Publications by authors named "Salvatore Grosso"

115 Publications

Case Report: A Case of Glioblastoma in a Patient With Haberland Syndrome.

Front Pediatr 2021 8;9:648717. Epub 2021 Mar 8.

Department of Molecular Medicine and Development, University of Siena, Siena, Italy.

Haberland syndrome or encephalocraniocutaneous lipomatosis is a rare ectomesodermal dysgenesis defined by the triad including ocular, skin, and central nervous system involvement, which is commonly unilateral. This disorder is attributed to a post-zygotic mutation responsible for a neural tube and neural crest dysgenesis. We report the case of a 15-year-old female with Haberland syndrome with pharmacoresistant epilepsy who developed a World Health Organization-grade IV glioblastoma. This is the first case of pediatric glioblastoma associated with Haberland syndrome. The previously reported pediatric cases included benign brain tumors. To our knowledge, this is the fifth case of brain tumor associated with encephalocraniocutaneous lipomatosis and the second case of glioblastoma associated with this syndrome. The hypothesis that Haberland syndrome is associated with an increased risk of tumor development is intriguing, although the rarity of the condition is nowadays preventing us from drawing definitive conclusions about this potential link between the two entities. Further studies are needed to establish the real relationship between encephalocraniocutaneous lipomatosis and the risk of brain tumors.
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http://dx.doi.org/10.3389/fped.2021.648717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982648PMC
March 2021

Appropriate use of generic and branded antiseizure medications in epilepsy: Updated recommendations from the Italian League Against Epilepsy (LICE).

Epilepsy Behav 2021 Mar 10;116:107804. Epub 2021 Feb 10.

Science of Health Department, School of Medicine, University of Catanzaro, Italy. Electronic address:

Generic drugs are increasingly used to treat many diseases including epilepsy. The growing importance of generic antiseizure medications (ASMs) has led the ASMs commission of the Italian League Against Epilepsy (LICE) to review current evidence in the literature about efficacy and safety of these products. Recommendations from other scientific organizations have also been considered to provide an update of the LICE position about their utilization (List of Recommendations). Compared with the previous literature review, randomized controlled trials assessing bioequivalence among branded drugs and generics are currently available. Although some contrasting results have been reported, brand-to-generic switching was effective and tolerable in real-life settings, with similar adverse event ratios. Based on these findings, LICE concluded that, conforming to the rigorous regulation of USA and EU markets, generic ASMs are not inferior to the respective branded, providing a cost advantage for patients starting or replacing monotherapy or add-on, and for those with incomplete seizure control. Branded-to-generic (and vice versa) switching is not recommended (although applicable) during seizure remission, as well as the generic-to-other generic switching. Other recommendations focus on the appropriateness of therapeutic drug monitoring (TDM) when switching is required, paying attention to avoiding the erroneous switch between modified and immediate-release formulations during dispensation. Finally, to support patients' compliance, they should be assured of generics' safety and efficacy and carefully informed with practical advice, particularly when the switching is associated with aspect modifications (e.g. color and shape changes) of the pill or the packaging.
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http://dx.doi.org/10.1016/j.yebeh.2021.107804DOI Listing
March 2021

Cyclic Vomiting Syndrome in Children.

Front Neurol 2020 2;11:583425. Epub 2020 Nov 2.

Chair of Pediatrics, Department of Neuroscience, Mental Health and Sense Organs (NESMOS), Faculty of Medicine & Psychology, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.

Cyclic Vomiting Syndrome (CVS) is an underdiagnosed episodic syndrome characterized by frequent hospitalizations, multiple comorbidities, and poor quality of life. It is often misdiagnosed due to the unappreciated pattern of recurrence and lack of confirmatory testing. CVS mainly occurs in pre-school or early school-age, but infants and elderly onset have been also described. The etiopathogenesis is largely unknown, but it is likely to be multifactorial. Recent evidence suggests that aberrant brain-gut pathways, mitochondrial enzymopathies, gastrointestinal motility disorders, calcium channel abnormalities, and hyperactivity of the hypothalamic-pituitary-adrenal axis in response to a triggering environmental stimulus are involved. CVS is characterized by acute, stereotyped and recurrent episodes of intense nausea and incoercible vomiting with predictable periodicity and return to baseline health between episodes. A distinction with other differential diagnoses is a challenge for clinicians. Although extensive and invasive investigations should be avoided, baseline testing toward identifying organic causes is recommended in all children with CVS. The management of CVS requires an individually tailored therapy. Management of acute phase is mainly based on supportive and symptomatic care. Early intervention with abortive agents during the brief prodromal phase can be used to attempt to terminate the attack. During the interictal period, non-pharmacologic measures as lifestyle changes and the use of reassurance and anticipatory guidance seem to be effective as a preventive treatment. The indication for prophylactic pharmacotherapy depends on attack intensity and severity, the impairment of the QoL and if attack treatments are ineffective or cause side effects. When children remain refractory to acute or prophylactic treatment, or the episode differs from previous ones, the clinician should consider the possibility of an underlying disease and further mono- or combination therapy and psychotherapy can be guided by accompanying comorbidities and specific sub-phenotype. This review was developed by a joint task force of the Italian Society of Pediatric Gastroenterology Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP) to identify relevant current issues and to propose future research directions on pediatric CVS.
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http://dx.doi.org/10.3389/fneur.2020.583425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667239PMC
November 2020

Coffin-Siris syndrome and epilepsy.

Neurol Sci 2021 Feb 2;42(2):727-729. Epub 2020 Oct 2.

Dipartimento di Medicina Molecolare e dello Sviluppo, Universita' degli Studi di Siena, viale Bracci 16, 53100, Siena, Italy.

