Publications by authors named "Claudia Nesti"

64 Publications

Focal status and acute encephalopathy in a 13-year-old boy with de novo DNM1L mutation: Video-polygraphic pattern and clues for differential diagnosis.

Brain Dev 2021 May 21;43(5):644-651. Epub 2021 Jan 21.

Neonatal and Pediatric Intensive Care Unit, Department of Critical Care, IRCCS Giannina Gaslini, Genova, Italy.

Background: Pathogenic variants in the dynamin 1 like gene are related to abnormal mitochondrial dynamics and distributions and are associated to variable clinical phenotypes. A few patients harboring the p.Arg403Cys missense variant appears to be different from the classical, more severe phenotypes, showing sudden onset of drug resistant seizures after a previously normal or slightly delayed development.

Case Report: We report on a boy with abrupt onset of focal status and coma at the age of 13, initially treated as autoimmune encephalitis, with final diagnosis of de novo missense p.Arg403Cys variant in the DNM1L gene.

Discussion: We compare his clinical, electrophysiological, biochemical, neuroradiological and histopathological picture to the rare cases reported to date and provide diagnostic clues that can help clinicians in differentiate p.Arg403Cys-related phenotype from that of immune-mediated encephalopathies.

Conclusion: The clinical picture related to p.Arg403Cys mutations should be considered alongside acquired pathologies in the differential diagnosis of young patients with focal refractory epilepsy and encephalopathy, also occurring during late childhood or adolescence. Prompt genetic testing allows to avoid unnecessary treatments and procedures and to better define the prognosis and management strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2020.12.017DOI Listing
May 2021

Leopard-like retinopathy and severe early-onset portal hypertension expand the phenotype of KARS1-related syndrome: a case report.

BMC Med Genomics 2021 01 21;14(1):25. Epub 2021 Jan 21.

Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

Background: Mutations in lysyl-tRNA synthetase (KARS1), an enzyme that charges tRNA with the amino acid lysine in both the cytoplasm and mitochondria, have been associated thus far with autosomal recessive Charcot-Marie-Tooth type CMTRIB, hearing loss type DFNB89, and mitochondrial encephalohepatopathy (MEH) featuring neurodevelopmental disorders with microcephaly, white matter changes, and cardiac and hepatic failure in less than 30 patients.

Case Presentation: We report the clinical, biochemical and molecular findings of a 14-month-old girl with severe MEH compatible clinical features, profound sensorineural hearing loss, leopard spot retinopathy, pancytopenia, and advanced liver disease with portal hypertension leading to death at the age of 30 months.

Conclusions: Whole exome sequencing identified two rare variants in KARS1 gene. Our report expands the allelic and clinical features of tRNA synthase disorders. Moreover, with our report we confirm the usefulness of WES as first tier diagnostic method in infants with complex multisystem phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12920-020-00863-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818779PMC
January 2021

Optic Atrophy and Generalized Chorea in a Patient Harboring an OPA10/RTN4IP1 Pathogenic Variant.

Neuropediatrics 2020 12 11;51(6):425-429. Epub 2020 May 11.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal, and Child Health, University of Genoa, Genoa, Italy.

pathogenic variants (OPA10 syndrome) have been described in patients with early-onset recessive optic neuropathy and recently associated with a broader clinical spectrum, from isolated optic neuropathy to severe encephalopathies with epilepsy. Here we present a case of a patient with a complex clinical picture characterized by bilateral optic nerve atrophy, horizontal nystagmus, myopia, mild intellectual disability, generalized chorea, isolated small subependymal heterotopia, and asynchronous self-resolving midbrain MRI (magnetic resonance imaging) lesions. By using massive gene sequencing, we identified in this patient the c.308G > A (p.Arg103His) homozygous pathogenic variant in the gene. Complex movement disorders and relapsing-remitting neuroradiological lesions have not been previously reported in this condition. Our case expands the clinical spectrum of OPA10 syndrome and opens new opportunities for the molecular diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1708539DOI Listing
December 2020

A homozygous MRPL24 mutation causes a complex movement disorder and affects the mitoribosome assembly.

