOI Listing
November 2008

Telomere length and obesity.

Acta Paediatr 2008 Jul;97(7):952-4

Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Pediatrics, Policlinico Le Scotte, University of Siena, Siena, Italy.

Aim: To assess the telomere length in apparently healthy obese and normal-weight subjects.

Methods: Seventy-six Caucasian subjects were chosen including 53 children (age 8.2+/-3.5 years) and 23 adults (age 40.5+/-8.4 years). Among these, 22 (12 children and 10 adults) were obese with a body mass index (BMI, kg/m2)>2 SD above the norm. Bioelectrical impedance analysis (BIA), measured with a multiple frequency analyzer, was used to estimate body composition. DNA extraction from white blood cells was used to estimate the telomere length by detection of terminal restriction fragments (TRF).

Results: No difference was found between the TRF lengths of obese and normal children. Obese adults had shorter TRF lengths than adults who were not obese (mean TRF length difference, -884.5; 95% confidence intervals -1727 to -41.8; t=2.183; df=17; p<0.041).

Conclusions: Obese adults have shorter telomeres than their normal-weight counterparts, while this phenomenon is not present in childhood.
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http://dx.doi.org/10.1111/j.1651-2227.2008.00783.xDOI Listing
July 2008

New neurocutaneous syndrome with defect in cell trafficking and melanosome pathway: the future challenge.

Brain Dev 2008 Aug 28;30(7):461-8. Epub 2008 Jan 28.

Department of Pediatrics, Section of Pediatrics Neurology and Pediatrics Neuropsychiatric Unit, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, University of Siena, Viale Bracci, I-53100 Siena, Italy.

Objective: Case study of a CNS impairment lacking in presumptive cause; case presents with a clinical phenotype encompassing multiple differently expressed and combined symptoms, as well as a subtle skin defect.

Materials And Methods: A 6-year-old male with apparently isolated mental delay, speech delay, attention deficit/hyperactivity disorder, epilepsy, and subtle and insignificant skin dyschromias. The patient underwent a systematic evaluation, including clinical history; medical, neurological and ophthalmologic examinations. Skin, teeth, nails, hair and sudation were examined for defects. Routine laboratory tests for blood, urine, were performed. The proband had thyroid function tests, electrocardiography, genitourinary system and abdominal examinations. Special examinations pertaining to mental performance, biochemistry, chromosome studies, imaging and electrodiagnostic studies, and skin biopsy were also performed.

Results: Investigators ruled out genetic syndromes, congenital infections, fetal deprivation, perinatal insults, intrauterine exposure to drug abuse, and postnatal events such as CNS infections as possible common causes of brain impairment. Being all further test negative, the patient exhibited an ultrastructural defect of the skin, identical to that previously described [Buoni S, Zannolli R, de Santi MM, Macucci F, Hayek J, Orsi A et al. Neurocutaneous syndrome with mental delay, autism, blockage in intracellular vesicular trafficking and melanosome defects. Eur J Neurol 2006;13:842-51], suggesting that some cell compartments, such as rough endoplasmic reticulum, lysosomes, Golgi apparatus, and the vesicular zone (racket) of Birbeck granules, sharing similar components, can be altered, resulting in a common defect in cell trafficking, associated to melanosome defects.

Conclusions: This new devasting, ultrastructural phenotype accompanied by apparently unspecific and mixed neurological symptoms should represent a future challenge to finally discover the pathogenesis of many childhood CNS symptoms, that currently seem to lack any apparent cause.
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http://dx.doi.org/10.1016/j.braindev.2007.12.008DOI Listing
August 2008

Polydactyly with ectodermal defect, osteopenia, and mental delay.

J Child Neurol 2008 Jun 8;23(6):683-9. Epub 2008 Jan 8.

Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Pediatrics, Policlinico Le Scotte, University of Siena, Siena, Italy.

