Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia

Horga, Alejandro; Pitceathly, Robert D S; Blake, Julian; Woodward, Catherine E; Zapater, Pedro; Fratter, Carl; Mudanohwo, Ese; Plant, Gordon T.; Houlden, Henry; Sweeney, Mary G.; Hanna, Michael G.; Reilly, Mary M.

doi:10.1093/brain/awu279

Cited by 42 publications

(33 citation statements)

References 49 publications

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“…Overall, peripheral neuropathy was rare in our cohort (&4 %), coherently with the notion that neuropathy is rare in patients with mtDNA single deletion, especially compared with mitochondrial diseases due to other etiologies [24].…”

Section: Discussionsupporting

confidence: 89%

Redefining phenotypes associated with mitochondrial DNA single deletion

et al. 2015

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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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Section: Discussionsupporting

confidence: 89%

Redefining phenotypes associated with mitochondrial DNA single deletion

et al. 2015

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“…In this study, 67% of PEO patients had a single mitochondrial DNA deletion, whereas 10% had a point mutation of mtDNA and 22% had mutations in either POLG, C10orf2, RRM2B, or had multiple mtDNA deletions in muscle without an identified nuclear gene defect. The prevalence of peripheral neuropathy was significantly lower in patients with single, sporadic mitochondrial DNA deletion (2%) as compared to those with a mtDNA point mutation or with a nuclear DNA defect (44% and 52%, respectively; P < 0.001) [10]. Therefore, our results confirm the suggestion by Horga et al, that in PEO patients peripheral neuropathy is rarely found in association with single mtDNA deletions, whereas it is highly predictive of an underlying nuclear DNA defect [10,11].…”

Section: Discussionmentioning

confidence: 86%

“…The prevalence of peripheral neuropathy was significantly lower in patients with single, sporadic mitochondrial DNA deletion (2%) as compared to those with a mtDNA point mutation or with a nuclear DNA defect (44% and 52%, respectively; P < 0.001) [10]. Therefore, our results confirm the suggestion by Horga et al, that in PEO patients peripheral neuropathy is rarely found in association with single mtDNA deletions, whereas it is highly predictive of an underlying nuclear DNA defect [10,11]. Indeed, our data extend this concept to the entire population of mitochondrial patients, in addition to those with PEO; furthermore, we show that a "mitochondrial neuropathies" are predominantly associated with a few specific nuclear genes associated: POLG, TYMP and SURF1.…”

Section: Discussionmentioning

confidence: 86%

“…Recently, Horga et al [10] reported that peripheral neuropathy might suggest a nuclear gene defect in patients with mitochondrial progressive external ophthalmoplegia (PEO). In this study, 67% of PEO patients had a single mitochondrial DNA deletion, whereas 10% had a point mutation of mtDNA and 22% had mutations in either POLG, C10orf2, RRM2B, or had multiple mtDNA deletions in muscle without an identified nuclear gene defect.…”

Section: Discussionmentioning

confidence: 99%

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“Mitochondrial neuropathies”: A survey from the large cohort of the Italian Network

Mancuso

Orsucci

Angelini

et al. 2016

Neuromuscular Disorders

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Involvement of the peripheral nervous system in mitochondrial disorders has been previously reported. However, the prevalence of peripheral neuropathy in mitochondrial disorders is still unclear. Based on the large database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", we reviewed the clinical data of 1200 patients, with special regard to peripheral neuropathy (mean age at onset 24.3 ± 20.1 years; age at last evaluation 39.8 ± 22.3 years; females 52.7%; childhood onset [before age 16 years] 43.1%). Peripheral neuropathy was present in 143/1156 patients (12.4%), being one of the ten most common signs and symptoms. POLG mutations cause a potentially painful, axonal/mixed, mainly sensory polyneuropathy; TYMP mutations lead to a demyelinating sensory-motor polyneuropathy; SURF1 mutations are associated with a demyelinating/mixed sensory-motor polyneuropathy. The only mtDNA mutation consistently associated with peripheral neuropathy (although less severely than in the above-considered nuclear genes) was the m.8993T > G (or the rarer T > C) changes, which lead to an axonal, mainly sensory polyneuropathy. In conclusion, peripheral neuropathy is one of the most common features of a mitochondrial disorder, and may negatively impact on the quality of life of these patients. Furthermore, the presence or absence of peripheral neuropathy, as well as its specific forms and the association with neuropathic pain (indicative of a POLG-associated disease) can guide the molecular analysis.

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“…Progressive external ophthalmoplegia is the the most common disorder of cranial musculature and is seen with both nuclear and mitochondrial DNA mutations w76. The presence of Duane syndrome, a congenital and non-progressive strabismus with a mild sensory and motor axonal neuropathy is seen with dominant mutations in TUBB3 w77…”

Section: Introductionmentioning

confidence: 99%

Peripheral neuropathy in complex inherited diseases: an approach to diagnosis

Rossor

Carr

Devine

et al. 2017

J Neurol Neurosurg Psychiatry

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Peripheral neuropathy is a common finding in patients with complex inherited neurological diseases and may be subclinical or a major component of the phenotype. This review aims to provide a clinical approach to the diagnosis of this complex group of patients by addressing key questions including the predominant neurological syndrome associated with the neuropathy e.g. spasticity, the type of neuropathy, and the other neurological and nonneurological features of the syndrome. Priority is given to the diagnosis of treatable conditions. Using this approach, we associated neuropathy with one of three major syndromic categories -1) ataxia, 2) spasticity, and 3) global neurodevelopmental impairment. Syndromes that do not fall easily into one of these three categories can be grouped according to the predominant system involved in addition to the neuropathy e.g. cardiomyopathy and neuropathy. We also include a separate category of complex inherited relapsing neuropathy syndromes, some of which may mimic Guillain Barré syndrome, as many will have a metabolic aetiology and be potentially treatable.

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Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia

Cited by 42 publications

References 49 publications

Redefining phenotypes associated with mitochondrial DNA single deletion

Redefining phenotypes associated with mitochondrial DNA single deletion

“Mitochondrial neuropathies”: A survey from the large cohort of the Italian Network

Peripheral neuropathy in complex inherited diseases: an approach to diagnosis

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