Neurobiol Dis 2020 07 25;141:104880. Epub 2020 Apr 25.

Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address:

Mitochondrial ribosomal protein large 24 (MRPL24) is 1 of the 82 protein components of mitochondrial ribosomes, playing an essential role in the mitochondrial translation process. We report here on a baby girl with cerebellar atrophy, choreoathetosis of limbs and face, intellectual disability and a combined defect of complexes I and IV in muscle biopsy, caused by a homozygous missense mutation identified in MRPL24. The variant predicts a Leu91Pro substitution at an evolutionarily conserved site. Using human mutant cells and the zebrafish model, we demonstrated the pathological role of the identified variant. In fact, in fibroblasts we observed a significant reduction of MRPL24 protein and of mitochondrial respiratory chain complex I and IV subunits, as well a markedly reduced synthesis of the mtDNA-encoded peptides. In zebrafish we demonstrated that the orthologue gene is expressed in metabolically active tissues, and that gene knockdown induced locomotion impairment, structural defects and low ATP production. The motor phenotype was complemented by human WT but not mutant cRNA. Moreover, sucrose density gradient fractionation showed perturbed assembly of large subunit mitoribosomal proteins, suggesting that the mutation leads to a conformational change in MRPL24, which is expected to cause an aberrant interaction of the protein with other components of the 39S mitoribosomal subunit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2020.104880DOI Listing
July 2020

A novel mutation of Twinkle in Perrault syndrome: A not rare diagnosis?

Ann Hum Genet 2020 09 12;84(5):417-422. Epub 2020 Apr 12.

Clinical Genetics Unit, Ospedale Policlinico IRCCS San Martino, Genoa, Italy.

Perrault syndrome is a rare disorder characterized by ovarian dysgenesis, bilateral sensorineural hearing loss and associated with mutations in six mitochondrial proteins. Additional neurological features were also described. Herein, we report on a 27-year-old woman with Perrault syndrome (PS), moderate ataxia and axonal sensory-motor peripheral neuropathy in whom we identified compound heterozygous mutations in the TWNK gene (p.Val507Ile and the novel p.Phe248Ser variant). Fewer than 30 patients with PS have been reported worldwide. Neurological involvement is more frequently associated with mutations in TWNK and indicates possible genotype-phenotype correlations. TWNK mutations should be searched in patients with sensory ataxia, early onset bilateral sensorineural hearing loss, and ovarian dysfunction in women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ahg.12384DOI Listing
September 2020

Proteomic and functional analyses in disease models reveal CLN5 protein involvement in mitochondrial dysfunction.

Cell Death Discov 2020 30;6:18. Epub 2020 Mar 30.

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Pisa, Italy.

CLN5 disease is a rare form of late-infantile neuronal ceroid lipofuscinosis (NCL) caused by mutations in the gene that encodes a protein whose primary function and physiological roles remains unresolved. Emerging lines of evidence point to mitochondrial dysfunction in the onset and progression of several forms of NCL, offering new insights into putative biomarkers and shared biological processes. In this work, we employed cellular and murine models of the disease, in an effort to clarify disease pathways associated with CLN5 depletion. A mitochondria-focused quantitative proteomics approach followed by functional validations using cell biology and immunofluorescence assays revealed an impairment of mitochondrial functions in different CLN5 KO cell models and in cerebral cortex, which well correlated with disease progression. A visible impairment of autophagy machinery coupled with alterations of key parameters of mitophagy activation process functionally linked CLN5 protein to the process of neuronal injury. The functional link between impaired cellular respiration and activation of mitophagy pathways in the human CLN5 disease condition was corroborated by translating organelle-specific proteome findings to CLN5 patients' fibroblasts. Our study highlights the involvement of CLN5 in activation of mitophagy and mitochondrial homeostasis offering new insights into alternative strategies towards the CLN5 disease treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41420-020-0250-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105465PMC
March 2020

Expanding the clinical and genetic heterogeneity of SPAX5.

