Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 16 de 16
Filter
1.
Eye (Lond) ; 31(3): 475-480, 2017 Mar.
Article in English | MEDLINE | ID: mdl-27858935

ABSTRACT

PurposeAutosomal-dominant optic atrophy (ADOA), often associated with mutations in the OPA1 gene (chromosome 3q28-q29) is rarely reported in Asia. Our aim was to identify and describe this condition in an Asian population in Singapore.Patients and methodsPreliminary cross-sectional study at the Singapore National Eye Centre, including patients with clinical suspicion of ADOA, who subsequently underwent genetic testing by direct sequencing of the OPA1 gene.ResultsAmong 12 patients (10 families) with clinically suspected ADOA, 7 patients (5 families) from 3 different ethnic origins (Chinese, Indian, and Malay) carried a heterozygous pathogenic variant in the OPA1 gene. The OPA1 mutations were located on exons 8, 9, 11, and 17: c.869G>A (p.Arg290Glu), c.892A>G (p.Ser298Gly), c.1140G>A (splicing mutation), and c.1669C>T (p.Arg557*), respectively. One splicing mutation (c.871-1G>A) was identified in intron 8. We also identified a novel mutation causing optic atrophy and deafness (c.892A>G (p.Ser298Gly)). Among the phenotypic features, colour pupillometry disclosed a dissociation between low vision and preserved pupillary light reflex in ADOA.ConclusionWe report the first cases of genetically confirmed OPA1-related ADOA from Singapore, including a novel mutation causing 'ADOA plus' syndrome. Further epidemiological studies are needed in order to determine the prevalence of ADOA in South-East Asia.


Subject(s)
GTP Phosphohydrolases/genetics , Genetic Predisposition to Disease , Mutation , Optic Atrophy, Autosomal Dominant/genetics , Adult , Aged , Asian People , Cross-Sectional Studies , DNA Mutational Analysis , Female , Humans , Male , Middle Aged , Optic Atrophy, Autosomal Dominant/ethnology , Singapore , Visual Acuity
3.
Cell Death Discov ; 2: 16017, 2016 Mar 07.
Article in English | MEDLINE | ID: mdl-27275396

ABSTRACT

In vertebrates, 14-3-3 proteins form a family of seven highly conserved isoforms with chaperone activity, which bind phosphorylated substrates mostly involved in regulatory and checkpoint pathways. 14-3-3 proteins are the most abundant protein in the brain and are abundantly found in the cerebrospinal fluid in neurodegenerative diseases, suggesting a critical role in neuron physiology and death. Here we show that 14-3-3eta-deficient mice displayed auditory impairment accompanied by cochlear hair cells' degeneration. We show that 14-3-3eta is highly expressed in the outer and inner hair cells, spiral ganglion neurons of cochlea and retinal ganglion cells. Screening of YWHAH, the gene encoding the 14-3-3eta isoform, in non-syndromic and syndromic deafness, revealed seven non-synonymous variants never reported before. Among them, two were predicted to be damaging in families with syndromic deafness. In vitro, variants of YWHAH induce mild mitochondrial fragmentation and severe susceptibility to apoptosis, in agreement with a reduced capacity of mutated 14-3-3eta to bind the pro-apoptotic Bad protein. This study demonstrates that YWHAH variants can have a substantial effect on 14-3-3eta function and that 14-3-3eta could be a critical factor in the survival of outer hair cells.

4.
Rev Neurol (Paris) ; 170(5): 344-54, 2014 May.
Article in English | MEDLINE | ID: mdl-24798923

ABSTRACT

Mitochondrial dysfunction leads to cellular energetic impairment, which may affect the visual pathways, from the retina to retrochiasmal structures. The most common mitochondrial optic neuropathies include Leber's hereditary optic neuropathy and autosomal dominant optic atrophy, but the optic nerve can be affected in other syndromic conditions, such as Wolfram syndrome and Friedreich's ataxia. These disorders may result from mutations in either the mitochondrial DNA or in the nuclear genes encoding mitochondrial proteins. Despite the inconstant genotype-phenotype correlations, a clinical classification of mitochondrial disorders may be made on the basis of distinct neuro-ophthalmic presentations such as optic neuropathy, pigmentary retinopathy and retrochiasmal visual loss. Although no curative treatments are available at present, recent advances throw new light on the pathophysiology of mitochondrial disorders. Current research raises hopes for novel treatment of hereditary optic neuropathies, particularly through the use of new drugs and mitochondrial gene therapy.


