Clinical and molecular spectrum associated with Polymerase-γ related disorders

Jha, Ruchika; Patel, H. R.; Dubey, Rachana; Goswami, Jyotindra Narayan; Bhagwat, Chandana; Saini, Lokesh; Manokaran, Ranjith Kumar; John, Biju; Kovilapu, Uday Bhanu; Mohimen, Aneesh; Saxena, Apoorv; Sondhi, Vishal

doi:10.1177/08830738211067065

Cited by 7 publications

(16 citation statements)

References 26 publications

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“…We read with interest the article by Jha et al 1 about a retrospective study of 22 patients carrying a pathogenic POLG1 mutation collected over a period of 5.5 years (January 2015–August 2020). Phenotypically, these patients were classified as Alpers-Huttenlocher disease (n = 8), progressive external ophthalmoplegia (n = 8), Leigh syndrome (n = 2), and ataxia-neuropathy spectrum disorders (n = 2).…”

Section: Letter To the Editormentioning

confidence: 99%

“…1 Two patients remained unclassified. 1 The most common clinical abnormalities included developmental delay (n = 14), neuroregression (n = 14), encephalopathy (n = 11), epilepsy (n = 11), ophthalmoplegia (n = 8), and liver dysfunction (n = 8). The study is appealing but raises concerns that need to be discussed.According to the Method section, only patients <15 years of age were included.…”

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confidence: 99%

“…According to Table 1, 5 patients received valproic acid as an antiseizure therapy. 1 Because valproic acid is contraindicated as it can be even fatal, we should know why 5 of the patients with Alpers-Huttenlocher disease nonetheless received valproate. 1 Because POLG1-related epilepsy may favorably respond to a ketogenic/low-carbohydrate diet, 7 we should be told how many of those with epilepsy profited from ketogenic diet.…”

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confidence: 99%

“…Missing are the creatine-kinase values. Because 1 patient manifested with myopathy, 1 we should know if creatine-kinase was elevated in this particular patient.…”

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Heterogeneous Manifestation of POLG1 Variants: Heterogeneity of POLG1 Phenotypes

Finsterer¹

2022

J Child Neurol

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We read with interest the article by Jha et al 1 about a retrospective study of 22 patients carrying a pathogenic POLG1 mutation collected over a period of 5.5 years (January 2015-August 2020). Phenotypically, these patients were classified as Alpers-Huttenlocher disease (n = 8), progressive external ophthalmoplegia (n = 8), Leigh syndrome (n = 2), and ataxianeuropathy spectrum disorders (n = 2). 1 Two patients remained unclassified. 1 The most common clinical abnormalities included developmental delay (n = 14), neuroregression (n = 14), encephalopathy (n = 11), epilepsy (n = 11), ophthalmoplegia (n = 8), and liver dysfunction (n = 8). The study is appealing but raises concerns that need to be discussed.According to the Method section, only patients <15 years of age were included. 1 However, according to Table 1, age at onset ranged from 7.8 to 53 years. 1 This discrepancy should be clarified. Furthermore, the lowest age at diagnosis was, according to Table 1, 19 years. 1 This figure does not comply with the inclusion criteria either. Additionally, the earliest age at onset was 7.8 years, 1 but the earliest age at onset of developmental delay was 4 years. 1 This discrepancy too requires clarification.According to Table 1, more than two-thirds of the parents were consanguineous, but in the Result section only 8 patients with consanguineous parents were described. 1 This discrepancy requires an explanation.A limitation of the study is its retrospective design. Therefore, it cannot be expected that all included patients underwent the same protocol of diagnostic workup and received the same treatment.Because POLG1 carriers can manifest with cardiomyopathy, 2,3 we should be told if the included patients were systematically screened for cardiac involvement.Because some patients carrying a pathogenic POLG1 variant may manifest with Parkinson disease, 3 we should be told if any of the 22 included patients developed typical stigmata of Parkinson disease, such as rigidity, tremor, or bradykinesia.Because 2 patients developed neuropathy of peripheral nerves, 1 we should be informed which type of neuropathy was diagnosed. Specifically, was there demyelinating or axonal neuropathy, or a mixture of both? There are also POLG1-mutation carriers who manifested with small fiber neuropathy.Because POLG1 mutation carriers frequently develop cognitive impairment, 3 we should be informed if developmental

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Section: Letter To the Editormentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

“…Missing are the creatine-kinase values. Because 1 patient manifested with myopathy, 1 we should know if creatine-kinase was elevated in this particular patient.…”

mentioning

confidence: 99%

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Heterogeneous Manifestation of POLG1 Variants: Heterogeneity of POLG1 Phenotypes

Finsterer¹

2022

J Child Neurol

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Reply to Correspondence “Heterogeneous Manifestation of POLG1 Variants”

Jha

Sondhi

2022

J Child Neurol

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We thank Dr Finsterer for his interest in our article and value the opportunity to clarify some aspects of our study. 1 First, in the context of the age of patients, Table 1 mentions the age in months. The median (interquartile range [IQR]) age of onset of disease symptoms was 36 (7.8-53) months. Similarly, the median (IQR) age of diagnosis was 56 (19-84) months. As illustrated in Table 1, 7 of 22 patients (31.8%) were born of consanguineous marriage.Second, we appreciate the concerns of Dr Finsterer regarding other systemic manifestations and monitoring and managing strategies for patients with POLG-1 variants. This was a retrospective study including patients diagnosed over >5 years. The diagnostic, monitoring, and treatment protocols continued to evolve and were not the same for all patients. Five of 8 patients with progressive external ophthalmoplegia (PEO) and 1 of 2 with Leigh disease and unclassified disease underwent electrocardiogram and echocardiography within 6 months of establishing the diagnosis. None of the patients had manifestations suggestive of cardiomyopathy or rhythm disturbances. However, details of systematic follow-up cardiac evaluations are not available. These would have been important as the cardiac disability may manifest later in the disease. Furthermore, none of the patients had features of Parkinson disease; the neuropathy in 2 affected patients was of the axonal type, and all patients with developmental delay (n = 3) and neuroregression (n = 3) had cognitive impairment. The 2 unclassifiable patients were additionally investigated and noted to have mitochondrial depletion. Our study mentions the use of valproic acid in 5 of 8 patients. The use of valproic acid preceded the diagnosis of POLG-related disorder, and it precipitated Alpers-Huttenlocher syndrome (AHS) in all 5 patients to whom it was administered. Therapeutically, POLG1-related epilepsy may favorably respond to ketogenic diet; however, none of our patients was administered ketogenic diet. 2 One patient had presented with a strokelike episode; however, no obvious trigger was identified. No definitive therapies (like L-arginine or L-citrulline) were administered for the same as the individual had presented more than 1 week after the episode.Third, Dr Finsterer has asked about the creatine kinase (CK) values. The details for CK have been mentioned in Table 2. Eighteen patients underwent CK assessment, of whom 5 had elevated CK, including 4 of 6 patients with PEO and 1 of 4 patients with AHS.Lastly, in our study, encephalopathy was defined as a clinical syndrome characterized by altered states of consciousness and/ or altered cognition or personality. 3 Neuroregression was defined as the loss of previously attained function(s) involving 1 or multiple domains, including cognitive, affective, psychomotor, social, perceptual, and/or linguistic. 4 We agree that our study is limited by its retrospective design, lack of phenotype-matched controls, and small cohort size. We have acknowledged the same in the manuscript. However, despi...

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