Publications by authors named "Elena Cardaioli"

31 Publications

Fibroblast growth factor 21 and grow differentiation factor 15 are sensitive biomarkers of mitochondrial diseases due to mitochondrial transfer-RNA mutations and mitochondrial DNA deletions.

Neurol Sci 2020 Dec 6;41(12):3653-3662. Epub 2020 Jun 6.

UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.

Background: Diagnosis of mitochondrial diseases (MDs) is challenging, since they are multisystemic disorders, characterized by a heterogeneous symptomatology. Recently, an increase in serum levels of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has been found in the majority of patients with MDs compared with healthy controls. On the other hand, the finding of low FGF21 and GDF15 levels in some patients with MDs suggests that different types of respiratory chain defects may lead to different profiles of these two proteins.

Objective: In this study, we aimed to validate the diagnostic reliability of FGF21 and GDF15 assays in MDs and to evaluate a possible correlation between serum levels of the two biomarkers with genotype of MD patients. Serum FGF21 and GDF15 levels were measured by a quantitative ELISA.

Results: Our results showed increased serum FGF21 and GDF15 levels in MD patients; however, GDF15 measurement seems to be more sensitive and specific for screening tests for MD than FGF21. Moreover, we showed a positive correlation with both FGF21 and GDF15 levels and the number of COX-negative fibers.

Conclusion: Finally, we also demonstrated that the increase of FGF21 and GDF15 was related to MDs caused by mitochondrial translation defects, and multiple and single mtDNA deletions, but not to MDs due to mutations in the respiratory chain subunits.
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http://dx.doi.org/10.1007/s10072-020-04422-5DOI Listing
December 2020

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

Replay to: Phenotypic spectrum of POLG1 mutations.

Neurol Sci 2018 03 2;39(3):575. Epub 2018 Feb 2.

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

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http://dx.doi.org/10.1007/s10072-017-3229-6DOI Listing
March 2018

Novel POLG mutations and variable clinical phenotypes in 13 Italian patients.

Neurol Sci 2017 Apr 27;38(4):563-570. Epub 2017 Jan 27.

Department of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100, Siena, Italy.

POLG gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA (mtDNA) replication and repair. Mutations in POLG have been linked to a spectrum of clinical phenotypes, resulting in autosomal recessive or dominant mitochondrial diseases. These mutations have been associated with heterogeneous phenotypes, presenting with varying severity and at different ages of onset, ranging from the neonatal period to late adult life. We screened 13 patients for POLG mutations. All patients underwent a complete neurological examination, and in most of cases, muscle biopsy was performed. We detected 15 different variations in 13 unrelated Italian patients. Two mutations were novel and mapped in the pol domain (p.Thr989dup and p.Ala847Thr) of the enzyme. We also report new cases carrying controversial variations previously described as incompletely penetrant or a variant of unknown significance. Our study increases the range of clinical presentations associated with mutations in POLG gene, underlining some peculiar clinical features, such as PEO associated with corneal edema, and epilepsy, severe neuropathy with achalasia. The addition of two new substitutions, including the second report of an in-frame duplication, to the growing list of defects increases the value of POLG genetic diagnosis in a range of neurological presentations.
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http://dx.doi.org/10.1007/s10072-016-2734-3DOI Listing
April 2017

Complex I deficiency related to T10158C mutation ND3 gene: A further definition of the clinical spectrum.

Brain Dev 2017 Mar 11;39(3):261-265. Epub 2016 Oct 11.

Department of Neurological, Neurosurgical and Behavioral Sciences, University of Siena, Italy.

Background: Complex I deficiency is the most common energy generation disorder which may clinically present at any age with a wide spectrum of symptoms and signs. The T10158C mutation ND3 gene is rare and occurs in patients showing an early rapid neurological deterioration invariably leading to death after a few months.