Subject(s)
Mitochondrial Diseases/complications , Mitochondrial Diseases/physiopathology , Optic Nerve Diseases/etiology , Visual Pathways/physiopathology , Animals , Humans , Optic Nerve Diseases/physiopathology , Retinitis Pigmentosa/etiology , Retinitis Pigmentosa/physiopathology , Visual Fields
5.
Rev Neurol (Paris) ; 170(5): 390-400, 2014 May.
Article in English | MEDLINE | ID: mdl-24792485

ABSTRACT

Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have no effective therapies. The development of new metabolic treatments will be useful not only for rare mitochondrial disorders but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A better understanding of the mitochondrial regulating pathways raised several promising perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet.


Subject(s)
Mitochondrial Diseases/drug therapy , Molecular Targeted Therapy/methods , Neurodegenerative Diseases/prevention & control , Neuroprotective Agents/therapeutic use , Animals , Cytoprotection/drug effects , Humans , Neurons/drug effects
8.
Rev Neurol (Paris) ; 166(12): 959-65, 2010 Dec.
Article in French | MEDLINE | ID: mdl-21056443

ABSTRACT

INTRODUCTION: Hereditary optic neuropathies, resulting from retinal ganglion cell degeneration, are a heterogeneous group of diseases ranging from asymptomatic forms to legal blindness. STATE OF KNOWLEDGE: Two most frequent phenotypes are Kjer's disease, an autosomal dominant optic atrophy caused by OPA1 gene mutations, and Leber's disease due to maternally inherited mitochondrial DNA mutations. PROSPECTS AND CONCLUSION: Both optic neuropathies usually isolated are sometimes associated with extraocular symptoms, especially neurological symptoms, thus justifying a systematic neurological evaluation and brain imaging.


Subject(s)
Optic Atrophies, Hereditary/genetics , Optic Atrophies, Hereditary/pathology , DNA, Mitochondrial/genetics , GTP Phosphohydrolases/genetics , Humans , Mutation , Optic Atrophies, Hereditary/diagnosis , Optic Atrophy, Autosomal Dominant/genetics , Optic Atrophy, Autosomal Dominant/pathology , Optic Atrophy, Hereditary, Leber/genetics , Optic Atrophy, Hereditary, Leber/pathology , Retinal Ganglion Cells/pathology
9.
Brain ; 133(Pt 3): 771-86, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20157015

ABSTRACT

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.


Subject(s)
Central Nervous System Diseases/complications , GTP Phosphohydrolases/genetics , Optic Atrophy, Autosomal Dominant/complications , Adolescent , Adult , Aged , Central Nervous System Diseases/genetics , Central Nervous System Diseases/metabolism , Central Nervous System Diseases/pathology , Child , Cohort Studies , DNA, Mitochondrial/analysis , DNA, Mitochondrial/genetics , Family , Female , Heterozygote , Humans , Male , Middle Aged , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Mutation , Optic Atrophy, Autosomal Dominant/genetics , Optic Atrophy, Autosomal Dominant/metabolism , Optic Atrophy, Autosomal Dominant/pathology , Phenotype , Young Adult
10.
J Med Genet ; 47(1): 22-9, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19592390

ABSTRACT

BACKGROUND: Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved our ability to detect cryptic unbalanced rearrangements in patients with syndromic mental retardation. METHOD: Molecular karyotyping of six patients with syndromic mental retardation was carried out using whole-genome oligonucleotide array-CGH. RESULTS: 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb were detected in five unrelated patients with the following phenotypic similarities: severe mental retardation with absent speech, hypotonia and stereotypic movements. Facial dysmorphic features, epilepsy and/or cerebral malformations were also present in most of these patients. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, the gene for a protein known to act in brain as a neurogenesis effector, which regulates excitatory synapse number. In a patient with a similar phenotype, an MEF2C nonsense mutation was subsequently identified. CONCLUSION: Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.


Subject(s)
Cerebrum/abnormalities , Chromosome Deletion , Chromosomes, Human, Pair 5/genetics , Epilepsy/genetics , Intellectual Disability/genetics , MADS Domain Proteins/genetics , Myogenic Regulatory Factors/genetics , Stereotypic Movement Disorder/genetics , Cerebrum/metabolism , Child , Child, Preschool , Haploidy , Humans , Infant , MEF2 Transcription Factors
11.
Diabetes Metab ; 34(6 Pt 1): 620-6, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18955007

