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TRIT1-associated combined oxidative phosphorylation deficiency-35: Two cases from opposite ends of the epilepsy spectrum

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction
Introduction

Combined oxidative phosphorylation deficiency 35 (COXPD35) is a rare autosomal recessive disorder characterized by neurodevelopmental abnormalities, microcephaly, myoclonic epilepsy, and other types of seizure. COXPD35 is caused by pathogenic variants in the TRIT1. There is only 14 patients with COXPD35 have been reported in the literature. 

 

Aim & Method

To define the clinical and molecular findings of two unrelated patients with COXPD35, bringing the total number of patients reported to 16 patients.

 





 

 

Case Presentation
Case presentation

Patient 1:

A 7-year-old male with intermittent tremors, global developmental delay, feeding difficulties, axial hypotonia, and peripheral hypertonia with hyperreflexia noted since infancy. He developed generalized tonic-clonic seizures at 4 years, which was warranted to start levetiracetam but stopped shortly. The patient stayed clinically seizure-free. At 5 years of age, he was diagnosed with ADHD and acquired frequent stereotypical movements and insomnia. He is currently in a multiple disabilities classroom. He speaks using 2–3-word sentences. He has a wide-based ataxic gait, facial dysmorphism, and a growth curve below the 5th percentile but no microcephaly. 

 

Patient 2:

A 5-year-old male presented with daily spells of twitching and jerking movements of the head at 6 months, diagnosed as myoclonic seizures. By 12 months, he had severe global developmental delay. He had electroencephalogram (EEG) which was consistent with epileptic encephalopathy. Epilepsy was refractory to multiple medications, leading to consider medications that are not often used. He also has ADHD and insomnia. On physical examination, he was able to walk independently with an ataxic gait. He had axial hypotonia with lower limb hypertonia and spasticity. He eats independently and has learned 20–30 words. Facial dysmorphism and microcephaly were noted. 

Diagnostic Workup
Diagnostic Work-up:

Patient1

Brain MRI showed left optic nerve hypoplasia. Biochemical investigations showed a slight decrease in total glutathione, whereas plasma amino acid (PAA) acylcarnitine profiles (ACP) and lactate  were normal. Exome sequencing revealed a de-novo TRIT1 variant c.702A>C (p.Ala234Ala) and a paternally inherited TRIT1 variant c.22C>T (p.Arg8Ter).

Patient2

Brain MRI showed bilateral reduced white matter and diffusely thin corpus callosum. Lactate levels, have been normal. ACP was normal, and PAA was notable for intermittent elevation of alanine. Exome sequencing revealed compound heterozygous variants in TRIT1:  c.334delC (p.Arg112Glufs*36) and c.326T>C (p.Ile109Thr), inherited in trans.

Discussion
Discussion:

Our reports expand the phenotypes of COXPD35 and identify features that may be underappreciated, including dysmorphic facial features, ataxia, insomnia, and hyperactivity. It also shows the variable severity of this disorder with better development in our patients than reported patients. Furthermore, our patients presented the far ends regarding the epilepsy spectrum; one did not have clinical seizures, despite abnormal EEG, or microcephaly, unlike all previously reported patients, whereas the other had refractory seizures and epileptic encephalopathy.

 

Conclusion
Conclusion:

It improtant to consider COXPD35 in patients with infantile-onset developmental delays with or without seizures to help diagnose more cases and define the clinical spectrum, allowing for direct management of this rare disease

Agenda

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