A diagnostic flow chart for<i>POLG-</i>related diseases based on signs sensitivity and specificity

Tchikviladzé, Maya; Gilleron, Mylène; Maisonobe, Thierry; Galanaud, Damien; Laforêt, Pascal; Dürr, Alexandra; Eymard, B.; Mochel, Fanny; Ogier, H.; Béhin, Anthony; Stojkovic, Tanya; Degos, Bertrand; Gourfinkel‐An, Isabelle; Sedel, Frédéric; Anheim, Mathieu; Elbaz, Alexis; Viala, Karine; Vidailhet, Marie; Brice, Alexis; Jardel, Claude; Lombès, Anne

doi:10.1136/jnnp-2013-306799

Cited by 32 publications

(25 citation statements)

References 40 publications

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“…Three patients (patient 1, 4 and 5) had a history of migraine but in one of these three patients, genetic testing showed that migraine did not co-segregate with the mutation in his family. Six of our patients had sensory axonal polyneuropathy which is in line with the high percentage of 94 % reported in a recent paper of Tchikviladze et al [29]. In our cohort, no patient showed psychiatric comorbidity [29,30].…”

Section: Additional Clinical Featuressupporting

confidence: 90%

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The spectrum of epilepsy caused by POLG mutations

et al. 2015

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Mutations in POLG are increasingly recognized as a cause of refractory occipital lobe epilepsy (OLE) and status epilepticus (SE). Our aim was to describe the epilepsy syndrome in seven patients with POLG mutations. We retrospectively reviewed the medical records of seven patients with POLG mutations and epilepsy. Mutation analysis was performed by direct sequencing of the coding exons of the POLG gene. Disease onset was at a median age of 18 years (range 12-26). Epilepsy was the presenting problem in six patients. All had focal seizures, with motor (n = 6) and visual (n = 6) phenomena. Six patients had secondarily generalized seizures and two patients had myoclonic seizures. Six patients had one or more episodes of refractory SE, including focal (n = 5), subtle (n = 4), myoclonic (n = 2) and convulsive (n = 3) SE. During or after SE, brain MRI showed lesions affecting the occipital lobe in all patients, probably due to continuous epileptic activity. Five of the six patients with SE died during treatment of SE, one due to valproate-induced hepatotoxicity. Associated clinical symptoms were ataxia (n = 6), polyneuropathy (n = 6), progressive external ophthalmoplegia (PEO) (n = 3) and migraine (n = 3). Epilepsy may be the first and dominant neurological problem caused by POLG mutations. The epilepsy may be severe and the condition of the patient may end in fatal SE. Refractory OLE and SE in a patient with polyneuropathy, ataxia, PEO or migraine warrant screening for POLG mutations. In this clinical setting, valproate should not be given in view of the risk of fatal hepatotoxicity.

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Section: Additional Clinical Featuressupporting

confidence: 90%

“…Six of our patients had sensory axonal polyneuropathy which is in line with the high percentage of 94 % reported in a recent paper of Tchikviladze et al [29]. In our cohort, no patient showed psychiatric comorbidity [29,30].…”

Section: Additional Clinical Featuressupporting

confidence: 90%

The spectrum of epilepsy caused by POLG mutations

et al. 2015

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“…Mutations of the mitochondrial DNA (mtDNA) encoded by the POLG gene are an important cause of pediatric and adult-onset mitochondrial disease. In adults, they are associated with multiple mtDNA deletions leading to a wide spectrum of dominant and recessive progressive neurological disorders, often described as syndromes, such as progressive external ophthalmoplegia, Alpers syndrome, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (65, 66). POLG mutation should also be considered in patients with PAPT or progressive ataxia with inferior olive hypersignal (54), even in sporadic cases, and even without other frequently associated neurological signs such as sensory neuronopathy associated with weakness of ocular, pharyngeal, axial, and/or limb muscles (66).…”

