scholarly journals Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease

2017 ◽  
Vol 3 (3) ◽  
pp. e149 ◽  
Author(s):  
Enrico Bugiardini ◽  
Olivia V. Poole ◽  
Andreea Manole ◽  
Alan M. Pittman ◽  
Alejandro Horga ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Mitochondrial Disease ◽  
Haplotype Analysis ◽  
Progressive External Ophthalmoplegia ◽  
Mtdna Deletions ◽  
Clinical Presentations ◽  
Human Rnase ◽  
Disease Haplotype ◽  
Founder Event ◽  
Pathophysiologic Mechanisms

Objective:Pathologic ribonuclease H1 (RNase H1) causes aberrant mitochondrial DNA (mtDNA) segregation and is associated with multiple mtDNA deletions. We aimed to determine the prevalence of RNase H1 gene (RNASEH1) mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations.Methods:RNASEH1 was analyzed in patients with (1) multiple deletions/depletion of muscle mtDNA and (2) mendelian progressive external ophthalmoplegia (PEO) with neuropathologic evidence of mitochondrial dysfunction, but no detectable multiple deletions/depletion of muscle mtDNA. Clinicopathologic and molecular evaluation of the newly identified and previously reported patients harboring RNASEH1 mutations was subsequently undertaken.Results:Pathogenic c.424G>A p.Val142Ile RNASEH1 mutations were detected in 3 pedigrees among the 74 probands screened. Given that all 3 families had Indian ancestry, RNASEH1 genetic analysis was undertaken in 50 additional Indian probands with variable clinical presentations associated with multiple mtDNA deletions, but no further RNASEH1 mutations were confirmed. RNASEH1-related mitochondrial disease was characterized by PEO (100%), cerebellar ataxia (57%), and dysphagia (50%). The ataxia neuropathy spectrum phenotype was observed in 1 patient. Although the c.424G>A p.Val142Ile mutation underpins all reported RNASEH1-related mitochondrial disease, haplotype analysis suggested an independent origin, rather than a founder event, for the variant in our families.Conclusions:In our cohort, RNASEH1 mutations represent the fourth most common cause of adult mendelian PEO associated with multiple mtDNA deletions, following mutations in POLG, RRM2B, and TWNK. RNASEH1 genetic analysis should also be considered in all patients with POLG-negative ataxia neuropathy spectrum. The pathophysiologic mechanisms by which the c.424G>A p.Val142Ile mutation impairs human RNase H1 warrant further investigation.

scholarly journals POLRMT mutations impair mitochondrial transcription causing neurological disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Monika Oláhová ◽  
Bradley Peter ◽  
Zsolt Szilagyi ◽  
Hector Diaz-Maldonado ◽  
Meenakshi Singh ◽  
...  
Keyword(s):  
Progressive External Ophthalmoplegia ◽  
Global Developmental Delay ◽  
Disease Mechanism ◽  
Mitochondrial Transcription ◽  
Functional Studies ◽  
Mtdna Deletions ◽  
Molecular Nature ◽  
Important Disease

AbstractWhile >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism.

A common ancestral glycoprotein (GP) 9 1828A>G (Asn45Ser) gene mutation occurring in European families from Australia and Northern Europe with Bernard-Soulier syndrome (BSS)

2005 ◽  
Vol 94 (09) ◽  
pp. 599-605 ◽  
Author(s):  
Marie-Christine Morel-Kopp ◽  
Jeannine M. Clemetson ◽  
Kenneth J. Clemetson ◽  
Riitta Kekomaki ◽  
Hartmut Kroll ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Haplotype Analysis ◽  
Great Majority ◽  
European Population ◽  
Single Individual ◽  
Adhesion Receptor ◽  
Northern European ◽  
Founder Event ◽  
Bernard Soulier Syndrome ◽  
Autosomal Recessive Manner

SummaryBernard-Soulier syndrome (BSS) is an extremely rare hereditary bleeding disorder, caused by mutations occurring in the Glycoprotein (GP) Ibα, GPIbβ and GP9 genes that encode for the corresponding subunits of platelet GPIb-V-IX adhesion receptor complex. BSS has been reported in many populations, mostly behaving in an autosomal-recessive manner. While the great majority of BSS mutations are unique to a single individual or family, the GP9 1828A>G Asn45Ser mutation, which we have identified in an undocumented Australian Caucasian, has already been reported in multiple unrelated Caucasian families from various Northern and Central European countries. Haplotype analysis of 19 BSS patients from 15 unrelated Northern European families (including 2 compound heterozygote siblings from a British family previously published, and 17 1828A>G Asn45Ser homozygotes), showed that 14 of these BSS patients from 11 of the 1828A>G Asn45Ser homozygote families share a common haplotype at the chromosomal region 3’ to the GP9 gene. Hence, the results suggest that the GP9 1828A>GAsn45Ser mutation in these families is ancient, and its frequent emergence in the European population is the result of a founder effect rather than recurrent mutational events. Association of the 1828A>G Asn45Ser mutation with variant haplotypes in 4 other Northern European BSS families raised the possibility of a second founder event, or rare recombinations in these families. Additional members from these ‘atypical’ lineages would need to be screened to resolve this question.