Coffin-Siris syndrome is a rare genetic disorder defined by the presence of particular facial traits, congenital malformations, intellectual disability, and speech impairment. Epilepsy in Coffin-Siris syndrome has only occasionally been reported, and its features are poorly defined. We provide a detailed description of the clinical and instrumental findings of three patients with Coffin-Siris syndrome and epilepsy. The clinical diagnosis in our patients was confirmed by molecular analysis, which identified the presence of de novo mutations of ARID1B and SMARCB1 genes, in two patients and one patient, respectively. All the patients presented with epilepsy, with a mean age of seizure onset of 5.5 years. Seizures were brief and had a focal onset with secondary generalization. Electroencephalographic recording documented a unilateral, and less commonly bilateral, paroxysmal activity in the temporal, parietal, and occipital regions. Clinical response to anticonvulsive therapy was satisfactory, with a low rate of seizure recurrence. Our case series contributes to delineate the phenotype of Coffin-Siris syndrome. We wish this report could pave the way for further studies that will better define the prevalence and clinical manifestations of epilepsy in this rare syndrome.
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http://dx.doi.org/10.1007/s10072-020-04782-yDOI Listing
February 2021

Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF- Receptor-Associated Periodic Syndrome (TRAPS): A Series of 80 Cases from the AIDA Network.

Mediators Inflamm 2020 7;2020:8562485. Epub 2020 Aug 7.

Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

This study explores demographic, clinical, and therapeutic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a cohort of 80 patients recruited from 19 Italian referral Centers. Patients' data were collected retrospectively and then analyzed according to age groups (disease onset before or after 16 years) and genotype (high penetrance (HP) and low penetrance (LP) gene variants). Pediatric- and adult-onset were reported, respectively, in 44 and 36 patients; HP and LP variants were found, respectively, in 32 and 44 cases. A positive family history for recurrent fever was reported more frequently in the pediatric group than in the adult group ( < 0.05). With reference to clinical features during attacks, pericarditis and myalgia were reported more frequently in the context of adult-onset disease than in the pediatric age (with < 0.01 and < 0.05, respectively), while abdominal pain was present in 84% of children and in 25% of adults ( < 0.01). Abdominal pain was significantly associated also to the presence of HP mutations ( < 0.01), while oral aphthosis was more frequently found in the LP variant group ( < 0.05). Systemic amyloidosis occurred in 25% of subjects carrying HP variants. As concerns laboratory features, HP mutations were significantly associated to higher ESR values ( < 0.01) and to the persistence of steadily elevated inflammatory markers during asymptomatic periods ( < 0.05). The presence of mutations involving a cysteine residue, abdominal pain, and lymphadenopathy during flares significantly correlated with the risk of developing amyloidosis and renal impairment. Conversely, the administration of colchicine negatively correlated to the development of pathologic proteinuria ( < 0.05). Both NSAIDs and colchicine were used as monotherapy more frequently in the LP group compared to the HP group ( < 0.01). Biologic agents were prescribed to 49 (61%) patients; R92Q subjects were more frequently on NSAIDs monotherapy than other patients ( < 0.01); nevertheless, they required biologic therapy in 53.1% of cases. At disease onset, the latest classification criteria for TRAPS were fulfilled by 64/80 (80%) patients (clinical plus genetic items) and 46/80 (57.5%) patients (clinical items only). No statistically significant differences were found in the sensitivity of the classification criteria according to age at onset and according to genotype ( < 0.05). This study describes one of the widest cohorts of TRAPS patients in the literature, suggesting that the clinical expression of this syndrome is more influenced by the penetrance of the mutation rather than by the age at onset itself. Given the high phenotypic heterogeneity of the disease, a definite diagnosis should rely on both accurate working clinical assessment and complementary genotype.
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http://dx.doi.org/10.1155/2020/8562485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428902PMC
August 2020

Characteristics of Acute Nystagmus in the Pediatric Emergency Department.

Pediatrics 2020 08;146(2)

Pediatric Emergency Department and.

Objectives: Acute nystagmus (AN) is an uncommon neurologic sign in children presenting to pediatric emergency departments. We described the epidemiology, clinical features, and underlying causes of AN in a large cohort of children, aiming at identifying features associated with higher risk of severe underlying urgent conditions (UCs).

Methods: Clinical records of all patients aged 0 to 18 years presenting for AN to the pediatric emergency departments of 9 Italian hospitals in an 8-year period were retrospectively reviewed. Clinical and demographic features and the underlying causes were analyzed. A logistic regression model was applied to detect predictive variables associated with a higher risk of UCs.

Results: A total of 206 patients with AN were included (male-to-female ratio: 1.01; mean age: 8 years 11 months). The most frequently associated symptoms were headache (43.2%) and vertigo (42.2%). Ataxia (17.5%) and strabismus (13.1%) were the most common neurologic signs. Migraine (25.7%) and vestibular disorders (14.1%) were the most common causes of AN. Idiopathic infantile nystagmus was the most common cause in infants <1 year of age. UCs accounted for 18.9% of all cases, mostly represented by brain tumors (8.3%). Accordant with the logistic model, cranial nerve deficits, ataxia, or strabismus were strongly associated with an underlying UC. Presence of vertigo or attribution of a nonurgent triage code was associated with a reduced risk of UCs.

Conclusions: AN should be considered an alarming finding in children given the risk of severe UCs. Cranial nerve palsy, ataxia, and strabismus should be considered red flags during the assessment of a child with AN.
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http://dx.doi.org/10.1542/peds.2020-0484DOI Listing
August 2020

The current status of biological treatment for uveitis.

Expert Rev Clin Immunol 2020 08 1;16(8):787-811. Epub 2020 Aug 1.

Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease, and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena, Italy.

Introduction: Noninfectious uveitis represents one of the leading causes of blindness in developed Countries, compromising patients' quality of life and social functioning. The main treatment goals are the control of ocular inflammation, to avert and treat sight-threatening complications, thus preserving and/or restoring visual function.

Areas Covered: This manuscript deals with systemic therapy with biologic drugs for noninfectious uveitis. An extensive literature search in the MEDLINE database (via PubMed) has been performed up to June 2020. The major classes of biologic molecules employed in ocular inflammatory diseases have been reviewed, focusing on TNF inhibitors, IL-1, IL-6, IL-17, IL-23 inhibitors, interferons, rituximab, and abatacept efficacy and safety. An overview of most recent developments in the field has been provided as well, with reference to the experience with JAK inhibitors and with biosimilar drugs.

Expert Opinion: The development of the concept of targeted therapy and the subsequent introduction of biologic molecules in clinical practice have revolutionized the prognosis of uveitis. The target of a rapid and sustained steroid-free remission of ocular inflammation should be pursued for all patients early in the disease course, in order to have a better chance to improve the final visual outcome.
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http://dx.doi.org/10.1080/1744666X.2020.1798230DOI Listing
August 2020

Focus on progressive myoclonic epilepsy in Berardinelli-Seip syndrome.

Neurol Sci 2020 Nov 21;41(11):3345-3348. Epub 2020 May 21.

Dipartimento di Medicina Molecolare e dello Sviluppo, Universita' degli Studi di Siena, viale Bracci 16, 53100, Siena, Italy.

Introduction: Berardinelli-Seip syndrome or congenital generalized lipodystrophy type 2 is a rare genetic disorder characterized by selective loss of subcutaneous adipose tissue associated with peripheral insulin resistance and its complications. Nonprogressive mental retardation, dystonia, ataxia, and pyramidal signs are commonly present, whereas epilepsy has only occasionally been observed.

Case Report: We report the case of two sisters, 11 and 18 years old respectively, with an overlapping clinical phenotype compatible with Berardinelli-Seip syndrome and progressive myoclonic epilepsy. Molecular analysis identified an autosomal recessive c.1048C > t;(p(Arg350*)) pathogenic mutation of exon 8 of the BSCL2 gene, which was present in a homozygous state in both patients.

Conclusions: Our paper contributes to further delineate a complex phenotype associated with BSCL2 mutation, underlining how seipin has a central and partially still unknown role that goes beyond adipose tissue metabolism, with a prominent involvement in central nervous system pathology.
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http://dx.doi.org/10.1007/s10072-020-04418-1DOI Listing
November 2020

Association of celiac disease in patients with multiple sclerosis in Tuscany.

Rev Esp Enferm Dig 2020 Jun;112(6):474-476

Clinical Pediatrics, Department of Pediatrics , University of Siena.

Background and study purpose: to describe the comorbidity of celiac disease among a large cohort of multiple sclerosis patients in Tuscany.

Methods: the association of celiac disease among multiple sclerosis adult patients (n=2050) was retrospectively evaluated.

Results: 13 patients were diagnosed with celiac disease, the female:male ratio was 3.3:1 and the median age at diagnosis was 34.2 years (SD 13). Seventy-seven per cent of subjects complained about gastrointestinal symptoms. IgA anti- transglutaminase was positive in 85 % of cases and there was 70 % of villous atrophy.

Conclusions: the frequency of celiac disease among multiple sclerosis patients examined was lower than in the general population, 0.6 % vs 1 %)(p = 0.65).
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http://dx.doi.org/10.17235/reed.2020.6123/2018DOI Listing
June 2020

17p13.3 microdeletion including YWHAE and CRK genes: towards a clinical characterization.

Neurol Sci 2020 Aug 22;41(8):2259-2262. Epub 2020 Apr 22.

Dipartimento di Medicina Molecolare e dello Sviluppo, Universita' degli Studi di Siena, viale Bracci 16, 53100, Siena, Italy.

Introduction: The short arm of chromosome 17 is characterized by a high density of low copy repeats, creating the opportunity for non-allelic homologous recombination to occur. Microdeletions of the 17p13.3 region are responsible for neuronal migration disorders including isolated lissencephaly sequence and Miller-Dieker syndrome.

Case Report: We describe the case of a 4-year and 2-month-old female with peculiar somatic traits and neurodevelopmental delay. At the age of 6 months, she started to present with infantile spasms syndrome; therefore, we administered vigabatrin followed by two cycles of adrenocorticotropic hormone, with good response. The coexistence of epileptic activity, neuropsychological delay, brain imaging abnormalities, and peculiar somatic features oriented us towards the hypothesis of a genetic etiology that could explain her clinical picture. Array CGH identified a 730 Kb deletion in the p13.3 region of the short arm of chromosome 17 including eleven genes, among these are YWHAE and CRK.

Discussion: Microdeletions of the 17p13.3 region involving only YWHAE and CRK, sparing PAFAH1B1, result in neurodevelopmental delay, growth retardation, craniofacial dysmorphisms, and mild structural brain abnormalities. Differently from the previously described patients carrying YWHAE and CRK deletions, the main complaint of our patient was represented by seizures. The absence of clear neuronal migration defects and mutations of the PAFAH1B1 gene in our patient underlines the central role of additional genes located in the 17p13.3 chromosomal region in the pathogenesis of epilepsy and helps to expand the phenotype of 17p13.3 microdeletion syndrome.
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http://dx.doi.org/10.1007/s10072-020-04424-3DOI Listing
August 2020

An Unusual Case of Hypoproteinemia in Childhood: Keep in Mind Trichobezoar.