Ann Clin Transl Neurol 2020 04 1;7(4):595-601. Epub 2020 Apr 1.

IRCCS Fondazione Stella Maris, Calambrone, Pisa, Italy.

Mutations in the ATPase family 3-like gene (AFG3L2) have been linked to autosomal-dominant spinocerebellar ataxia type 28 and autosomal recessive spastic ataxia-neuropathy syndrome. Here, we describe the case of a child carrying bi-allelic mutations in AFG3L2 and presenting with ictal paroxysmal episodes associated with neuroimaging suggestive of basal ganglia involvement. Studies in skin fibroblasts showed a significant reduction of AFG3L2 expression. The relatively mild clinical presentation and the benign course, in spite of severe neuroimaging features, distinguish this case from data reported in the literature, and therefore expand the spectrum of neurological and neuroradiological features associated with AFG3L2 mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187698PMC
April 2020

Intrafamilial "DOA-plus" phenotype variability related to different OMI/HTRA2 expression.

Am J Med Genet A 2020 01 14;182(1):176-182. Epub 2019 Oct 14.

Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases and Inter University Center for Research in Neurosciences, University of Campania "Luigi Vanvitelli", Naples, Italy.

Dominant Optic Atrophy and Deafness (DOAD) may be associated with one or more of the following disorders such as myopathy, progressive external ophthalmoplegia, peripheral neuropathy, and cerebellar atrophy ("DOA-plus"). Intra- and interfamilial variability of the "DOA-plus" phenotype is frequently observed in the majority of the patients carrying the same mutation in the OPA1 gene. We are describing two familial cases of "DOA-plus" carrying the same c.1334G>A (p.Arg445His) mutation in OPA1 and disclosing different clinical, pathological and biochemical features. The two patients showed different expression levels of the mitochondrial OMI/HTRA2 molecule, which acts as a mitochondrial stress sensor and has been described to interplay with OPA1 in in vitro studies. Our data offer the cue to inquire the role of OMI/HTRA2 as a modifier gene in determining the "DOAplus" phenotype variability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61381DOI Listing
January 2020

Novel homozygous TSFM pathogenic variant associated with encephalocardiomyopathy with sensorineural hearing loss and peculiar neuroradiologic findings.

Neurogenetics 2019 08 2;20(3):165-172. Epub 2019 Jul 2.

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris, Calambrone, Pisa, Italy.

TSFM is a nuclear gene encoding the elongation factor Ts (EFTs), an essential component of mitochondrial translational machinery. Impaired mitochondrial translation is responsible for neurodegenerative disorders characterized by multiple respiratory chain complex defects, multisystemic involvement, and neuroradiological features of Leigh-like syndrome. With the use of a next-generation sequencing (NGS)-based multigene panel for mitochondrial disorders, we identified the novel TSFM homozygous variant c.547G>A (p.Gly183Ser) in a 5-year-old boy with infantile early onset encephalocardiomyopathy, sensorineural hearing loss, and peculiar partially reversible neuroimaging features. Our findings expand the phenotypic spectrum of TSFM-related encephalopathy, offering new insights into the natural history of brain involvement and suggesting that TSFM should be investigated in pediatric mitochondrial disorders with distinctive neurologic and cardiac involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-019-00582-5DOI Listing
August 2019

VARS2-linked mitochondrial encephalopathy: two case reports enlarging the clinical phenotype.

BMC Med Genet 2019 05 7;20(1):77. Epub 2019 May 7.

Unit of Child Neuropsychiatry Residency Program, University Hospital of Sassari, Viale San Pietro 43/B, I-07100, Sassari, Italy.

Background: Mitochondrial respiratory chain consists of five complexes encoded by nuclear and mitochondrial genomes. Mitochondrial aminoacyl-tRNA synthetases are key enzymes in the synthesis of such complexes. Bi-allelic variants of VARS2, a nuclear gene encoding for valyl-tRNA (Val-tRNA) synthetase, are associated to several forms of mitochondrial encephalopathies or cardiomyoencephalopathies. Among these, the rare homozygous c.1100C > T (p.Thr367Ile) mutation variably presents with progressive developmental delay, axial hypotonia, limbs spasticity, drug-resistant epilepsy leading, in some cases, to premature death. Yet only six cases, of which three are siblings, harbouring this homozygous mutation have been described worldwide.

