Clinical and molecular spectrum associated with Polymerase-γ related disorders

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.

Point Prevalence and Associated Factors of Hip Displacement in Pediatric Patients With Mitochondrial Disease

Objective: Mitochondrial disease is a multisystem disorder resulting from mitochondrial dysfunction. Although musculoskeletal system is vulnerable to mitochondrial dysfunction, little information is available on orthopedic issues such as hip displacement and scoliosis in patients with mitochondrial disease. We aimed to examine the point prevalence of hip displacement and investigate the associated factors in patients with mitochondrial disease.Methods: We retrospectively reviewed the medical records and plain radiographs of patients diagnosed with mitochondrial disease between January 2006 and January 2019 at a single institution. Data, including patient age, sex, follow-up duration, syndromic diagnosis, and gross motor function were collected. Migration percentage was measured on the radiographs. The clinical and radiologic variables were compared between patients classified according to the presence of hip displacement and motor function level.Results: We included 225 patients (135 men, 90 women). The mean age at the latest follow-up was 11.1 years, and the mean follow-up duration was 7.0 years. Hip displacement was noted in 70 (31.1%) patients. The proportion of patients with Leigh disease (p = 0.007) and the ratio of non-ambulators (p &lt; 0.001) were higher among patients with hip displacement. The proportion of patients with Leigh disease was higher in the non-ambulators than the ambulators.Conclusion: One-third of patients with mitochondrial disease developed hip displacement. Hip displacement was more common in non-ambulators or patients with hypertonia. Careful and serial monitoring for hip problems is required for non-ambulatory patients with mitochondrial disease who have increased muscle tone.

Status Dystonicus in Children with Secondary Dystonia: Reporting 3 Cases of Cerebral Palsy, Leigh Disease and Molybodynum Co Factor Deficiency

Objective: Patients with primary and secondary dystonic syndromes occasionally develop severe episodes of generalized dystonia and rigidity which is known as status dystonicus (SD) or dystonic storm. This is a frightening hyperkinetic movement disorder and it is an emergency. Marked, rapid exacerbation of dystonia requires prompt intervention and admission in the hospital. It is critical to recognize early and differentiate dystonic storm from other hyperkinetic movement disorder as it may lead to metabolic complications such as rhabdomyolysis, leading to acute renal failure. This paper has been written to describe three cases of SD, all having secondary dystonia with different etiologies to highlight the mode of presentation, diagnosis, treatment and outcome. Methodology: We report 3 cases of severe secondary dystonia culminating in SD necessitating management in hospital setting. All the three cases were admitted in a tertiary care hospital and evaluated. Results: One patient was treated in intensive care unit. In brief 1st case was a 5 year boy with dyskinetic CP who was treated with trihexiphenidyl (THP), baclofen and midazolam infusion. Second case was a 15 month old boy, diagnosed case of mitochondrial encephalopathy (Leigh disease) who was treated with THP, baclofen, haloperidol, clonazepam and infusion midazolam. The third case was a 13 month old boy, diagnosed case of Molybdenum Cofactor deficiency who was treated with THP, tizanidine but they refused to take midazolam. Conclusion: In this case series, three cases with SD with different etiology have been described with clinical features, modalities of treatment and outcome.