Front Pediatr 2020 4;8:82. Epub 2020 Mar 4.

Pediatric Section, Department of Health Sciences, Meyer Children's University Hospital, University of Florence, Florence, Italy.

Protein-losing enteropathy (PLE) is a rare condition characterized by protein loss through the gastrointestinal tract, leading to hypo-proteinemia. Patients may be asymptomatic or present with variety of complications of hypoproteinemia (e.g., oedema, ascites, pleural, and cardial effusions). We describe a case report of a young girl suffering from behavioral disorder since childhood who presented with generalized oedema, hypoproteinaemia, and microcytic hypochromic anemia. In addition, the girl had an intervention for jejunal atresia and intestinal malrotation in her past medical history. Upper gastrointestinal endoscopy revealed a trichobezoar extending from stomach into the small bowel, thus classified as Rapunzel Syndrome (RS), causing mechanical obstruction of intestinal lumen and intestinal lymphatic drainage resulting in a protein-losing enteropathy (PLE). Trichobezoar was successfully removed by a surgical laparotomy resulting in resolution of symptoms and normalization of biochemical parameters. Possibly, previous surgery might have had an influence on intestinal dysmotility and trichobezoar formation. PLE is a very rare presenting symptom of RS, developing as result of intestinal obstruction caused by large trichobezoars. RS has to be considered in patients, especially adolescents, suffering from behavior disorder as trichotillomania and trichophagia. Surgical removal and nutritional supplementation are the gold treatment of large trichobezoar.
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http://dx.doi.org/10.3389/fped.2020.00082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065258PMC
March 2020

Comparison of Early vs. Delayed Anakinra Treatment in Patients With Adult Onset Still's Disease and Effect on Clinical and Laboratory Outcomes.

Front Med (Lausanne) 2020 21;7:42. Epub 2020 Feb 21.

Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

Aim of this study was to search for any difference in the outcome of patients with adult onset Still's disease (AOSD) treated with anakinra (ANK) in relation with the interval between disease onset and the start of anti-interleukin(IL)-1 treatment and according with the different lines of ANK treatment. One hundred and forty-one AOSD patients treated with ANK have been retrospectively assessed. Statistically significant differences ( < 0.05) were analyzed in the frequency of ANK effectiveness, primary or secondary inefficacy to ANK and rate of resolution of clinical and laboratory AOSD manifestations after 3, 6, and 12 months since ANK treatment according with different lines of treatment and different times between AOSD onset and start of ANK. No significant differences were identified in the ANK effectiveness and frequency of primary or secondary inefficacy for patients starting ANK within 6 months ( = 0.19, = 0.14, and = 0.81, respectively) or 12 months ( = 0.37, = 0.23, and = 0.81, respectively) since AOSD onset compared with patients starting ANK thereafter; no significant differences were identified in ANK effectiveness and primary or secondary inefficacy according with different lines of ANK treatment ( = 0.06, = 0.19, and = 0.13, respectively). Patients starting ANK within 6 and 12 months since AOSD onset showed a significantly quicker decrease of erythrocyte sedimentation rate and C-reactive protein than observed among patients undergoing ANK treatment after 6 and 12 months. The number of swollen joints at the 3 month follow-up visit was significantly lower among patients undergoing ANK within 6 months since AOSD onset ( = 0.01), while no significance was identified at the 6 and 12 month assessments ( = 0.23 and = 0.45, respectively). At the 3 and 6 month visits, the number of swollen joints was significantly higher among patients previously treated with conventional and biological disease modifying anti-rheumatic drugs (DMARDs) compared with those formerly treated only with conventional DMARDs ( < 0.017). Clinical and therapeutic outcomes are substantially independent of how early ANK treatment is started in AOSD patients. However, a faster ANK effectiveness in controlling systemic inflammation and resolving articular manifestations may be observed in patients benefiting from IL-1 inhibition as soon as after disease onset.
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http://dx.doi.org/10.3389/fmed.2020.00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047849PMC
February 2020

Hints for Genetic and Clinical Differentiation of Adult-Onset Monogenic Autoinflammatory Diseases.

Mediators Inflamm 2019 31;2019:3293145. Epub 2019 Dec 31.

Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

Monogenic autoinflammatory diseases (mAIDs) are inherited errors of innate immunity characterized by systemic inflammation recurring with variable frequency and involving the skin, serosal membranes, synovial membranes, joints, the gastrointestinal tube, and/or the central nervous system, with reactive amyloidosis as a potential severe long-term consequence. Although individually uncommon, all mAIDs set up an emerging chapter of internal medicine: recent findings have modified our knowledge regarding mAID pathophysiology and clarified that protean inflammatory symptoms can be variably associated with periodic fevers, depicting multiple specific conditions which usually start in childhood, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, and mevalonate kinase deficiency. There are no evidence-based studies to establish which potential genotype analysis is the most appropriate in adult patients with clinical phenotypes suggestive of mAIDs. This review discusses genetic and clinical hints for an ideal diagnostic approach to mAIDs in adult patients, as their early identification is essential to prompt effective treatment and improve quality of life, and also highlights the most recent developments in the diagnostic work-up for the most frequent hereditary periodic febrile syndromes worldwide.
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http://dx.doi.org/10.1155/2019/3293145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012260PMC
July 2020

A case of Bickerstaff encephalitis associated with Mycoplasma pneumoniae infection.

Neurol Sci 2020 Jun 2;41(6):1605-1606. Epub 2020 Jan 2.

U.O.C. Pediatria, Azienda Ospedaliera Universitaria Senese, viale Bracci 16, 53100, Siena, Italy.