Case Presentation: Hereby, we report two additional cases of two non-related young girls from Sardinia, born from non-consanguineous and healthy parents, carrying the aforesaid homozygous VARS2 variant. At onset both the patients presented with worsening psychomotor delay, muscle hypotonia and brisk tendon reflexes. Standard genetic tests were normal, as well as metabolic investigations. Brain MRI showed unspecific progressive abnormalities, such as corpus callosum hypoplasia (patient A) and cerebellar atrophy (patient A and B). Diagnosis was reached by adopting massive parallel next generation sequencing. Notably clinical phenotype of the first patient appears to be milder compared to previous known cases. The second patient eventually developed refractory epilepsy and currently presents with severe global impairment. Because no specific treatment is available as yet, both patients are treated with supporting antioxidant compounds along with symptomatic therapies.

Conclusions: Given the paucity of clinical data about this very rare mitochondrial encephalopathy, our report might contribute to broaden the phenotypic spectrum of the disorder. Moreover, noteworthy, three out of five pedigrees so far described belong to the Northern Sardinia ethnicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12881-019-0798-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505124PMC
May 2019

The features of the m.10197G>A mtDNA mutation.

J Neurol Sci 2019 05 4;400:184-185. Epub 2019 Apr 4.

IRCCS Fondazione Stella Maris, viale del Tirreno 331, 56128 Calambrone, Pisa, Italy. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2019.04.005DOI Listing
May 2019

Complex multisystem phenotype associated with the mitochondrial DNA m.5522G>A mutation.

Neurol Sci 2019 Aug 1;40(8):1705-1708. Epub 2019 Apr 1.

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, via dei Giacinti 2, 56128, Pisa, Italy.

Mitochondrial tRNAs are responsible for more than half of pathogenic point mutations in the mitochondrial genome (mtDNA). Different mutations give rise to widely differing phenotypes, ranging from isolated organ-specific diseases to multisystem conditions. Herein, we report a 40-year-old woman presenting with a complex multisystem phenotype including sensorineural hearing loss, retinopathy, severe dilated cardiomyopathy, non-insulin dependent diabetes mellitus, and renal failure. Sequence analysis of mtDNA identified the m.5522G>A mutation in MT-TW, the gene encoding mitochondrial tRNA for tryptophan. The heteroplasmic variant, thus far described once, was almost exclusively confined to skeletal muscle tissue, as shown by massive parallel sequencing and corroborated by an ad hoc designed PCR-based strategy. This patient, presenting a severe, multisystem involvement apparently sparing the brain, contributes to the genetic heterogeneity of mitochondrial diseases caused by mutations in mitochondrial tRNAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10072-019-03864-wDOI Listing
August 2019

Clinical and molecular studies in two new cases of ARSACS.

Neurogenetics 2019 03 24;20(1):45-49. Epub 2019 Jan 24.

Molecular Medicine, IRCCS Fondazione Stella Maris, via dei Giacinti 2 Calambrone, 56128, Pisa, Italy.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodevelopmental disorder characterized by the association of spastic ataxia and sensorimotor neuropathy. Additional features include retinal changes and cognitive impairment. Today, next-generation sequencing (NGS) techniques are allowing the rapid identification of a growing number of missense variants, even in less typical forms of the disease, but the pathogenic significance of these changes is often difficult to establish on the basis of classic bioinformatics criteria and genotype/phenotype correlations. Herein, we describe two novel cases of missense mutations in SACS. The two individuals were identified during the genetic screening of a large cohort of patients with inherited ataxias. We discuss how protein studies and specialized ophthalmological investigations could represent useful pointers for the interpretation of genetic data. Combination of these tools with NGS for rapid genotyping might help to identify new true ARSACS cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-019-00564-7DOI Listing
March 2019

Teaching NeuroImages: Leigh-like features expand the picture of -related disorders.