Five members from 3 generations, including a 35-year-old woman and her 2 sons, both mentally impaired to a different degree, were studied in a tertiary care hospital. Anamnestic, clinical, neurological, and radiological evaluations were used to describe phenotypes. A and B postaxial polydactyly, transmitted likely as autosomal dominant, was associated with an extensive variability of phenotypic features: (1) cutaneous syndactyly, (2) nail-teeth dysplasia, (3) osteopenia, and (4) mental delay. The likelihood that the constellation of observations we report here is caused by mutation of a single gene that subsequently affects multiple physiological activities, although fascinating, remains to be proven. Instead, we hypothesize that it likely develops as a contiguous gene syndrome.
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http://dx.doi.org/10.1177/0883073807309778DOI Listing
June 2008

Focal cortical dysplasia type 1b as a cause of severe epilepsy with multiple independent spike foci.

Brain Dev 2008 Jan 20;30(1):53-8. Epub 2007 Jun 20.

Department of Pediatrics, Section of Pediatric Neurology, Policlinico Le Scotte, University of Siena, Siena, Italy.

To investigate the clinical picture, the neurophysiological pattern, and neuropathological features of a young woman with severe drug-resistant epilepsy of unknown cause. We used the patient's clinical records from the age of 2 to 20years including neurophysiological patterns recorded via both scalp and cortex electrodes and results of studies conducted on the brain neuropathological specimen. The patient, with severe mental/psychomotor retardation, suffered from severe epilepsy from an early age, characterized by daily seizures of multiple types (atypical absences, tonic, and complex partial seizures), high frequency, and intractability. The neurophysiological pattern indicated multiple independent spike foci (SE-MISF). When she was 16, a vagal nerve stimulator was implanted without success. Neither neuroimaging (brain MRI and ictal SPECT) nor surface EEGs identified unique loci of seizure onset, establishing her as a candidate for a complete callosotomy. When the patient was 19, before the callosotomy, invasive EEG (i.e., electrocorticography) using just a few electrodes in different lobes showed the presence of a distinctive pattern. The surgical specimen, taken very close to one of the activity sites, showed architectural abnormalities and neurons that were giant or immature but not dysmorphic, indicative of focal cortical dysplasia (FCD) type 1b. Twelve months after the callosotomy, according to the Engel score, the patient exhibited a large improvement in quality of life, without permanent complications from the interhemispheric disconnection. (1) Hidden FCD type 1b could represent a missing diagnosis in patients with SE-MISF in the absence of other causes for their seizures. (2) Complete callosotomy can be efficacious in patients with SE-MISF with hidden FCD type 1b.
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http://dx.doi.org/10.1016/j.braindev.2007.05.010DOI Listing
January 2008

Hypohidrotic ectodermal dysplasia and intrathoracic neuroblastoma.

Pediatr Dermatol 2007 May-Jun;24(3):267-71

Department of Pediatrics, Section of Pediatric Neurology, Policlinico Le Scotte, University of Siena, Siena, Italy.

We report a 6-year-old girl with a subtle form of hypohidrotic ectodermal dysplasia and a phenotype consisting of curly hair, a round face, a stocky build, and obesity, which was associated with intrathoracic neuroblastoma. Although this new association could be a chance occurrence, its description may alert physicians to look for similar combinations and report these, as it may lead to better syndrome delineation, and patient care.
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http://dx.doi.org/10.1111/j.1525-1470.2007.00400.xDOI Listing
July 2007

Kabuki syndrome with trichrome vitiligo, ectodermal defect and hypogammaglobulinemia A and G.

Brain Dev 2007 Jul 14;29(6):373-6. Epub 2006 Dec 14.

Department of Pediatrics, Section of Neurology, Policlinico Le Scotte, University of Siena, Siena, Italy.

We report a unique combination of symptoms in a case of Kabuki syndrome (KS), a multiple malformation/mental retardation syndrome that has a prevalence of 1:32,000 to 1:86,000. The patient was a mentally delayed 12-year-old male with trichrome vitiligo, ectodermal defect, and hypogammaglobulinemia A and G. This unique combination of signs, described here for the first time, indicates that KS comprises multiple deficits that affect not only the brain, but ectoderm-derived structures and the immune system as well. Our report may provide important clues for understanding the pathogenesis of the KS.
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http://dx.doi.org/10.1016/j.braindev.2006.11.004DOI Listing
July 2007

Betamethasone and improvement of neurological symptoms in ataxia-telangiectasia.