Case Presentation: We report a 9year-old boy with a mtDNA T10158C mutation showing a mild MELAS-like phenotype and brain MRI features congruent with both MELAS and Leigh syndrome. Epilepsia partialis continua also occurred in the clinical course and related to a mild cortical atrophy of the left perisylvian area.

Discussion: The present case confirms that the clinical spectrum of Complex I deficiency related to T10158C mutation ND3 gene is wider than previously described. Our observation further suggests that testing mutation in the MT-ND3 gene should be included in the diagnostic work-up of patients presenting with epilepsia partialis continua accompanied by suspicion of mitochondrial disorder.
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http://dx.doi.org/10.1016/j.braindev.2016.09.013DOI Listing
March 2017

Multiple sclerosis and chronic progressive external ophthalmoplegia associated with a large scale mitochondrial DNA single deletion.

J Neurol 2016 Jul 25;263(7):1449-51. Epub 2016 Apr 25.

Dipartimento di Medicina, Clinica Neurologica, Università degli Studi di Perugia, Ospedale S. Maria della Misericordia, 06156, Perugia, Italy.

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http://dx.doi.org/10.1007/s00415-016-8120-5DOI Listing
July 2016

Mitochondrial dysfunction in hereditary spastic paraparesis with mutations in DDHD1/SPG28.

J Neurol Sci 2016 Mar 4;362:287-91. Epub 2016 Feb 4.

Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.

Mutations in DDHD1 cause the SPG28 subtype of hereditary spastic paraplegia (HSP). Recent studies suggested that mitochondrial dysfunction occurs in SPG28. Here we describe two siblings with SPG28, and report evidence of mitochondrial impairment in skeletal muscle and skin fibroblasts. Patient 1 (Pt1) was a 35-year-old man with spastic paraparesis and urinary incontinence, while his 25-year-old brother (Pt2) had gait spasticity and motor axonal neuropathy. In these patients we identified the novel homozygous c.1429C>T/p.R477* mutation in DDHD1, using a next-generation sequencing (NGS) approach. Histochemical analyses in muscle showed mitochondrial alterations, and multiple mitochondrial DNA (mtDNA) deletions were evident. In Pt1, respiratory chain enzyme activities were altered in skeletal muscle, mitochondrial ATP levels reduced, and analysis of skin fibroblasts revealed mitochondrial fragmentation. It seems possible that the novel nonsense mutation identified abolishes DDHD1 protein function thus altering oxidative metabolism. Qualitative alterations of mtDNA could have a pathogenetic significance. We suggest to perform DDHD1 analysis in patients with multiple mtDNA deletions.
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http://dx.doi.org/10.1016/j.jns.2016.02.007DOI Listing
March 2016

Sporadic PEO caused by a novel POLG variation and a Twinkle mutation: digenic inheritance?

Neurol Sci 2015 Sep 7;36(9):1713-5. Epub 2015 Jun 7.

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

Progressive external ophthalmoplegia (PEO) with multiple deletions of mitochondrial DNA (mtDNA) is associated with several mutations in nuclear genes. They include POLG, POLG2, ANT1, C10orf2/Twinkle, and OPA1. However, digenic inheritance in mitochondrial disorders has been documented in a few cases over the years. Here we describe an 80-year-old man with sporadic PEO associated with mtDNA deletions. Sequencing of the POLG revealed a novel heterozygous mutation (c.2831A>G; p.Glu944Gly), predicted in silico as damaging, in the patient who also carried a heterozygous mutation in C10orf2/Twinkle (c.1142T>C; p.Leu381Pro). This case provides a second report of a PEO with different mutations in the POLG and C10orf2/Twinkle genes, supporting the hypothesis that the PEO phenotype can be determined by the co-existence of two abnormalities in separate genes, both involved in the maintenance and stability of mtDNA. Finally, this study expands the spectrum of POLG mutations and highlights the need to sequence the whole set of nuclear genes associated with PEO and multiple mtDNA deletions.
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http://dx.doi.org/10.1007/s10072-015-2247-5DOI Listing
September 2015

Redefining phenotypes associated with mitochondrial DNA single deletion.