Neurology 2019 01;92(2):e168-e169

From Molecular Medicine & Neurogenetics (A.R., C.D., F.M.S., C.N.), Neuroradiology (R.P., R.C.), and Child Neurology (G.A.), IRCCS Fondazione Stella Maris, Pisa, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000006740DOI Listing
January 2019

Relapsing-Remitting Course of Cystic Leukoencephalopathy.

Pediatr Neurol 2018 12 24;89:63-65. Epub 2018 Aug 24.

Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2018.08.021DOI Listing
December 2018

Reversible Valproate-Induced Subacute Encephalopathy Associated With a Variant in the Mitochondrial Genome.

Front Neurol 2018 30;9:728. Epub 2018 Aug 30.

Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.

There are several reported cases of patients developing motor and cognitive neurological impairment under treatment with valproic acid (VPA). We describe a woman who developed a subacute encephalopathy after VPA intake, harboring a mitochondrial DNA variant, previously described as causing VPA sensitivity in one pediatric patient. A 65-year old woman developed a progressive, severe neurological deterioration after a 3 month treatment with valproate sodium, 800 mg daily. Magnetic resonance spectroscopy (MRS), muscle histochemical analysis and assay of mitochondrial enzymatic activities, and mitochondrial DNA sequencing were performed. Neurological examination showed drowsiness, vertical gaze palsy, inability to either stand or walk, diffuse weakness, increased tendon reflexes. Blood lactate was increased, EEG showed diffuse theta and delta activity, MRI subcortical atrophy and leukoencephalopathy, MRS marked reduction of the NAA spectrum, with a small signal compatible with presence of lactate. Muscle biopsy evidenced presence of ragged red fibers (20%) and reduced COX reactivity. Assay of the muscle enzymatic activities showed multiple deficiencies of the electron transport chain and reduced ATP production. The mt.8393C>T variant in the gene was found in homoplasmy. The patient considerably improved after valproate withdrawal. The variant we found has been reported both as a polymorphism and, in a single patient, as related to the valproate-induced encephalopathy. The present case is the first bearing this mutation in homoplasmy. In case of neurological symptoms after starting VPA therapy, once hyperammonemia and liver failure have been ruled out, mtDNA abnormalities should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2018.00728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125373PMC
August 2018

Next generation sequencing technologies for a successful diagnosis in a cold case of Leigh syndrome.

BMC Neurol 2018 Jul 20;18(1):99. Epub 2018 Jul 20.

Molecular Genetics Laboratory, Santa Chiara University Hospital, Via Roma 67, 56126, Pisa, Italy.

Background: Leigh Syndrome (LS, OMIM 256000) is an early-onset, progressive neurodegenerative disorder characterized by broad clinical and genetic heterogeneity; it is the most frequent disorder of mitochondrial energy production in children. LS inheritance is complex because patients may present mutations in mitochondrial DNA (mtDNA) or in nuclear genes, which predominantly encode proteins involved in respiratory chain structure and assembly or in coenzyme Q10 biogenesis. However, during the last 15 years, the discovery of several genetic mutations and improved knowledge of the natural history of LS has significantly increased our understanding of this mitochondrial disorder.

Case Presentation: Here we describe a 19-year-old male with clinical and neuroimaging LS diagnosed at 3 years of age. Genetic analyses of the whole mtDNA for maternally inherited LS (MILS) and neuropathy ataxia retinitis pigmentosa (NARP) syndrome failed to reveal any pathogenic mutations.

Conclusions: Recently, a missense mutation in ECHS1 and a ~ 35 kb deletion in 10q26.3 involving the region including the gene were identified by WES (whole exome sequencing), uncovering the genetic diagnosis clinically hypothesized for 15 years. We also report the long-term follow-up of this patient, showing a comparison with classical LS or other Leigh-like pictures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12883-018-1103-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054728PMC
July 2018

Four years follow up of ACY1 deficient patient and pedigree study.