Arch Neurol 2006 Oct;63(10):1479-82

Department of Pediatrics, University of Siena, Siena, Italy.

Background: To our knowledge, there have been no reports on the control of central nervous system symptoms in patients with ataxia-telangiectasia.

Objective: To preliminarily determine the effectiveness of corticosteroid therapy on the central nervous system symptoms of a child with ataxia-telangiectasia in whom neurological signs improved when, occasionally, he was given betamethasone to treat asthmatic bronchitis attacks.

Design: Case report.

Setting: Tertiary care hospital. Patient A 3-year-old boy with the classic hallmarks and a proved molecular diagnosis of ataxia-telangiectasia.

Interventions: We used betamethasone, 0.1 mg/kg per 24 hours, divided every 12 hours, for 4 weeks to preliminarily determine its effectiveness on the child's central nervous system symptoms and its safety. Methylprednisolone, 2 mg/kg per 24 hours, divided every 12 hours, was then given in an attempt to perform a long-term treatment.

Results: There were improvements in the child's neurological symptoms 2 or 3 days after the beginning of the drug treatment. After 2 weeks of treatment, the improvement was dramatic: the disturbance of stance and gait was clearly reduced, and the control of the head and neck had increased, as had control of skilled movements. At 4 weeks of treatment, adverse effects mainly included increased appetite and body weight and moon face. No beneficial effect was obtained when, after 4 weeks, betamethasone was replaced with methylprednisolone. Six months later, without therapy, the child continued to experience severe signs of central nervous system impairment.

Conclusion: Controlled studies to better understand the most appropriate drug and therapeutic schedule are required.
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http://dx.doi.org/10.1001/archneur.63.10.1479DOI Listing
October 2006

Familial robertsonian 13;14 translocation with mental retardation and epilepsy.

J Child Neurol 2006 Jun;21(6):531-3

Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Pediatrics, Policlinico Le Scotte, University of Siena, Siena, Italy.

Familial reports of a robertsonian translocation in more than two generations are rare. We report three generations (a daughter, the mother, and the mother's father) with a heterozygous, balanced robertsonian translocation t(13;14)(q11;q11). Central nervous system disease was present, but differentially expressed, in generations I and III. The daughter presented with mental delay and epilepsy, and the mother was apparently healthy, whereas the mother's father was again symptomatic, with borderline intelligence. Fluorescent in situ hybridization analysis was performed to exclude a loss or gain of chromosomal material. No uniparental disomy was present. We concluded that genetic counseling in the presence of this rearrangement was extremely difficult, independent of the affected parent being symptomatic or asymptomatic.
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http://dx.doi.org/10.1177/08830738060210060701DOI Listing
June 2006

D-bifunctional protein deficiency associated with drug resistant infantile spasms.

Brain Dev 2007 Jan 21;29(1):51-4. Epub 2006 Aug 21.

Department of Pediatrics, Section of Pediatric Neurology, Policlinico Le Scotte, University of Siena, Siena, Italy.

Peroxisomal disorders appear with a frequency of about 1:5000 in newborns. Peroxisomal D-bifunctional protein (D-BP), encoded by the HSD17B4 gene (gene ID: 3294; locus tag: HGNC:5213, chromosome 5q2; official symbol: HSD17B4; name: hydroxysteroid (17-beta) dehydrogenase; gene type: protein coding) (OMIM *601860), comprises an 80 kDa multifunctional enzyme involved in peroxisomal beta-oxidation of certain fatty acids and the synthesis of bile acids. Its deficiency causes a very severe, Zellweger-like clinical phenotype and most patients die within the first year of life. In this paper, we report a case of D-BP deficiency in a patient with two heterozygous trinucleotide deletions (233_235 del AAG and 824_826 del AGA) in the HSD17B4 gene. The patient suffered from a peculiar epileptic phenotype (i.e. a West syndrome with a "modified hypsarrhythmic pattern"--Hrachovy et al. Epilepsia 1984;25:317-25), clinically appearing as drug-resistant asymmetric spasms. Vigabatrin seemed the most effective among the antiepileptic drugs. The patient died at the age of 23 months owing to respiratory complications. To date, only a few patients with D-BP deficiency have been described in the literature. This case adds to our knowledge of the clinical presentation of bifunctional protein deficiency.
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http://dx.doi.org/10.1016/j.braindev.2006.06.004DOI Listing
January 2007

Surgery removes EEG abnormalities in patients with Chiari type I malformation and poor CSF flow.