J Neurol 2015 May 26;262(5):1301-9. Epub 2015 Mar 26.

Neurological Clinic, University of Pisa, Via Roma 67, 56126, Pisa, Italy,

Progressive external ophthalmoplegia (PEO), Kearns-Sayre syndrome (KSS) and Pearson syndrome are the three sporadic clinical syndromes classically associated with single large-scale deletions of mitochondrial DNA (mtDNA). PEO plus is a term frequently utilized in the clinical setting to identify patients with PEO and some degree of multisystem involvement, but a precise definition is not available. The purpose of the present study is to better define the clinical phenotypes associated with a single mtDNA deletion, by a retrospective study on a large cohort of 228 patients from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". In our database, single deletions account for about a third of all patients with mtDNA-related disease, more than previously recognized. We elaborated new criteria for the definition of PEO and "KSS spectrum" (a category of which classic KSS represents the most severe extreme). The criteria for "KSS spectrum" include the resulting multisystem clinical features associated with the KSS features, and which therefore can predict their presence or subsequent development. With the new criteria, we were able to classify nearly all our single-deletion patients: 64.5% PEO, 31.6% KSS spectrum (including classic KSS 6.6%) and 2.6% Pearson syndrome. The deletion length was greater in KSS spectrum than in PEO, whereas heteroplasmy was inversely related with age at onset. We believe that the new phenotype definitions implemented here may contribute to a more homogeneous patient categorization, which will be useful in future cohort studies of natural history and clinical trials.
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http://dx.doi.org/10.1007/s00415-015-7710-yDOI Listing
May 2015

Eye movement changes in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

J Neurol Sci 2015 Mar 29;350(1-2):107-9. Epub 2015 Jan 29.

Eye-tracking and Visual Application Lab (EVALab), University of Siena, Italy; Neurometabolic Unit Department of Medicine, Surgery and Neurosciences, University of Siena, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2015.01.031DOI Listing
March 2015

Mitochondrial recessive ataxia syndrome: A neurological rarity not to be missed.

J Neurol Sci 2015 Feb 3;349(1-2):254-5. Epub 2015 Jan 3.

Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.

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http://dx.doi.org/10.1016/j.jns.2014.12.040DOI Listing
February 2015

A case of 3243A>G mutation in mtDNA presenting as apparently idiopathic hyperCKemia.

J Neurol Sci 2014 Mar 14;338(1-2):232-4. Epub 2014 Jan 14.

Dept. of Medical, Surgical and Neurological Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy.

The 3243A>G mutation of mtDNA usually is associated with MELAS syndrome. Here we report a patient with the 3243A>G mutation presenting only recurrent muscle fatigue and elevated levels of serum creatine kinase (CK). The mother of the proband was referred to us for type 2 diabetes mellitus, muscle pain and sensorineural hearing loss. The percentage of mutation load in different tissues was similar in both subjects, except in the urinary epithelium. The mutation load in the son's urinary epithelial cells (UEC) was consistently higher (nearly 50%) than in his muscle (nearly 20%). We conclude that a correlation between the proportion of the UEC mutation load and the severity of the disease was lacking in this pedigree. The use of UEC as the tissue of choice in the noninvasive diagnosis of the 3243A>G mutation offers a very attractive alternative to muscle biopsy. Finally, our data expand the clinical spectrum of the 3243A>G mutation.
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http://dx.doi.org/10.1016/j.jns.2014.01.010DOI Listing
March 2014

Sporadic myopathy, myoclonus, leukoencephalopathy, neurosensory deafness, hypertrophic cardiomyopathy and insulin resistance associated with the mitochondrial 8306 T>C MTTK mutation.

J Neurol Sci 2012 Oct 24;321(1-2):92-5. Epub 2012 Aug 24.

Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Siena, Italy.

