Mitochondrial Disorders: A Potentially Under-recognized Etiology of Infantile Spasms

Abstract

Infantile spasms represent an age-dependent response of the immature brain to a wide variety of insults. An unselected group of children with infantile spasms were reviewed to determine etiology; a metabolic work-up was undertaken if the etiology was unclear from history and examination (cryptogenic). Of the 56 infants, 34 had a recognizable etiology (symptomatic), 1 had normal development (idiopathic), and 21 had cryptogenic infantile spasms. Among the latter, results of plasma lactate and pyruvate or urine organic acids were available in 17. In 2 infants (monozygotic twins), mitochondrial DNA testing revealed the relatively common A3243G mitochondrial mutation. In these twins and 11 of the remaining 15, body fluid metabolite testing suggested possible defective energy metabolism. Our twins and previous reports suggest that mitochondrial disorders should be considered in the differential diagnosis of infantile spasms. Among our cases remaining cryptogenic, signs of abnormal energy metabolism were prevalent, suggesting that metabolic derangements may be common causes or secondary consequences of infantile spasms.

West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

“…40,50 They are, however, easily overlooked as an etiology of IS possibly because of the difficulty to correctly gauge the activity of the respiratory chain complexes, especially when no lactate and/or pyruvate increase is identified in blood and/or CSF. 45,51 We show that exome sequencing is a suitable strategy to identify causative genes in familial WS and potentially IS. Exploiting this approach, we identified a novel homozygous c.1825G4T variant in the universally conserved elongation factor GUF1 in three siblings affected with WS.…”

“…They also showed increased CSF lactate levels, a common feature in Leigh syndrome. 47 Among the 13 patients with IS reported in Shah et al, 45 a possibly causing variant was found only in two monozygotic twin sisters who had increased lactate plasma levels. They carried the m.3243A4G change in the tRNA Leu1 gene, which is commonly associated with MELAS (mitochondrial myopathy, encephalopathy, lactate acidosis and stroke-like episodes; OMIM#540000) syndrome.…”

“…43,44 Conversely, in 13 out of the 17 children affected with IS the monitoring of body fluid metabolites suggested a defect in energy metabolism. 45 Definite molecular confirmation could be completed only in a minority of patients: within the El Sabbagh's cohort, three patients had the m.8993T4G variant in MT-ATP6 (ATP synthase subunit 6) while a fourth one had a variant in the nuclear SDHA gene. 46,47 The m.8993T4G variant is commonly found in patients with Leigh (OMIM#256000) or NARP (neuropathy, ataxia and retinitis pigmentosa; OMIM#551500) syndromes.…”

Epileptic Syndromes With Possible Immunological Mechanisms (Rasmussen Encephalitis, FIRES, West Syndrome, Landau-Kleffner Syndrome)

“…[ [63][64][65][66][67][68][69] Olası İmmünolojik Mekanizmalı Epileptik Sendromlar mu etiyolojilerinin düşük bir yüzdesini oluşturmaktadırlar. Dolayısıyla genetik kökenli ve semptomatik olguların dışın-da etiyolojisi açıklanamamış büyük bir grup halen etiyolojisinin aydınlatılmasını beklemektedir.…”

Role of Mitochondria in Epilepsy

“…Ragged-red fibers and abnormal electron transport chain activities are frequently absent, particularly in younger children. Although the A3243G mutation is usually thought of as being causal for MELAS, the mutation is more often associated with maternally inherited diabetes, deafness, cognitive impairment, short stature and/or migraine, as well as a wide variety of other disease manifestations (Wallace DC, et al 200;Shah NS, et al 2002;Harrison TJ, et al 1997;and Majamaa K, et al 1998). 2.…”