Clin Neurophysiol 2006 May 20;117(5):959-63. Epub 2006 Mar 20.

Section of Pediatric Neurology, Department of Pediatrics, University of Siena, Policlinico Le Scotte, Viale Bracci, 53100 Siena, Italy.

Objective: To study the outcome of EEG from patients with Chiari I malformations and nonspecific EEG abnormalities, after posterior fossa decompression and CSF flow normalization.

Methods: Three 'apparently asymptomatic' children who had been diagnosed with Arnold-Chiari type 1 EEG abnormalities and who exhibited (a) a wide range of abnormalities according to common anatomical Chiari MRI classifications (Elster AD, Chen MY. Chiari I malformations: clinical and radiologic reappraisal. Radiology 1992;183:347-53), (b) a lack of specific, clinical signs of increased intracranial pressure, and (c) apparently unrelated, EEG-nonspecific abnormalities (focal intermittent rhythmic delta activity (IRDA)--solely in patients 1 and 3, and with focal IRDA plus spikes and spike waves of high voltage in patient 2). Standard EEGs were recorded before surgery and within one month of surgery, which was performed in conjunction with intraoperative echo-Doppler ultrasonography to control CSF flow. Subsequent EEGs and clinical follow-ups were performed within 6-12 months of surgery.

Results: In all patients, intraoperative echo-Doppler ultrasonographic control demonstrated poor CSF flow, which was completely restored by posterior fossa decompression. In all patients, the EEG abnormalities disappeared within one month of surgery and the EEGs were normal at follow-up.

Conclusions: A new CNS symptom, identified as focal IRDA alone or focal IRDA plus spikes and spike waves of high voltage in the EEG, seems to be associated with poor CSF flow in 'apparently asymptomatic' patients with Chiari type I malformations.

Significance: The identified, paroxysmal EEG abnormalities should be interpreted as an indirect sign of subtle CNS distress.
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http://dx.doi.org/10.1016/j.clinph.2006.01.019DOI Listing
May 2006

A child with vestibular neuritis. is adenovirus implicated?

Brain Dev 2006 Jul 28;28(6):410-2. Epub 2006 Feb 28.

Department of Pediatrics, Section of Pediatric Neurology, Policlinico Le Scotte, University of Siena, Siena, Italy.

Vertigo in children is relatively under examined in the literature. Among its causes, vestibular neuritis (VN) represents only 2% of cases, with its etiology remaining unknown. We report for the first time a 4-year-old boy with vestibular neuritis and serological results compatible with adenoviral infection. Serological diagnosis was performed on the basis of a rise and consequent normalization of complement fixation (CF) titers of the plasma antibodies. Although we were not able to detect exactly when the infection started, we were able to detect an increased level of adenovirus antibodies by CF titers, followed by a decrease (i.e. 1/16, then 1/8, then <1/4) during the recovery. This is typical of a resolving infection. Furthermore, that this increase in antibodies was specific to an adenovirus infection was suggested by the observation that we did not detect increases in antibodies to other common viruses (i.e. herpes simplex and zoster viruses, Epstein-Barr virus, cytomegalovirus, influenza and parainfluenza viruses). This allows us to exclude the chance of nonspecific antibody activation. We concluded that, although our data do not formally demonstrate an involvement of adenovirus in VN, they suggest such an involvement. This may be of interest, given that a viral etiology for VN has been proposed but not definitively proven.
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http://dx.doi.org/10.1016/j.braindev.2005.12.001DOI Listing
July 2006

Classical lissencephaly associated with dolichocephaly, hair and nail defect.