We report a new T8306C transition in the D-stem of the MTTK gene of a 67-year-old man who manifested severe adult onset myopathy, myoclonus, leukoencephalopathy, neurosensory hypoacusis, hypertrophic cardiomyopathy and insulin resistance. No other family member was affected, suggesting that our patient was a sporadic case. The T8306C mutation was heteroplasmic in several tissues of the proband, while it was absent from his asymptomatic siblings. Single fibre analysis confirmed the segregation of higher mutational load in cytochrome c oxidase-deficient fibres. The mutation T8306C is predicted to disrupt a highly conserved base pair and was not found in more than 120 controls. This finding broadens the phenotypic and molecular spectrum of mitochondrial tRNA(Lys) associated disorders.
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http://dx.doi.org/10.1016/j.jns.2012.07.027DOI Listing
October 2012

Mitochondria, oxidative stress and neurodegeneration.

J Neurol Sci 2012 Nov 4;322(1-2):254-62. Epub 2012 Jun 4.

Department of Neurological, Neurosurgical and Behavioural Sciences, Medical School, University of Siena, Italy.

Mitochondria are involved in ATP supply to cells through oxidative phosphorylation (OXPHOS), synthesis of key molecules and response to oxidative stress, as well as in apoptosis. They contain many redox enzymes and naturally occurring inefficiencies of oxidative phosphorylation generate reactive oxygen species (ROS). CNS functions depend heavily on efficient mitochondrial function, since brain tissue has a high energy demand. Mutations in mitochondrial DNA (mtDNA), generation and presence of ROS and environmental factors may contribute to energy failure and lead to neurodegenerative diseases. Many rare metabolic disorders have been associated with mitochondrial dysfunction. More than 300 pathogenic mtDNA mutations involve proteins that regulate OXPHOS and mitochondrial structural integrity, and have also been described in neurodegenerative diseases with autosomal inheritance. Mitochondria may have an important role in ageing-related neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). In primary mitochondrial and neurodegenerative disorders, there is strong evidence that mitochondrial dysfunction occurs early and has a primary role in pathogenesis. In the present review, we discuss several mitochondrial diseases as models of neurodegeneration.
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http://dx.doi.org/10.1016/j.jns.2012.05.030DOI Listing
November 2012

Spastic paraplegia in 'dominant optic atrophy plus' phenotype due to OPA1 mutation.

Brain 2011 Nov 6;134(Pt 11):e195. Epub 2011 Jun 6.

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http://dx.doi.org/10.1093/brain/awr101DOI Listing
November 2011

Progressive mitochondrial myopathy, deafness, and sporadic seizures associated with a novel mutation in the mitochondrial tRNASer(AGY) gene.

J Neurol Sci 2011 Apr 22;303(1-2):142-5. Epub 2011 Jan 22.

Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Siena, Italy.

We sequenced the mitochondrial genome from a patient with progressive mitochondrial myopathy associated with deafness, sporadic seizures, and histological and biochemical features of mitochondrial respiratory chain dysfunction. Direct sequencing showed a heteroplasmic mutation at nucleotide 12262 in the tRNASer(AGY) gene. RFLP analysis confirmed that 63% of muscle mtDNA harboured the mutation, while it was absent in all the other tissues. The mutation is predicted to influence the functional behaviour of the aminoacyl acceptor stem of the tRNA. Several point mutations on mitochondrial tRNA genes have been reported in patients affected by encephalomyopathies, but between them only four were reported for tRNASer(AGY).
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http://dx.doi.org/10.1016/j.jns.2010.12.020DOI Listing
April 2011

A novel point mutation in the mitochondrial tRNA((Trp)) gene produces late-onset encephalomyopathy, plus additional features.

J Neurol Sci 2010 Oct 13;297(1-2):105-8. Epub 2010 Aug 13.

Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Siena, Italy.

Background: Mitochondrial diseases due to mitochondrial tRNA genes mutations are usually multisystem disorders with infantile or adult onset.

Objective: To identify the molecular defect underlying a mitochondrial encephalomyopathy.