Section: Etiologiesmentioning

confidence: 99%

Hypertrophic Olivary Degeneration and Palatal or Oculopalatal Tremor

2017

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Hypertrophic degeneration of the inferior olive is mainly observed in patients developing palatal tremor (PT) or oculopalatal tremor (OPT). This syndrome manifests as a synchronous tremor of the palate (PT) and/or eyes (OPT) that may also involve other muscles from the branchial arches. It is associated with hypertrophic inferior olivary degeneration that is characterized by enlarged and vacuolated neurons, increased number and size of astrocytes, severe fibrillary gliosis, and demyelination. It appears on MRI as an increased T2/FLAIR signal intensity and enlargement of the inferior olive. There are two main conditions in which hypertrophic degeneration of the inferior olive occurs. The most frequent, studied, and reported condition is the development of PT/OPT and hypertrophic degeneration of the inferior olive in the weeks or months following a structural brainstem or cerebellar lesion. This “symptomatic” condition requires a destructive lesion in the Guillain–Mollaret pathway, which spans from the contralateral dentate nucleus via the brachium conjunctivum and the ipsilateral central tegmental tract innervating the inferior olive. The most frequent etiologies of destructive lesion are stroke (hemorrhagic more often than ischemic), brain trauma, brainstem tumors, and surgical or gamma knife treatment of brainstem cavernoma. The most accepted explanation for this symptomatic PT/OPT is that denervated olivary neurons released from inhibitory inputs enlarge and develop sustained synchronized oscillations. The cerebellum then modulates/accentuates this signal resulting in abnormal motor output in the branchial arches. In a second condition, PT/OPT and progressive cerebellar ataxia occurs in patients without structural brainstem or cerebellar lesion, other than cerebellar atrophy. This syndrome of progressive ataxia and palatal tremor may be sporadic or familial. In the familial form, where hypertrophic degeneration of the inferior olive may not occur (or not reported), the main reported etiologies are Alexander disease, polymerase gamma mutation, and spinocerebellar ataxia type 20. Whether or not these are associated with specific degeneration of the dentato–olivary pathway remain to be determined. The most symptomatic consequence of OPT is eye oscillations. Therapeutic trials suggest gabapentin or memantine as valuable drugs to treat eye oscillations in OPT.

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“…They are the most common monogenic cause of inherited autosomal mitochondrial disease. Their wide clinical phenotype spectrum ranges ABBREVIATIONS: ADA, adenosine deaminase; dAdo, deoxyadenosine; dATP, dAdo triphosphate; dCtd, deoxycytidine; dCTP, dCtd triphosphate; dGTP, dGuo triphosphate; dGuo, deoxyguanosine; dIno, deoxyinosine; dN, deoxyribonucleoside; dNTP, deoxyribonucleoside triphosphate; dThd, deoxythymidine; dTTP, dThd triphosphate; dUrd, deoxyuridine; EHNA, erythro-9-(2-hydroxy-3-nonyl) adenine; EtBr, ethidium bromide; FBS, fetal bovine serum; mip1, DNA-directed DNA polymerase g; mtDNA, mitochondrial DNA; PDB, Protein Data Bank; PEO, progressive external ophtalmoplegia; POLG, polymerase g catalytic subunit; TK2, thymidine kinase 2 from severe infantile to mild adult-onset manifestations (4,5). Infantile forms include Alpers-Huttenlocher syndrome and myohepatocerebral syndromes.…”

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confidence: 99%

Increased dNTP pools rescue mtDNA depletion in human POLG‐deficient fibroblasts

et al. 2019

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Polymerase γ catalytic subunit (POLG) gene encodes the enzyme responsible for mitochondrial DNA (mtDNA) synthesis. Mutations affecting POLG are the most prevalent cause of mitochondrial disease because of defective mtDNA replication and lead to a wide spectrum of clinical phenotypes characterized by mtDNA deletions or depletion. Enhancing mitochondrial deoxyribonucleoside triphosphate (dNTP) synthesis effectively rescues mtDNA depletion in different models of defective mtDNA maintenance due to dNTP insufficiency. In this study, we studied mtDNA copy number recovery rates following ethidium bromide‐forced depletion in quiescent fibroblasts from patients harboring mutations in different domains of POLG. Whereas control cells spontaneously recovered initial mtDNA levels, POLG‐deficient cells experienced a more severe depletion and could not repopulate mtDNA. However, activation of deoxyribonucleoside (dN) salvage by supplementation with dNs plus erythro‐9‐(2‐hydroxy‐3‐nonyl) adenine (inhibitor of deoxyadenosine degradation) led to increased mitochondrial dNTP pools and promoted mtDNA repopulation in all tested POLG‐mutant cells independently of their specific genetic defect. The treatment did not compromise POLG fidelity because no increase in multiple deletions or point mutations was detected. Our study suggests that physiologic dNTP concentration limits the mtDNA replication rate. We thus propose that increasing mitochondrial dNTP availability could be of therapeutic interest for POLG deficiency and other conditions in which mtDNA maintenance is challenged.—Blázquez‐Bermejo, C., Carreño‐Gago, L., Molina‐Granada, D., Aguirre, J., Ramon, J., Torres‐Torronteras, J., Cabrera‐Pérez, R., Martín, M. Á., Domínguez‐González, C., de la Cruz, X., Lombès, A., García‐Arumí, E., Martí, R., Cámara, Y. Increased dNTP pools rescue mtDNA depletion in human POLG‐deficient fibroblasts. FASEB J. 33, 7168–7179 (2019). http://www.fasebj.org

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A diagnostic flow chart forPOLG-related diseases based on signs sensitivity and specificity

Abstract: Phenotypes associated with POLG mutations follow a reproducible pattern, which allows establishing a diagnostic flow chart.

Cited by 32 publications

References 40 publications

The spectrum of epilepsy caused by POLG mutations

The spectrum of epilepsy caused by POLG mutations

Hypertrophic Olivary Degeneration and Palatal or Oculopalatal Tremor

Increased dNTP pools rescue mtDNA depletion in human POLG‐deficient fibroblasts

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