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http://dx.doi.org/10.1007/s10072-019-04223-5DOI Listing
June 2020

Treating juvenile idiopathic arthritis (JIA)-related uveitis beyond TNF-α inhibition: a narrative review.

Clin Rheumatol 2020 Feb 10;39(2):327-337. Epub 2019 Dec 10.

Research Center of Systemic Autoinflammatory Diseases, Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

Chronic anterior uveitis is the most frequent among extra-articular manifestations of juvenile idiopathic arthritis (JIA) and a relevant cause of ocular morbidity in children. Asymmetric arthritis, early onset disease, female sex, and anti-nuclear antibody (ANA) positivity are counted among risk factors for developing this complication. It usually has insidious onset and asymptomatic chronic-relapsing course, but the persistence of low-grade chronic inflammation can lead to irreversible structural ocular damage and to vision-threatening complications. For such reasons, achieving a complete absence of inflammation through early targeted and aggressive treatments is a primary therapeutic goal in these patients. This review is aimed at summarizing scientific evidence about biologic rescue therapy of JIA-related uveitis in patients who fail to achieve clinical remission, in spite of being treated with conventional disease-modifying anti-rheumatic drugs (cDMARDs) and at least one biologic tumor necrosis factor (TNF)-α inhibitor. Interleukin (IL)-6 inhibition appears a promising and safe option for refractory JIA-related uveitis. Abatacept and rituximab proved to be beneficial as well, but their efficacy together with some safety concerns needs to be more extensively evaluated.
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http://dx.doi.org/10.1007/s10067-019-04763-3DOI Listing
February 2020

Acute flaccid myelitis temporally associated with rhinovirus infection: just a coincidence?

Neurol Sci 2020 Feb 25;41(2):457-458. Epub 2019 Oct 25.

U.O.C. Pediatria, Azienda Ospedaliera Universitaria Senese, viale Bracci 16, 53100, Siena, Italia.

We report the case of a 3.6-year-old male child who developed progressive hyposthenia of the left lower limb. Symptoms were preceded by rhinitis, malaise, and fever. Brain and spinal magnetic resonance imaging revealed diffuse signal abnormalities compatible with a subacute myeloencephalitis. A diagnostic lumbar puncture was performed and followed by an empirical therapy including Acyclovir, Ceftriaxone, and Clarithromycin. The cerebrospinal fluid analysis revealed clear fluid, glucose, proteins, albumin within the reference range, and 144 leukocytes/mm. Oligoclonal bands were absent and a search for viruses was negative. Wide microbiological surveillance was performed on surface swabs, blood, urine, and stool. Both nasal and pharyngeal swabs were positive for PicoRNAvirus: sequencing identified Rhinovirus A44. This virus has been detected in association with acute flaccid paralysis in only a few patients worldwide, whereas in the great majority of patients with acute flaccid paralysis other Enterovirus species were identified. The most appropriate therapeutic approach towards acute flaccid paralysis is still a matter of debate in the scientific community, with no current definitivere commendations available. With a combined immunosuppressive and anti-inflammatory therapy including intravenous immunoglobulins, intravenous Methylprednisolone, oral Prednisone, and oral Ibuprofen, we experienced a positive outcome both from the clinical point of view and from three-month follow-up imaging studies. Given the rarity and the complexity of this condition, additional studies are needed to better define the potential role of Rhinovirus A44 in the pathogenesis of the disease and the efficacy of any therapeutic measure in the management of acute flaccid paralysis.
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http://dx.doi.org/10.1007/s10072-019-04094-wDOI Listing
February 2020

A case of Friedreich ataxia in an adolescent with 16p11.2 microdeletion syndrome.

Neurol Sci 2020 03 2;41(3):721-722. Epub 2019 Oct 2.

Dipartimento di Medicina Molecolare e dello Sviluppo, Universita' degli Studi di Siena, viale Bracci, 53100, Siena, Italy.

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http://dx.doi.org/10.1007/s10072-019-04075-zDOI Listing
March 2020

Next-generation sequencing approach to hyperCKemia: A 2-year cohort study.

Neurol Genet 2019 Oct 16;5(5):e352. Epub 2019 Aug 16.

IRCCS Fondazione Stella Maris (A.R., G.A., J.B., G.B., S.L., F.M.S., D.C.), Pisa, Italy; Department of Medicine (A.M., C.B., M.T.D., A.F., F.G., S.S., N.V.), Surgery and Neurosciences, University of Siena; Department of Clinical and Experimental Medicine (C.D., G.S., D.T.), University of Pisa; Metabolic Disease Unit (M.A.D., M.S.), AOU Meyer Children Hospital, Florence; Department of Molecular and Developmental Medicine (S.G.), University of Siena, Siena; Pediatric Neurology (R.G., F.M.), AOU Meyer Children Hospital, Florence; Neurophysiopathology Multiple Sclerosis Center Hospital Binaghi (M.A.M.), Cagliari; Pediatric Neurology and Nemo Clinical Centre (E.M.), Fondazione Policlinico Universitario "A. Gemelli IRCSS", Università Cattolica del Sacro Cuore, Rome; and Department of Neurosciences (P.T.), Biomedicine and Movement Sciences, University of Verona, Italy.

Objective: Next-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition.

Methods: Sixty-six patients with undiagnosed asymptomatic or paucisymptomatic hyperCKemia, referred to tertiary neuromuscular centers over an approximately 2-year period, were analyzed using a customized, targeted sequencing panel able to investigate the coding exons and flanking intronic regions of 78 genes associated with limb-girdle muscular dystrophies, rhabdomyolysis, and metabolic and distal myopathies.