Methods/patients: Case report of a 51year-old woman presenting with late-onset myoclonic epilepsy plus additional features. Proband's mother presented hypothyroidism and diabetes.

Results: Muscle biopsy showed mitochondrial changes. Respiratory chain activities were reduced. The novel G5538A mutation was identified in different tissues DNAs from the proband and from her mother.

Conclusion: We were able to identify a novel mtDNA tRNA((Trp)) gene pathogenic mutation.
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http://dx.doi.org/10.1016/j.jns.2010.06.009DOI Listing
October 2010

A second MNGIE patient without typical mitochondrial skeletal muscle involvement.

Neurol Sci 2010 Aug 16;31(4):491-4. Epub 2010 Mar 16.

Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Viale Bracci 2, 53100, Siena, Italy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by mutations in the gene encoding thymidine phosphorylase (TYMP). Clinically, MNGIE is characterized by gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. Most MNGIE patients have signs of mitochondrial dysfunction in skeletal muscle at morphological and enzyme level, as well as mitochondrial DNA depletion, multiple deletions and point mutations. A case without mitochondrial skeletal muscle involvement and with a TYMP splice-acceptor site mutation (c. 215-1 G>C) has been reported. Here, we describe an Italian patient with the same mutation and without mitochondrial skeletal muscle involvement, suggesting a possible genotype-phenotype correlation.
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http://dx.doi.org/10.1007/s10072-010-0225-5DOI Listing
August 2010

Alu-element insertion in an OPA1 intron sequence associated with autosomal dominant optic atrophy.

Mol Vis 2010 Feb 10;16:178-83. Epub 2010 Feb 10.

Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, 53100 Siena, Italy.

Purpose: Autosomal dominant optic atrophy (ADOA) is the most common form of hereditary optic neuropathy caused by mutations in the optic atrophy 1 (OPA1) gene. It is characterized by insidious onset with a selective degeneration of retinal ganglion cells, variable loss of visual acuity, temporal optic nerve pallor, tritanopia, and development of central, paracentral, or cecocentral scotomas. Here we describe the clinical and molecular findings in a large Italian family with ADOA.

Methods: Routine ophthalmologic examination and direct sequencing of all coding regions of the OPA1 gene were performed. Further characterization of a new OPA1 gene insertion was performed by reverse transcription-PCR (RT-PCR) of RNA from patients and control subjects.

Results: We identified an Alu-element insertion located in intron 7 of OPA1 causing an in-frame deletion of exon 8 in 18 family members.

Conclusions: The predicted consequence of this mutation is the loss of the guanosine triphosphatase (GTPase) activity of OPA1. Alu insertions have been reported in the literature as causing human genetic disease. However, this is the first report of a pathogenic OPA1 gene mutation resulting from an Alu insertion.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820104PMC
February 2010

A novel mutation in the mitochondrial tRNA(Pro) gene associated with late-onset ataxia, retinitis pigmentosa, deafness, leukoencephalopathy and complex I deficiency.

Eur J Hum Genet 2009 Aug 18;17(8):1092-6. Epub 2009 Feb 18.

Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Italy.

We present a patient with ataxia, retinitis pigmentosa, dysarthria, neurosensorial deafness, nystagmus and leukoencephalopathy. A novel heteroplasmic G to A transition at nucleotide 15 975 was found, affecting the T arm of the mitochondrial (mt) tRNA(Pro) gene. A biochemical analysis of respiratory chain enzymes in muscle revealed isolated complex I deficiency. This is the fourth pathogenic tRNA(Pro) point mutation to be associated with an mt disorder. The result highlights the importance of molecular dissection of mtDNA in patients with defined mt disorder and confirms the clinical and biochemical heterogeneity associated with tRNA(Pro) mutations.
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http://dx.doi.org/10.1038/ejhg.2009.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986557PMC
August 2009

A novel heteroplasmic tRNA(Ser(UCN)) mtDNA point mutation associated with progressive external ophthalmoplegia and hearing loss.