Brain Dev 2006 Jul 20;28(6):392-4. Epub 2005 Dec 20.

Department of Medicine and Aging, Section of Obstetric and Gynecology, Nuovo Policlinico, University 'G. D'Annunzio', Medical School, University of Chieti, Chieti, Italy.

We report on an 1-day-old boy with classical lissencephaly (grade 1, according to Kato and Dobyns, 2003) associated with an extended phenotype, including dolichocephaly, and hair and nail defects. The diagnosis of lissencephaly was made in utero, allowing the rapid characterization of the phenotype at birth. Because previously reported cases were not associated with the features described in our proband, they might represent a newly identified condition.
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http://dx.doi.org/10.1016/j.braindev.2005.10.011DOI Listing
July 2006

Global developmental delay, osteopenia and ectodermal defect: a new syndrome.

Brain Dev 2006 Apr 20;28(3):155-61. Epub 2005 Dec 20.

Department of Paediatrics, Obstetrics and Reproductive Medicine, Section of Paediatrics, Policlinico Le Scotte, University of Siena, Siena, Italy.

Unlabelled: Global developmental delay is a serious social problem. It is often unrecognized and the phenotypes are inadequately studied. To investigate the phenotypes of children with aspecific central nervous system (CNS) impairment (poor speech, maladaptive behavioral symptoms such as temper tantrums, aggressiveness, poor concentration and attention, impulsiveness, and mental retardation).

Setting: Tertiary care hospital.

Patients: Three children (two male siblings, and one unrelated girl).

Methods: We used the results from clinical neurological evaluations; imaging and electrodiagnostic studies; metabolic and genetic tests; skin biopsies and bone mineral densitometry. All three children suffered from (A) global developmental delay, (B) osteopenia, and (C) identical skin defects. The skin ultrastructural abnormalities were abnormal keratin differentiation, consisting of hyperkeratosis and granular layer thickening; sweat gland abnormalities, consisting of focal, cytoplasmic clear changes in eccrine secretory cells; and melanocyte abnormalities, with both morphological changes (reduced number and size without evident dendritic processes), and functional changes (defects in the migration of melanosomes in the keratinocytes). These patients present a previously unrecognized syndrome. We retain useful to report this new association, to be recognized, in the next future, as a specific key-sign of a well-defined genetic defect.
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http://dx.doi.org/10.1016/j.braindev.2005.06.011DOI Listing
April 2006

Myoclonic encephalopathy in the CDKL5 gene mutation.

Clin Neurophysiol 2006 Jan 2;117(1):223-7. Epub 2005 Dec 2.

Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Pediatrics, Policlinico Le Scotte, University of Siena, Siena, Italy.

Objective: Epilepsy with mutation of the CDKL5 gene causes early seizures and is a variant of Rett syndrome (MIM (312750), which is reported typically as infantile spasms. The purpose of this study was to analyze the epileptic histories and EEGs of patients with the CDKL5 mutation.

Methods: We reviewed the epilepsy histories and electroclinical analyses of three girls aged 9.5, 7.4, and 9.4 years, each with a mutation of the CDKL5 gene.

Results: We revealed the presence of an encephalopathy that started by 1.5 months of age. At first, seizures involved tonic spasms or complex partial seizures, and were complicated by the later appearance of complex partial, tonic, and unexpectedly, myoclonic seizures. This form of epilepsy was drug resistant. Routine and prolonged video EEGs both displayed a homogeneous electroclinical pattern consisting of (a) unique background with diffuse high voltage sharp waves of 6-7 Hz, and absence of the typical rhythmic frontal-central theta activity present in Rett syndrome; (b) unique awake and sleep background, with diffuse, high voltage, continuous sharp waves with multifocal and diffuse spikes; (c) rhythmic, diffuse, 15 Hz activity accompanied clinically by tonic seizures; (d) intercritical pattern with pseudoperiodic, diffuse, sharp waves or pseudoperiodic, diffuse spike and polyspike or wave discharges; and (e) diffuse, spike, polyspike and wave discharges accompanied by massive or focal myoclonias or both.