Brain Dev 2018 Aug 10;40(7):570-575. Epub 2018 Apr 10.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Aminoacylase 1 deficiency (ACY1D) is a rare inborn error of metabolism characterized by increased urinary excretion of N-acetylated amino acids. Clinical phenotypes of 15 known patients with ACY1 deficiency have been described up to now. Findings are greatly variable, ranging from normality to relevant neurological and psychiatric impairments, but clinical follow up has been rarely reported. To partially fill this gap, we present a detailed clinical description and the outcome four years post-diagnosis of a patient already described, with mild intellectual disability, language delay, autistic traits and compound heterozygous mutations in ACY1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2018.03.009DOI Listing
August 2018

Myoclonus epilepsy, retinitis pigmentosa, leukoencephalopathy and cerebral calcifications associated with a novel m.5513G>A mutation in the MT-TW gene.

Biochem Biophys Res Commun 2018 06 13;500(2):158-162. Epub 2018 Apr 13.

Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Bracci 2, 53100, Siena, Italy.

We sequenced the mitochondrial genome from a 40-year-old woman with myoclonus epilepsy, retinitis pigmentosa, leukoencephalopathy and cerebral calcifications. Histological and biochemical features of mitochondrial respiratory chain dysfunction were present. Direct sequencing showed a novel heteroplasmic mutation at nucleotide 5513 in the MT-TW gene that encodes tRNA. Restriction Fragment Length Polymorphism analysis confirmed that about 80% of muscle mtDNA harboured the mutation while it was present in minor percentages in mtDNA from other tissues. The mutation is predicted to disrupt a highly conserved base pair within the aminoacyl acceptor stem of the tRNA. This is the 17° mutation in MT-TW gene and expands the known causes of late-onset mitochondrial diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2018.04.009DOI Listing
June 2018

A Child With Ichthyosis and Liver Failure.

J Pediatr Gastroenterol Nutr 2017 09;65(3):e70-e73

*Paediatric and Liver Unit, Meyer Children's University Hospital of Florence, Florence †Laboratory of Medical Genetics, Papa Giovanni XXIII Hospital, Bergamo ‡Department of Health Science, University of Florence, Florence §Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa ||Metabolic and Muscular Unit ¶Pathology Unit, Meyer Children's University Hospital of Florence, Florence, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000001645DOI Listing
September 2017

Novel mutations in provide clues to the pathomechanisms of HSAN-VI.

Neurology 2017 May 3;88(22):2132-2140. Epub 2017 May 3.

From the Departments of Neurosciences, Reproductive Sciences, and Odontostomatology (F.M., C.P., S.T., L.S.) and Department of Molecular Medicine and Medical Biotechnologies (S. Parisi, S. Paladino, T.R.), University of Naples "Federico II"; Neurology Department (M.N., V.P.), "Salvatore Maugeri" Foundation IRCCS-Medical Center of Telese, Telese Terme, Italy; Department of Human Genetics and Hussman Institute for Human Genomics (F.T., A.P.R., S.Z.), Miller School of Medicine, University of Miami, FL; Molecular Medicine Laboratory (C.N., F.M.S.), Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy; and Department of Neurology (M.E.S.), University of Iowa Carver College of Medicine, Iowa City.

Objective: To describe a second hereditary sensory autonomic neuropathy type VI (HSAN-VI) family harboring 2 novel heterozygous mutations in the dystonin () gene and to evaluate their effect on neurons derived from induced pluripotent stem cells (iPSC).

Methods: The family consisted of 3 affected siblings from nonconsanguineous healthy parents. All members underwent clinical and electrophysiologic evaluation and genetic analysis. Two patients underwent quantitative sensory testing (QST), cardiovascular reflexes, dynamic sweat test, and skin biopsy to evaluate somatic and autonomic cutaneous innervation and to get fibroblast cultures for developing iPSC-derived neurons.