Neuromuscul Disord 2007 Oct 5;17(9-10):681-3. Epub 2007 Jul 5.

Department of Neurological and Behavioural Sciences, University of Siena, Viale Bracci 2, Siena 53100, Italy.

We sequenced all mitochondrial tRNA genes from a patient with sporadic external ophthalmoplegia (PEO) and 5% COX-negative fibers in muscle biopsy, who had no detectable large mtDNA deletions. Direct sequencing showed a heteroplasmic mutation at nucleotide 7506 in the dihydrouridine stem of the tRNA(Ser(UCN)) gene. RFLP analysis confirmed that 30% of muscle and 20% of urinary epithelium mtDNA harbored the mutation, which was absent in other tissues of the proband as well as in mtDNA of his mother and 100 patients with various encephalomyopathies. Several point mutations on mitochondrial tRNA genes have been reported in PEO patients without large-scale rearrangements of mtDNA but no point mutations have hitherto been found in the gene coding for tRNA(Ser(UCN)).
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http://dx.doi.org/10.1016/j.nmd.2007.05.001DOI Listing
October 2007

The NDUFB11 gene is not a modifier in Leber hereditary optic neuropathy.

Biochem Biophys Res Commun 2007 Mar 2;355(1):181-7. Epub 2007 Feb 2.

Department of Medical Biochemistry, Medical Biology and Medical Physics, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy.

Over 95% of Leber hereditary optic neuropathy (LHON) cases are due to mutations in mitochondrial DNA-encoded subunits of NADH:ubiquinone oxidoreductase (E.C.1.6.5.3., complex I). A recessive X-linked susceptibility gene that acts synergistically with the primary mtDNA mutation to produce visual loss is suggested by the high male-to-female ratio among LHON patients. The ESSS protein is a recently isolated subunit of bovine heart mitochondrial complex I. We revisited the genomic sequence of NDUFB11, the human homolog mapping to chromosome Xp11.23, and identified two mRNA isoforms showing different expression profiles in human tissues. Cultured skin fibroblasts from four LHON patients showed a pattern of expression similar to normal controls. Moreover, NDUFB11 did not seem to influence risk and age at onset of visual loss in a total of 65 individuals from 35 Italian LHON families. Also, the gene was not affected in 11 children with a severe encephalopathy associated with decreased complex I activity in skeletal muscle.
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http://dx.doi.org/10.1016/j.bbrc.2007.01.140DOI Listing
March 2007

Rapidly progressive neurodegeneration in a case with the 7472insC mutation and the A7472C polymorphism in the mtDNA tRNA ser(UCN) gene.

Neuromuscul Disord 2006 Jan 20;16(1):26-31. Epub 2005 Dec 20.

Department of Neurological and Behavioural Sciences, Medical School, University of Siena, Viale Bracci 2, 53100 Siena, Italy.

The authors report the clinical, neuroimaging, muscle biopsy and mtDNA findings in a patient affected by bilateral hearing loss and mental retardation since infancy, presenting at age 31 years with a rapid deterioration of mental status and ataxia leading to vegetative condition and death at the age of 32 years. Clinical and genetic studies have been also performed in the mother, affected by neurosensorial hearing loss. Muscle biopsy showed severe mitochondrial alterations in the propositus and evidence of mitochondrial alterations in his mother. Direct mtDNA sequencing in all family members revealed the known 7472insC mutation and the recently described A7472C sequence variation in the tRNA(Ser(UCN))gene. RFLP-PCR confirmed the heteroplasmic nature of the two mutations and failed to find the second transversion in 200 controls. The percentage of mutant genomes harbouring 7472insC ranged from 3 to 7% in asymptomatic family members to 70% in the proband and his mother, whereas the percentage of A7472C mutant genomes was about 90% in all maternal relatives except the proband (56%) and his sister (5%). In conclusion, this is the first report of a rapidly progressive encephalopathy in association with the 7472insC mutation in mtDNA, combined with an A>C variation at the same nucleotide with a possible suppression effect on the pathogenic mutation.
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http://dx.doi.org/10.1016/j.nmd.2005.11.001DOI Listing
January 2006

Leber hereditary optic neuropathy in 2 of 4 siblings with 11778 mtDNA mutation: clinical variability or effect of toxic environmental exposure?

