POLG mutation in a patient with cataracts, early-onset distal muscle weakness and atrophy, ovarian dysgenesis and 3-methylglutaconic aciduria

Bekheirnia, Mir Reza; Zhang, Wei; Eble, Tanya N.; Willis, Alecia; Shaibani, Aziz; Wong, Lee‐Jun C.; Scaglia, Fernando; Dhar, Shweta U.

doi:10.1016/j.gene.2012.02.034

Cited by 16 publications

(10 citation statements)

References 24 publications

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“…Cachexia was also a typical feature, probably due to dysphagia as well as to the progressive neuromyopathy. Hyperproteinorrachia in CSF was also a feature, and hypogonadism, that was present in one of our patients, has been reported in association with early onset cataracts in a single patient with a heterozygous variant in POLG [9]. No additional manifestations reported in POLG-related disorders were observed: patients had a normal intelligence, with a substantially normal brain MRI, without epilepsy or heart involvement.…”

Section: Discussionsupporting

confidence: 65%

“…Lately, a new POLG-related phenotype characterized by slowly progressive mitochondrial distal myopathy and cataracts was described. This seems to be a relatively rare entity reported in single cases with dominant inheritance associated with cachexia [7][8][9]. Early onset cataract appears to be very rare in POLG-mutated patients and has been so far reported either in a few patients with recessive POLG variants [5,6] or, noteworthy, in 3 of the above-mentioned distal myopathy patients harboring dominant missense variants in exon 17, c.2687 T > G (p. (Leu896Arg)) or involving a different amino acid change in the same position (either p.(Tyr951Asn) or p.(Tyr951His)) [8,9].…”

Section: Introductionmentioning

confidence: 97%

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Neuromyopathy with congenital cataracts and glaucoma: a distinct syndrome caused by POLG variants

et al. 2018

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We identified three non-related patients manifesting a childhood-onset progressive neuromyopathy with congenital cataracts, delayed walking, distal weakness and wasting, glaucoma and swallowing difficulties. Electrophysiology and nerve biopsies showed a mixed axonal and demyelinating neuropathy, while muscle biopsy disclosed both neurogenic and myopathic changes with ragged red fibers, and muscle MRI showed consistent features across patients, with a peculiar concentric disto-proximal gradient of fatty replacement. We used targeted next generation sequencing and candidate gene approach to study these families. Compound biallelic heterozygous variants, p.[(Pro648Arg)]; [(His932Tyr)] and p.[(Thr251Ile),(Pro587Leu)]; [(Arg943Cys)], were found in the three patients causing this homogeneous phenotype. Our report on a subset of unrelated patients, that showed a distinct autosomal recessive childhood-onset neuromyopathy with congenital cataracts and glaucoma, expands the clinical spectrum of POLG-related disorders. It also confirms the association between cataracts and neuropathy with variants in POLG. Early onset cataract is otherwise rare in POLG-related disorders and so far reported only in a few patients with the clinical pattern of distal myopathy or neuromyopathy.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 97%

Neuromyopathy with congenital cataracts and glaucoma: a distinct syndrome caused by POLG variants

et al. 2018

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“…Recently, mutations in AARS2 have been described in females presenting with late-onset neurological dysfunctions associated with ovarian failure [Dallabona et al, 2014]. Mutations in other genes with mitochondrial roles have also been found to be implicated in isolated or syndromic primary ovarian failure [Bekheirnia et al, 2012;Brauner et al, 2015;Zhen et al, 2015]. Moreover, ovarian aging might be accompanied with mitochondrial dysfunction [Ben-Meir et al, 2015].…”

Section: Discussionmentioning

confidence: 99%

An Application of NGS for Molecular Investigations in Perrault Syndrome: Study of 14 Families and Review of the Literature

et al. 2016

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Perrault syndrome (PS) is a rare autosomal recessive condition characterized by deafness and gonadic dysgenesis. Recently, mutations in five genes have been identified: C10orf2, CLPP, HARS2, HSD17B4, and LARS2. Probands included are presented with sensorineural deafness associated with gonadic dysgenesis. DNA was sequenced using next-generation sequencing (NGS) with a panel of 35 deafness genes including the five Perrault genes. Exonic variations known as pathogenic mutations or detected with <1% frequency in public databases were extracted and subjected to segregation analysis within each family. Both mutations and low coverage regions were analyzed by Sanger sequencing. Fourteen female index patients were included. The screening in four cases has been extended to four family members presenting with PS phenotype. For four unrelated patients (28.6%), causative mutations were identified: three homozygous mutations in C10orf2, CLPP, and HARS2, and one compound heterozygous mutation in LARS2. Three additional heterozygous mutations in LARS2 and HSD17B4 were found in three independent familial cases. All these missense mutations were verified by Sanger sequencing. Familial segregation analyses confirmed the molecular diagnosis in all cases carrying biallelic mutations. Because of NGS, molecular analysis confirmed the clinical diagnosis of PS in 28.6% of our cohort and four novel mutations were found in four Perrault genes. For the unsolved cases, exome sequencing should be performed to search for a sixth unknown PS gene.

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“…Mutations in the POLG gene have been associated with primary testicular failure (Filosto et al, 2003), primary ovarian failure (Luoma et al, 2004; Hakonen et al, 2005), and ovarian dysgenesis (Bekheirnia et al, 2012). ar- PEO1 mutations are reported to cause female hypergonadotrophic hypogonadism by teen age (Lönnqvist et al, 2009).…”

Section: Hypogonadismmentioning

confidence: 99%

Endocrine disorders in mitochondrial disease

Schaefer

Walker

Turnbull

et al. 2013

Molecular and Cellular Endocrinology

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HighlightsMitochondrial disorders are common, genetically-heterogeneous diseases characterised by multisystem involvement.Endocrine dysfunction in mitochondrial disease is not uncommon.This is predominantly restricted to disease of the endocrine pancreas leading to diabetes mellitus.We review the common endocrine disorders associated with mitochondrial dysfunction.Optimal strategies for supporting and managing patients are discussed.

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POLG mutation in a patient with cataracts, early-onset distal muscle weakness and atrophy, ovarian dysgenesis and 3-methylglutaconic aciduria

Cited by 16 publications

References 24 publications

Neuromyopathy with congenital cataracts and glaucoma: a distinct syndrome caused by POLG variants

Neuromyopathy with congenital cataracts and glaucoma: a distinct syndrome caused by POLG variants

An Application of NGS for Molecular Investigations in Perrault Syndrome: Study of 14 Families and Review of the Literature

Endocrine disorders in mitochondrial disease

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