Results: Onset occurred in the first decade, with painless and progressive mutilating distal ulcerations leading to amputation and joint deformity. Sensation to pain, touch, and vibration was reduced. Autonomic disturbances included hypohidrosis, pupillary abnormalities, and gastrointestinal and sexual dysfunction. Nerve conduction studies showed a severe axonal sensory neuropathy. QST and autonomic functional studies were abnormal. Skin biopsy revealed a lack of sensory and autonomic nerve fibers. Genetic analysis revealed 2 pathogenic mutations in the gene affecting exclusively the DST neuronal isoform-a2. Neurons derived from iPSC showed absence or very low levels of DST protein and short and dystrophic neuritis or no projections at all.

Conclusions: Unlike the previous HSAN-VI family, our description indicates that mutations may be associated with a nonlethal and nonsyndromic phenotype. Neuronal loss affects large and small sensory nerve fibers as well as autonomic ones. Induced-PSC findings suggest that dystonin defect might alter proper development of the peripheral nerves. Dystonin-a2 plays a major role in the HSAN-VI phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000003992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447400PMC
May 2017

Leigh-like neuroimaging features associated with new biallelic mutations in OPA1.

Eur J Paediatr Neurol 2017 Jul 15;21(4):671-677. Epub 2017 Apr 15.

Molecular Medicine, IRCCS Stella Maris, Pisa, Italy. Electronic address:

Behr syndrome is characterized by the association of early onset optic atrophy, cerebellar ataxia, pyramidal signs, peripheral neuropathy and mental retardation. Recently, some cases were reported to be caused by biallelic mutations in OPA1. We describe an 11-year-old girl (Pt1) and a 7-year-old boy (Pt2) with cognitive delay, ataxic gait and clinical signs suggestive of a peripheral neuropathy, with onset in early infancy. In Pt1 ocular fundus examination revealed optic disk pallor whereas Pt2 exhibited severe optic atrophy. In both children neuroimaging detected a progressive cerebellar involvement accompanied by basal ganglia hyperintensities and pathological peak levels of lactate. In both patients, muscle biopsy showed diffuse reduction of cytochrome c oxidase stain, some atrophic fibers and type II fiber grouping. Using a targeted resequencing panel in next generation sequencing, we identified the homozygous c.1180G>A/p.Ala394Thr mutation in Pt1 and the c.2779-2A>C mutation in compound heterozygosity with the c.2809C>T/p.Arg937Cys mutation in Pt2. All variants were novel and segregated in the healthy parents. Expression of OPA1 protein was significantly reduced in muscle tissues of both patients by Western blotting. We also observed in patients' fibroblasts a higher proportion of fragmented and intermediate mitochondria upon galactose treatment compared to controls, as already seen in other patients harboring mutations in OPA1. The presence of Leigh-like neuroimaging features is a novel finding in Behr syndrome and further adds to the complex genotype-phenotype correlations in OPA1-associated disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2017.04.004DOI Listing
July 2017

Concentric muscle involvement in POLG-related distal myopathy.

Neuromuscul Disord 2017 05 7;27(5):500-501. Epub 2017 Mar 7.

Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2017.03.001DOI Listing
May 2017

Widening the Heterogeneity of Leigh Syndrome: Clinical, Biochemical, and Neuroradiologic Features in a Patient Harboring a NDUFA10 Mutation.

JIMD Rep 2017 1;37:37-43. Epub 2017 Mar 1.

Rare Diseases Unit, Istituto Giannina Gaslini, Genoa, Italy.

Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder, characterized by a wide clinical and genetic heterogeneity, and is the most frequent disorder of mitochondrial energy production in children. Beside its great variability in clinical, biochemical, and genetic features, LS is pathologically uniformly characterized by multifocal bilateral and symmetric spongiform degeneration of the basal ganglia, brainstem, thalamus, cerebellum, spinal cord, and optic nerves. Isolated complex I deficiency is the most common defect identified in Leigh syndrome. In 2011, the first child with a mutation of NDUFA10 gene, coding for an accessory subunits of complex I, was described. Here, we present an additional description of a child with Leigh syndrome harboring a homozygous mutation in NDUFA10, providing insights in clinical, biochemical, and neuroradiologic features for future earlier recognition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/8904_2017_9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740043PMC
March 2017

Sporadic chronic progressive external ophthalmoplegia with single large mitochondrial DNA deletion and neurogenic findings.