Results: A molecular diagnosis was reached in 33 cases, corresponding to a positive diagnostic yield of 50%. Variants of unknown significance were found in 17 patients (26%), whereas 16 cases (24%) remained molecularly undefined. The major features of the diagnosed cases were mild proximal muscle weakness (found in 27%) and myalgia (in 24%). Fourteen patients with a molecular diagnosis and mild myopathic features on muscle biopsy remained asymptomatic at a 24-month follow-up.

Conclusions: This study of patients with undiagnosed hyperCKemia, highlighting the advantages of NGS used as a first-tier diagnostic approach in genetically heterogeneous conditions, illustrates the ongoing evolution of molecular diagnosis in the field of clinical neurology. Isolated hyperCKemia can be the sole feature alerting to a progressive muscular disorder requiring careful surveillance.
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http://dx.doi.org/10.1212/NXG.0000000000000352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705647PMC
October 2019

Anakinra Drug Retention Rate and Predictive Factors of Long-Term Response in Systemic Juvenile Idiopathic Arthritis and Adult Onset Still Disease.

Front Pharmacol 2019 23;10:918. Epub 2019 Aug 23.

Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

Only a few studies have reported long-term efficacy of interleukin (IL)-1 inhibition in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Herein we report on the effectiveness of anakinra (ANA), expressed in terms of drug retention rate (DRR), and evaluate the predictive factors of drug survival in a cohort of patients with sJIA and AOSD. This is a multicenter study reviewing retrospectively the medical records from 61 patients with sJIA and 76 with AOSD, all treated with ANA in 25 Italian tertiary referral centers. The cumulative retention rate of ANA at 12-, 24-, 48-, and 60-month of follow-up was 74.3%, 62.9%, 49.4%, and 49.4%, respectively, without any significant differences between sJIA and AOSD patients ( = 0.164), and between patients treated in monotherapy compared with the subgroup coadministered with conventional disease-modifying antirheumatic drugs (cDMARDs) ( = 0.473). On the other hand, a significant difference in DRR was found between biologic-naïve patients and those previously treated with biotechnologic drugs ( = 0.009), which persisted even after adjustment for pathology ( = 0.013). In the regression analysis, patients experiencing adverse events (AEs) {hazards ratio (HR) = 3.029 [confidence interval (CI) 1.750-5.242], < 0.0001} and those previously treated with other biologic agents [HR = 1.818 (CI 1.007-3.282), = 0.047] were associated with a higher HR of ANA discontinuation. The median treatment delay was significantly higher among patients discontinuing ANA ( < 0.0001). Significant corticosteroid-sparing ( = 0.033) and cDMARD-sparing effects ( < 0.0001) were also recorded. Less than one-third of our cohort developed AEs, and 85% were deemed mild in nature, with 70% of them involving the skin. Our findings display an overall excellent DRR of ANA on the long run for both sJIA and AOSD, that may be further optimized by closely monitoring patient's safety issues and employing this IL-1 inhibitor as a first-line biologic as early as possible. Moreover, ANA allowed a significant drug-sparing effect and showed an overall good safety profile.
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http://dx.doi.org/10.3389/fphar.2019.00918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715768PMC
August 2019

Acute ataxia in paediatric emergency departments: a multicentre Italian study.

Arch Dis Child 2019 08 4;104(8):768-774. Epub 2019 Apr 4.

Pediatric Emergency Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Objectives: To evaluate the causes and management of acute ataxia (AA) in the paediatric emergency setting and to identify clinical features predictive of an underlying clinically urgent neurological pathology (CUNP).

Study Design: This is a retrospective medical chart analysis of children (1-18 years) attending to 11 paediatric emergency departments (EDs) for AA in an 8-year period. A logistic regression model was applied to identify clinical risk factors for CUNP.

Results: 509 patients (mean age 5.8 years) were included (0.021% of all ED attendances). The most common cause of AA was acute postinfectious cerebellar ataxia (APCA, 33.6%). Brain tumours were the second most common cause (11.2%), followed by migraine-related disorders (9%). Nine out of the 14 variables tested showed an OR >1. Among them, meningeal and focal neurological signs, hyporeflexia and ophthalmoplegia were significantly associated with a higher risk of CUNP (OR=3-7.7, p<0.05). Similarly, the odds of an underlying CUNP were increased by 51% by each day from onset of ataxia (OR=1.5, CI 1.1 to 1.2). Conversely, a history of varicella-zoster virus infection and vertigo resulted in a significantly lower risk of CUNP (OR=0.1 and OR=0.5, respectively; p<0.05).

Conclusions: The most frequent cause of AA is APCA, but CUNPs account for over a third of cases. Focal and meningeal signs, hyporeflexia and ophthalmoplegia, as well as longer duration of symptoms, are the most consistent 'red flags' of a severe underlying pathology. Other features with less robust association with CUNP, such as seizures or consciousness impairment, should be seriously taken into account during AA evaluation.
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http://dx.doi.org/10.1136/archdischild-2018-315487DOI Listing
August 2019

MEIS2 gene is responsible for intellectual disability, cardiac defects and a distinct facial phenotype.

Eur J Med Genet 2020 Jan 5;63(1):103627. Epub 2019 Feb 5.

Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

Myeloid ecotropic insertion site 2 (MEIS2) gene, encoding a homeodomain-containing transcription factor, has been recently related to syndromic intellectual disability with cleft palate and cardiac defects. Here, we present a male patient, aged 10, with cardiac defects, intellectual disability, facial dysmorphisms and gastroesophageal reflux. Whole exome sequencing revealed a novel de novo nonsense mutation in the MEIS2 gene. This patient represents another reported case with a de novo MEIS2 point mutation and helps to characterize a distinct facial phenotype consisting in low anterior hairline, thin eyebrows, anteverted nares, hypoplastic alae nasi, and M-shape upper lip. Furthermore, these data confirm the role of this gene in cardiac, nervous system development and gastrointestinal function.
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http://dx.doi.org/10.1016/j.ejmg.2019.01.017DOI Listing
January 2020

Drug Retention Rate and Predictive Factors of Drug Survival for Interleukin-1 Inhibitors in Systemic Juvenile Idiopathic Arthritis.