Eur Neurol 2005 10;53(1):32-4. Epub 2005 Feb 10.

Department of Neurological and Behavioral Sciences, Medical School, University of Siena, Siena, Italy.

Although mitochondrial (mt) DNA mutation at nucleotide position 11778 accounts for most cases of Leber's hereditary optic neuropathy (LHON), the phenotypic expression may vary greatly even in different members of the same family. The possible influence of exogenous toxicity on phenotypic expression is still debated in LHON. Here we describe 4 siblings carrying the 11778 mtDNA mutation with a different phenotype. The index case developed an atypical optic neuropathy at the age of 60 years after a long history of occupational exposure to polycyclic aromatic hydrocarbons (PAHs). This report underlines a number of unanswered questions about phenotypic variability of LHON including the possible influence of PAH toxicity.
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http://dx.doi.org/10.1159/000083927DOI Listing
May 2005

A novel heteroplasmic tRNA(Leu(CUN)) mtDNA point mutation associated with chronic progressive external ophthalmoplegia.

Biochem Biophys Res Commun 2005 Feb;327(3):675-8

Department of Neurological and Behavioural Sciences, University of Siena, Italy.

We have sequenced all mitochondrial tRNA genes from a patient with chronic progressive external ophthalmoplegia (CPEO) and mitochondrial myopathy, who had no detectable large mtDNA deletions. Direct sequencing failed to detect previously reported mutations and showed a heteroplasmic mutation at nucleotide 12,276 in the tRNA(Leu(CUN)) gene, in the dihydrouridine stem, which is highly conserved through the species during evolution. RFLP analyses confirmed that 18% of muscle mtDNA harbored the mutation, while it was absent from DNA of fibroblasts and lymphocytes of the proband and in 110 patients with other encephalomyopathies. To date, besides large and single nucleotide deletions, several point mutations on mitochondrial tRNA genes have been reported in CPEO patients, but only three were in the gene coding for tRNA(Leu(CUN)).
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http://dx.doi.org/10.1016/j.bbrc.2004.11.170DOI Listing
February 2005

Sequence analysis of the complete mitochondrial genome in patients with mitochondrial encephaloneuromyopathies lacking the common pathogenic DNA mutations.

Biochem Biophys Res Commun 2004 Nov;324(1):360-4

Unit of Neurology and Neurometabolic Diseases, Department of Neurological and Behavioural Sciences and Centre for Research, Therapy and Prevention of Neurohandicap, University of Siena, Italy.

The purpose of this study was to identify novel mitochondrial deoxyribonucleic acid (mtDNA) mutations in a series of patients with clinical and/or morphological features of mitochondrial dysfunction, but still no genetic diagnosis. A heterogeneous group of clinical disorders is caused by mutations in mtDNA that damage respiratory chain function of cell energy production. We developed a method to systematically screen the entire mitochondrial genome. The sequence-data were obtained with a rapid automated system. In the six mitochondrial genomes analysed we found 20 variants of the revised Cambridge reference sequence [Nat. Genet. 23 (1999) 147]. In skeletal muscle nineteen novel mtDNA variants were homoplasmic, suggesting secondary pathogenicity or co-responsibility in determination of the disease. In one patient we identified a novel heteroplasmic mtDNA mutation which presumably has a pathogenic role. This screening is therefore useful to extend the mtDNA polymorphism database and should facilitate definition of disease-related mutations in human mtDNA.
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http://dx.doi.org/10.1016/j.bbrc.2004.09.058DOI Listing
November 2004