J Neurol 2017 Mar 7;264(3):597-599. Epub 2017 Feb 7.

Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II of Naples, Naples, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-017-8409-zDOI Listing
March 2017

Cerium oxide nanoparticles: the regenerative redox machine in bioenergetic imbalance.

Nanomedicine (Lond) 2017 02 21;12(4):403-416. Epub 2016 Dec 21.

Istituto Italiano di Tecnologia, Center for Micro-BioRobotics @SSSA, Viale Rinaldo Piaggio 34, 56025 Pontedera (Pisa), Italy.

Aim: Owing to their catalytic properties as reactive oxygen species scavengers, cerium oxide nanoparticles (nanoceria) have become an extremely promising candidate for medical applications, especially in the treatment of diseases where oxidative stress has been proposed as one of the main pathogenesis factors.

Materials & Methods: In this work, nanoceria antioxidant power has been tested in primary cultured skin fibroblasts, derived from healthy individuals, by evaluating the mitochondrial function both in basal condition and after an oxidative insult.

Results & Conclusion: Combined with a clear lack of toxicity, antioxidant activity makes nanoceria promising in a wide range of clinical applications sharing the common signature of a global bioenergetic dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/nnm-2016-0342DOI Listing
February 2017

MELAS Syndrome with Cardiac Involvement: A Multimodality Imaging Approach.

Case Rep Cardiol 2016 7;2016:1490181. Epub 2016 Nov 7.

Division of Cardiology, IRCCS AOU San Martino, IST Genova, Largo Benzi 10, 16100 Genova, Italy.

A 49-year-old man presented with chest pain, dyspnea, and lactic acidosis. Left ventricular hypertrophy and myocardial fibrosis were detected. The sequencing of mitochondrial genome (mtDNA) revealed the presence of A to G mtDNA point mutation at position 3243 (m.3243A>G) in gene. Diagnosis of cardiac involvement in a patient with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes syndrome (MELAS) was made. Due to increased risk of sudden cardiac death, cardioverter defibrillator was implanted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2016/1490181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116498PMC
November 2016

A novel mitochondrial tRNA(Ala) gene variant causes chronic progressive external ophthalmoplegia in a patient with Huntington disease.

Mol Genet Metab Rep 2016 Mar 27;6:70-3. Epub 2016 Feb 27.

Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital "Spedali Civili", Brescia, Italy.

Chronic progressive external ophthalmoplegia is a mitochondrial disorder usually caused by single or multiple mitochondrial DNA (mtDNA) deletions and, more rarely, by maternally inherited mtDNA point mutations, most frequently in tRNA genes (MTT). We report on a patient presenting with a progressive eyelid ptosis with bilateral ophthalmoparesis, dysphagia, dysphonia and mild proximal limb weakness associate with a mild movement disorder characterized by abnormal involuntary movements involving head and limbs, imbalance and gait instability. Muscle biopsy demonstrated the presence of ragged red fibers and several cytochrome-C-oxidase negative fibers. Molecular analysis showed the novel m.5613T > C heteroplasmic mutation in the mitochondrial tRNA(Ala) gene (MTTA) which disrupts a conserved site and fulfills the accepted criteria of pathogenicity. Moreover, a 38 CAG trinucleotide repeat expansion was found on the huntingtin gene, thus configuring a singular CPEO/"reduced penetrance" Huntington disease "double trouble". With this novel MTTA point mutation, we extend the spectrum of provisional pathogenic changes in this gene, which is a very rare site of pathogenic mutation, and confirm that clinical expression of these mutations is hardly ever heterogeneous, including myopathy and CPEO. Mitochondrial involvement is an emerging key determinant in the pathogenesis of Huntington disease and it is well known that mutant huntingtin influences the mitochondrial respiratory complexes II and III. A synergist effect of the HTT and MTTA mutations on respiratory chain function may be hypothesized in our patient and should be regarded as a spur for further studies on the mtDNA/HTT reciprocal interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgmr.2016.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789388PMC
March 2016