Front Pharmacol 2018 8;9:1526. Epub 2019 Jan 8.

Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

Few studies have reported the drug retention rate (DRR) of biologic drugs in juvenile idiopathic arthritis (JIA), and none of them has specifically investigated the DRR of interleukin (IL)-1 inhibitors on systemic JIA (sJIA). This study aims to describe IL-1 inhibitors DRR and evaluate predictive factors of drug survival based on data from a real-world setting concerning sJIA. Medical records from sJIA patients treated with anakinra (ANA) and canakinumab (CAN) were retrospectively analyzed from 15 Italian tertiary referral centers. Seventy seven patients were enrolled for a total of 86 treatment courses. The cumulative retention rate of the IL-1 inhibitors at 12-, 24-, 48-, and 60-months of follow-up was 79.9, 59.5, 53.5, and 53.5%, respectively, without any statistically significant differences between ANA and CAN ( = 0.056), and between patients treated in monotherapy compared to the subgroup co-administered with conventional immunosuppressors ( = 0.058). On the contrary, significant differences were found between biologic-naive patients and those previously treated with biologic drugs ( = 0.038) and when distinguishing according to adverse events (AEs) occurrence ( = 0.04). In regression analysis, patients pre-treated with other biologics (HR = 3.357 [CI: 1.341-8.406], = 0.01) and those experiencing AEs (HR = 2.970 [CI: 1.186-7.435], = 0.020) were associated with a higher hazard ratio of IL-1 inhibitors withdrawal. The mean treatment delay was significantly higher among patients discontinuing IL-1 inhibitors ( = 0.0002). Our findings suggest an excellent overall DRR for both ANA and CAN that might be further augmented by paying attention to AEs and employing these agents as first-line biologics in an early disease phase.
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http://dx.doi.org/10.3389/fphar.2018.01526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331484PMC
January 2019

Electroencephalographic and epilepsy findings in mecp2 duplication syndrome. A family study.

Brain Dev 2019 May 11;41(5):456-459. Epub 2019 Jan 11.

Clinical Pediatrics, Pediatric Neurology Center, Department of Molecular Medicine and Development, University of Siena, Siena, Italy. Electronic address:

MECP2 duplication syndrome (MECP2 DS) is an X-linked disorder characterized by early-onset hypotonia, poor speech development, recurrent respiratory infections, epilepsy and progressive spasticity. Epilepsy occurs in more than 50% of the affected patients. Generalized tonic-clonic seizures (GTCS) are the most common seizure-type described but atonic seizures, absences and myoclonic seizures have also been reported. Electroencephalographic (EEG) and seizure types occurring in MECP2 DS have been poorly investigated. Here we report on two male siblings carrying a maternally-inherited MECP2 duplication. Patients underwent several EEG recordings and long-lasting video-EEG monitoring. The most represented seizure types were myoclonic and atonic seizures. GTCS were rarely observed. In patients, we found a slowing of the background activity with multifocal paroxysmal activity, prominent on the frontal areas. In conclusion, our observations seem to suggest that MECP2 syndrome seem to have a peculiar epileptic pattern mainly characterized by the occurrence of myoclonic seizures, the recognition of which is important in order to undertake an appropriate treatment.
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http://dx.doi.org/10.1016/j.braindev.2018.12.008DOI Listing
May 2019

Treatment options for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome in children and adults: a narrative review.

Clin Rheumatol 2019 Jan 28;38(1):11-17. Epub 2018 Nov 28.

Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most frequent non-hereditary autoinflammatory disorder in childhood: Its onset is usually observed before 5 years, though reports regarding adulthood are increasing. The pathogenesis of the syndrome is not completely understood, but a multifactorial origin, probably based on a polygenic pattern of susceptibility, is the most probable rational pathogenetic hypothesis. Treatment of PFAPA syndrome relies on the administration of low-dose corticosteroids, which promptly abort flares but cannot prevent subsequent disease episodes over time. Tonsillectomy with or without adenoidectomy has proved to be successful in some pediatric patients, as proven by different studies. On the other hand, colchicine, cimetidine, nonsteroidal anti-inflammatory drugs, and interleukin-1 inhibitors have shown efficacy, which require further definite confirmations. This review is aimed at summarizing all the recent evidence about treatment options available for PFAPA syndrome both in pediatric and adult patients.
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http://dx.doi.org/10.1007/s10067-018-4361-2DOI Listing
January 2019

Long-term follow-up in pediatric patients with paroxysmal hypothermia (Shapiro's syndrome).

Eur J Paediatr Neurol 2018 Nov 29;22(6):1081-1086. Epub 2018 Aug 29.

Neurology Unit, S. Anna Hospital, Como, Italy. Electronic address:

Introduction: Shapiro syndrome (SS) is characterized by spontaneous recurrent episodes of hypothermia, hyperhidrosis and corpus callosum (CC) agenesis. Less than 60 cases have been reported to date and the pathogenic mechanism as well as the prognosis of this syndrome are still debated. We describe the clinical features and long-term follow-up of a pediatric cohort of SS patients.

Methods: We collected 13 (10 novel) pediatric cases of SS and report their long-term follow-up and neurological outcome.