scholarly journals Late-onset presentation of POLG1-associated mitochondrial disease

2019 ◽  
Vol 12 (3) ◽  
pp. e228482 ◽  
Author(s):  
Bruna Meira ◽  
Rafael Roque ◽  
Miguel Pinto ◽  
André Caetano
Keyword(s):  
Mitochondrial Disease ◽  
Age Of Onset ◽  
Late Onset ◽  
Clinical Manifestations ◽  
Progressive External Ophthalmoplegia ◽  
Clinical Feature ◽  
Gait Ataxia ◽  
Chronic Progressive External Ophthalmoplegia ◽  
Genetic Studies ◽  
In Cis

Mutations in the nuclear POLG1 gene compromise the integrity of mitochondrial DNA and show great allelic and clinical heterogeneity. Among adult POLG1-associated mitochondrial disease, the main clinical feature is chronic progressive external ophthalmoplegia. Other related clinical manifestations are sensory or cerebellar ataxia, peripheral neuropathy, myopathy or extrapyramidal symptoms. We report the case of a 72-year-old man who presented with a late onset sensory neuronopathy, chronic progressive external ophthalmoplegia, gait ataxia and parkinsonism. Genetic studies showed a compound heterozygosity of known pathogenic mutations in the POLG1 gene (variant T252I/P587 L in cis configuration in allele 1 and variant R807C in allele 2). Late life presentation highlights that mitochondrial disorders should be considered regardless of age of onset of symptoms.

scholarly journals Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice

2005 ◽  
Vol 102 (49) ◽  
pp. 17687-17692 ◽  
Author(s):  
H. Tyynismaa ◽  
K. P. Mjosund ◽  
S. Wanrooij ◽  
I. Lappalainen ◽  
E. Ylikallio ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Late Onset ◽  
Mtdna Deletions

scholarly journals Kearns Sayer Syndrome- A Case Report

2020 ◽  
Vol 6 (6) ◽  
pp. 271-272
Author(s):  
Reshmi Mishra ◽  
Keyword(s):  
Case Report ◽  
Mitochondrial Disease ◽  
Prevalence Rate ◽  
Rare Case ◽  
Age Of Onset ◽  
Progressive External Ophthalmoplegia ◽  
Pigmentary Retinopathy ◽  
Kearns Sayre Syndrome

Kearns–Sayre syndrome (KSS) is a rare mitochondrial disease was first described in 1958. The characteristic triad is age of onset less than 20 years, progressive external ophthalmoplegia, pigmentary retinopathy, The prevalence rate of KSS is nearly 1–3 per 100 000 individuals. Here, we report a rare case of a 11-year-old male with KSS.

scholarly journals Kearns-Sayre Syndrome: A Rare Mitochondrial Disorder

2017 ◽  
Vol 19 (1) ◽  
pp. 66-69
Author(s):  
Quazi Tarikul Islam ◽  
Homayra Tahseen Hossain ◽  
Md Abul Kashem Khandaker ◽  
HAM Nazmul Ahasan ◽  
Maksudul Majumder ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Mitochondrial Disorder ◽  
Progressive External Ophthalmoplegia ◽  
Endocrine Disorders ◽  
Chronic Progressive External Ophthalmoplegia ◽  
Diagnostic Investigation ◽  
Kearns Sayre Syndrome ◽  
First Case ◽  
Wide Range ◽  
Clinical Background

Mitochondrial disease, once thought to be a rare clinical entity, is now recognized as an important cause of a wide range of neurologic, muscle, cardiac and endocrine disorders. Kearns Sayre syndrome is a rare mitochondrial disease, involving deletion of mitochondrial DNA. This syndrome ischaracterized by progressive external ophthalmoplegia (PEO), retinitis pigmentosa and an onset before the age of 20 years. First case was reported in 1958. We are reporting a case with chronic progressive external ophthalmoplegia, bilateral partial ptosis with onset at 10 years of age. He also had features of myopathy and neuropathy without any fatigable weakness. Our diagnosis is mostly based on clinical background and by exclusion of other common disorders, as definitive diagnostic investigation genetic testing due to unavailability so was not done.J MEDICINE Jan 2018; 19 (1) : 66-69

Relapsing remitting multiple sclerosis in progressive external ophthalmoplegia: A report of two cases

2018 ◽  
Vol 25 (6) ◽  
pp. 879-882 ◽  
Author(s):  
Kevin R Patel ◽  
Amel Karaa ◽  
Farrah J Mateen
Keyword(s):  
Multiple Sclerosis ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Progressive External Ophthalmoplegia ◽  
Genetic Mutations ◽  
Mcdonald Criteria ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

Evidence from genetic and pathologic studies suggests that mitochondrial dysfunction occurs in multiple sclerosis (MS). Furthermore, cases of MS have been reported in patients with mitochondrial disease. The phenotypic range of mitochondrial illness associating with MS is not yet well defined. In this report, we highlight two cases of patients with confirmed genetic mutations responsible for progressive external ophthalmoplegia who independently meet McDonald criteria for MS. Better characterization of the range of mitochondrial disease associated with MS may improve our understanding of MS disease pathophysiology.

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