ABSTRACT

AIMS: To report on a family with five members who carry the A3243G mutation in mitochondrial tRNA for leucine 1 (MTTL1) and present with diabetes, chronic intestinal pseudo-obstruction (CIPO) and recurrent pancreatitis, and to screen for this mutation in a cohort of 36 unrelated patients with recurrent pancreatitis. METHODS: The mutation was quantified in several tissue samples from patients. Respiratory chain activity was studied in muscle biopsies and fibroblast cultures. In addition, the thymidine phosphorylase gene (TP) involved in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and three genes involved in chronic pancreatitis - PRSS1, SPINK1 and CFTR - were sequenced in affected patients. Finally, the MTTL1 gene was examined in 36 unrelated patients who had recurrent pancreatitis, but no mutations in the PRSS1 and SPINK1 genes. RESULTS: Heteroplasmy for the mtDNA A3243G mutation was found in all tissue samples from these patients, but no mutations were found in the genes coding for thymidine phosphorylase, PRSS1, SPINK1 and CFTR. Also, none of the 36 unrelated patients with recurrent pancreatitis were carrying any MTTL1 mutations. CONCLUSION: The mtDNA A3243G mutation associated with the gastrointestinal manifestations observed in the affected family should be regarded as a possible cause of CIPO and unexplained recurrent pancreatitis. However, the mutation is probably only weakly involved in cases of isolated recurrent pancreatitis.


Subject(s)
DNA, Mitochondrial/genetics , Diabetes Complications/genetics , Diabetes Mellitus/genetics , Intestinal Pseudo-Obstruction/genetics , Pancreatitis/genetics , Polymorphism, Single Nucleotide , Deafness/genetics , Diabetes Complications/pathology , Diabetes Mellitus/pathology , Female , Humans , Male , Middle Aged , Muscle, Skeletal/pathology , Mutation , Pedigree , Recurrence
13.
J Fr Ophtalmol ; 30(2): 161-4, 2007 Feb.
Article in French | MEDLINE | ID: mdl-17318099

ABSTRACT

Autosomal dominant optic atrophy, or Kjer disease, is the most frequent form of autosomal dominant optic neuropathy. We report a novel mutation of the OPA1 gene in two brothers with autosomal dominant optic atrophy and describe their clinical features. The two patients, aged 41 and 37, presented with a bilateral visual impairment that had been detected at the age of 4 in both of them. Their ophthalmoscopic examinations disclosed a bilateral optic atrophy and their Goldmann visual fields showed cecocentral scotomas. The patients thought their disease might be a Leber's hereditary optic neuropathy; however, mutations had ever been sought. When first seen by us, they wished to know whether their disorder might be transmitted to their children. They had a family history of visual impairment. We carried out mtDNA sequencing but we did not identify any primary or rare Leber's hereditary optic neuropathy mutations. On the other hand, the 30 coding exons of the OPA1 gene and the intron-exon junctions were amplified by polymerase chain reaction and sequenced. A novel mutation of the OPA1 gene was found in both brothers: a deletion of four nucleotides in intron 19, associated with anomalous splicing, demonstrating the pathogenicity of the mutation. These molecular analyses contributed to identifying a novel mutation of the OPA1 gene with a clinical phenotype of isolated optic atrophy.


Subject(s)
GTP Phosphohydrolases/genetics , Mutation , Optic Atrophies, Hereditary/genetics , Adult , Functional Laterality , Genes, Dominant , Humans , Male , Siblings
14.
Rev Neurol (Paris) ; 161(4): 451-4, 2005 Apr.
Article in French | MEDLINE | ID: mdl-15924081

ABSTRACT

INTRODUCTION: In 1961, Garcin et al. described a family with several members affected with optic atrophy associated with cataract, and neurological symptoms. The authors believed this condition to be distinct from other diseases known at that time, e.g. the Behr syndrome, Marinesco-Sjogren syndrome and Friedreich's ataxia. METHOD: This family was followed over a period of 40 years and genes known to be responsible for optic atrophy were sequenced. RESULTS: The G277A mutation of OPA3 gene was responsible for this familial disease. DISCUSSION: A new clinical entity is identified: autosomal dominant optic atrophy and cataract, due to a heterozygous mutation of the OPA3 gene, a nuclear gene encoding a mitochondrial protein.


Subject(s)
Basal Ganglia Diseases/genetics , Cataract/genetics , Mutation , Optic Atrophies, Hereditary/genetics , Proteins/genetics , Adult , Aged , Aged, 80 and over , Basal Ganglia Diseases/complications , Cataract/complications , Child , Female , Follow-Up Studies , Humans , Middle Aged , Optic Atrophies, Hereditary/complications , Pedigree
SELECTION OF CITATIONS
SEARCH DETAIL
...