Results: All patients experienced recurring hypothermia, with body temperature below 35 °C during the episodes, often accompanied by hyperidrosis. CC agenesis was an inconstant structural feature in the present series (2/13 patients). Seven patients received antiepileptic drugs (AEDs) or other drug therapy for a mean period of 12 months. At long-term follow-up (mean = 61 months, range: 60-96), all individuals were free from episodes of paroxysmal hypothermia independently from previous AED use or other drug therapy.

Conclusion: Paroxysmal hypothermia, the core symptom of SS, behaved as a age-dependent feature in our cohort, supporting a good long-term prognosis for SS. A prompt diagnosis of SS is crucial to avoid unnecessary diagnostic investigations.
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http://dx.doi.org/10.1016/j.ejpn.2018.08.004DOI Listing
November 2018

Oxidative stress in epilepsy.

Expert Rev Neurother 2018 05 19;18(5):427-434. Epub 2018 Apr 19.

a Clinical Pediatrics , Department of Molecular Medicine and Development , University of Siena , Siena , Italy.

Introduction: The brain is particularly susceptible to oxidative stress being the most aerobically active organ in the body due to its high metabolic demands. There is evidence that neuronal hyperexcitability and oxidative injury produced by an excessive production of free radicals may play a role in the initiation and progression of epilepsy. Understanding the role of oxidative stress in epileptogenesis is essential to delineate appropriate therapeutic strategies. Neuroprotectant or antioxidant compounds may exert positive effects when associated with antiepileptic drugs (AEDs). Areas covered: This review aims to outline the current state of knowledge on the relationship between oxidative stress and epilepsy. The role of neuroprotectants in the therapeutic strategy to prevent or treating epilepsy is also discussed. PubMed/Medline database was searched for relevant articles on the relation between oxidative stress and epilepsy and on antioxidant strategies for epilepsy management. Expert commentary: Therapeutic intervention with antioxidants may represent a key strategy to counteract the epilepsy-related neurodegenerative process. However, in spite of the incredible development of new drugs for epilepsy treatment, definitive evidence about the neuroprotective ability of the existing compounds is still lacking. Therefore, there is great need for clinical trials to evaluate new antioxidant compounds specifically on epileptic patients.
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http://dx.doi.org/10.1080/14737175.2018.1465410DOI Listing
May 2018

Antiepileptic drugs: Role in paediatric poisoning.

J Paediatr Child Health 2018 05 2;54(5):475-479. Epub 2018 Jan 2.

Clinical Pediatrics, Pediatric Neurology Center, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.

Intoxications, both accidental and intentional, are common in children and adolescents and often require hospitalisation and intensive treatment. Antiepileptic drugs are a possible cause of poisoning and intoxications because this category of medications has shown a rising trend in recent years. They might be responsible for multi-organ dysfunctions of variable severity, ranging from subtle symptoms to life-threatening complications. No guidelines on the management of these intoxications in the paediatric population are currently available, and treatment is mainly supportive. Activated charcoal administration and extracorporeal circulation techniques for drug removal have been proposed. Facing the complexity of this clinical scenario, it is of utmost importance to maintain a high index of suspicion to guarantee a prompt intervention and ensure the best possible management for the patient.
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http://dx.doi.org/10.1111/jpc.13833DOI Listing
May 2018

Massive lamotrigine poisoning. A case report.

Brain Dev 2017 Apr 19;39(4):349-351. Epub 2016 Nov 19.

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

Lamotrigine (LTG) represents the most commonly prescribed of the so-called new generation antiepileptic drugs. We describe a child who was admitted to the emergency room because of generalized tonic-clonic status epilepticus followed by a complex neurological picture with hyperkinesia and acute ataxia as a result of a LTG intoxication. The experience on acute LTG intoxication is very limited in pediatrics. The present case provides information on the clinical picture related to LTG overdose and confirms that drug intoxications should be considered in the differential diagnosis strategy when severe and polymorphic neurological symptoms occur acutely.
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http://dx.doi.org/10.1016/j.braindev.2016.11.003DOI Listing
April 2017

Exome sequencing coupled with mRNA analysis identifies NDUFAF6 as a Leigh gene.

Mol Genet Metab 2016 11 3;119(3):214-222. Epub 2016 Sep 3.

Medical Genetics, University of Siena, Siena, Italy.

We report here the case of a young male who started to show verbal fluency disturbance, clumsiness and gait anomalies at the age of 3.5years and presented bilateral striatal necrosis. Clinically, the diagnosis was compatible with Leigh syndrome but the underlying molecular defect remained elusive even after exome analysis using autosomal/X-linked recessive or de novo models. Dosage of respiratory chain activity on fibroblasts, but not in muscle, underlined a deficit in complex I. Re-analysis of heterozygous probably pathogenic variants, inherited from one healthy parent, identified the p.Ala178Pro in NDUFAF6, a complex I assembly factor. RNA analysis showed an almost mono-allelic expression of the mutated allele in blood and fibroblasts and puromycin treatment on cultured fibroblasts did not lead to the rescue of the maternal allele expression, not supporting the involvement of nonsense-mediated RNA decay mechanism. Complementation assay underlined a recovery of complex I activity after transduction of the wild-type gene. Since the second mutation was not detected and promoter methylation analysis resulted normal, we hypothesized a non-exonic event in the maternal allele affecting a regulatory element that, in conjunction with the paternal mutation, leads to the autosomal recessive disorder and the different allele expression in various tissues. This paper confirms NDUFAF6 as a genuine morbid gene and proposes the coupling of exome sequencing with mRNA analysis as a method useful for enhancing the exome sequencing detection rate when the simple application of classical inheritance models fails.
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http://dx.doi.org/10.1016/j.ymgme.2016.09.001DOI Listing
November 2016