Background POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population. Methods Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia. Results A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain. Conclusions We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.

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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...

Background Polymicrogyria (PMG) has environmental or genetic etiologies. We report a 8-year-old boy with diffuse PMG and two novel adhesion G protein-coupled receptor G1 (ADGRG1)/G protein-coupled receptor 56 (GPR56) mutations. Case Report The proband has intellectual disability, spastic quadriparesis, and intractable epilepsy without antenatal or perinatal insults. Brain magnetic resonance imaging revealed PMG involving fronto-polar, parietal and occipital lobes with decreasing antero-posterior gradient, and a thinned-out brain stem. Targeted exome sequencing identified two novel compound heterozygote ADGRG1/GPR56 mutations (c.C209T and c.1010dupT), and each parent carries one of these mutations. Subsequent pregnancy was terminated because the fetus had the same mutations. Conclusion The detected mutations expanded the genetic etiology of PMG and helped the family to avoid another child with this devastating condition.