Conclusions: Patients with the CDKL5 mutation have an early onset, epileptic encephalopathy in infancy that evolves into myoclonic seizures in childhood with a unique EEG pattern.

Significance: Recognizing this type of encephalopathy could be useful in prompting clinicians to proceed further with their diagnostic work in patients not fitting the criteria of classical Rett syndrome.
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http://dx.doi.org/10.1016/j.clinph.2005.09.008DOI Listing
January 2006

Combined treatment with vigabatrin and topiramate in West syndrome.

J Child Neurol 2004 May;19(5):385-6

Department of Pediatrics, Obstetric and Reproductive Medicine, Policlinico Le Scotte, University of Siena, Italy.

The clinical and electroencephalographic (EEG) response to combined therapy with vigabatrin and topiramate was evaluated in five patients ages 7 to 15 months affected by West syndrome in an open-label trial. Four patients had cryptogenic and one patient had symptomatic (tuberous sclerosis) West syndrome. In cryptogenic patients who failed to respond to pyridoxine, vigabatrin was titrated to 80 to 100 mg/kg. Because control of infantile spasms or an EEG improvement was not obtained with vigabatrin treatment, topiramate was added (3-3.8 mg/kg/day). In all patients, the combined therapy with topiramate and vigabatrin achieved a rapid and complete normalization of infantile spasms, and in three patients with cryptogenic West syndrome, the EEG also became normal. In only one patient, transient anorexia was observed. This drug combination led to rapid neurodevelopmental normalization in cryptogenic patients. The results are promising and justify more trials in larger numbers of children with West syndrome.
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http://dx.doi.org/10.1177/088307380401900512DOI Listing
May 2004

Hereditary neuronal intranuclear inclusion disease with autonomic failure and cerebellar degeneration.

Arch Neurol 2002 Aug;59(8):1319-26

Department of Pediatrics, Obstetrics, and Reproductive Medicine, Section of Pediatrics, Policlinico Le Scotte, University of Siena, Siena, Italy.

Background: Neuronal intranuclear inclusion disease (NIID), a multiple-system degeneration, occurs usually as a sporadic disorder with onset in childhood. The disease has been found in monozygotic twins and in siblings. In 2 previously described families, the disorder has affected 2 generations.

Objective: To investigate the clinical, anatomical, and electrophysiological characteristics of NIID that affect the central nervous system and the central and peripheral components of the autonomic nervous system in 2 successive generations of a family.

Design: Case report.

Setting: Tertiary care hospital.

Patients: A 53-year old woman and her sons, aged 28 and 25 years. Symptoms began in childhood in 2 of the 3 cases, and consisted of urinary and fecal incontinence, erectile dysfunction in the men, and recurrent orthostatic hypotension.

Methods: We used results of clinical neurological evaluations; cranial magnetic resonance imaging; skeletal muscle and sphincter electromyography (EMG); peripheral nerve conduction and bulbocavernosus reflex studies; autonomic function tests; brainstem, visual, somatosensory, and motor evoked potentials; auditory and vestibular testing; metabolic and molecular genetic testing; and muscle and rectal biopsy with immunohistochemistry.

Results: We found variable degrees of ocular dysmetria in 2 cases, ataxic dysarthria and limb ataxia in 1, and hyperreflexia in 2. Magnetic resonance imaging revealed cerebellar atrophy in all 3 cases and diffuse cerebral cortical atrophy in 1. Results of peripheral nerve conduction studies were normal. Sphincter EMG findings were abnormal in 2 of the 3 cases, and results of autonomic function tests were abnormal in the same 2. The EMG in 1 case revealed a chronic neurogenic pattern in the distal limb muscles. Metabolic and molecular genetic testing revealed no abnormal findings. Results of the muscle biopsy were negative, but results of the rectal biopsy revealed eosinophilic ubiquitinated intranuclear inclusions in neurons.

Conclusion: Transmission of NIID in 2 generations presenting with autonomic failure and cerebellar ataxia was hereditary.
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http://dx.doi.org/10.1001/archneur.59.8.1319DOI Listing
August 2002