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Use of Tadalafil in MEGDEL Syndrome

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction
Tadalafil is a phosphodiesterase (PDE)-5 inhibitor used in the treatment of pulmonary arterial hypertension (PAH), erectile dysfunction, and benign prostatic hyperplasia. The mechanism of PDE-5 inhibitors is increasing cyclic guanosine monophosphate by preventing its degradation via PDE-5, leading to prolonged vasodilation. Recent literature suggests a beneficial effect of PDE-5 inhibitors on mitochondrial function. Here, we describe a case of infantile-onset MEGDEL Syndrome (3-methylglutaconic acidemia, deafness, encephalopathy, and Leigh-like syndrome) and the safe and successful off label use of Tadalafil.

MEGDEL Syndrome is an autosomal recessive mitochondrial disorder due to variants in the SERAC1 gene. Associated neurological symptoms include seizures, developmental delay and regression, progressive hearing loss, dystonia and spasticity, and Leigh syndrome.

Case Presentation
Patient developed persistent hypoglycemia, unresponsive to glucose gel, within 48 hours of life, prompting admission to NICU. During admission, labs were notable for continued hypoglycemia, hyperammonemia, and lactic acidosis.



 

Diagnostic Workup
Biochemical testing was notable for elevated 3-methylglutaconic acid in urine organic acid and molecular panel, identifying two pathogenic variants in the SERAC1 gene confirming the diagnosis of MEGDEL Syndrome. During the course of disease, the patient developed symptoms associated with MEGDEL, such as slow weight gain and feeding difficulties within the first year of life, hearing loss at 1 year of age, and by 2 years of age developed dystonia and spasticity affecting psychomotor development.

 

Treatment and Management
Currently, there is no treatment for MEGDEL Syndrome, and management is supportive. Previous drug screening on skin fibroblasts using NAD+/NADH ratio as a readout for abnormal complex 1 activity suggested Tadalafil as a drug candidate for our patient. Abnormal maximal in vitro respiratory capacity in patient fibroblasts measured by Seahorse improved significantly in our patient on Tadalafil supporting the drug screening results. A trial with Tadalafil was initiated off-label with dosage based on pediatric PAH.

Outcome and Follow-Up
Before the initiation of Tadalafil, there were concerns for global developmental delay and regression of milestones, such as loss of sitting up and good head control. Development was monitored, and the Nijmegen Mitochondrial Disease Scoring System was used to assess for multisystem changes. On follow-up after initiation of Tadalafil physical exam notable for improvements in dystonia and head control. Additionally, both physical exam and parents, report increased in alertness. No change was noted with hearing loss. No side effects were reported.

 

Discussion
The use of Tadalafil in MEGDEL syndrome is based on its presumed mechanism on complex I. Deficiency in Complex I has been one of the most common causes of Leigh syndrome, with Leigh-like syndrome being a feature of MEGDEL syndrome. Based on recent literature, Tadalafil was shown in a mouse model to help preserve mitochondrial function by improving rates of oxidative phosphorylation via complex I. Additionally, Udenafil was seen in mouse models to increase complex 1 activity via PDE-5 inhibitor’s role in decreasing reactive oxygen species production similar to previous finding. A non-complex I mediated mechanism was reported in which inhibition of PDE-5 via Sildenafil affects mitochondrial function in an Akt3-independent pathway by increasing cAMP.

 

Conclusion
Using both the literature review and our case presentation of MEGDEL syndrome with clinical improvements in alertness, dystonia, and head control, further investigation is warranted on the use of PDE-5 inhibitors in MEGDEL syndrome and or other mitochondrial disorders with Leigh syndrome/ Leigh-like syndrome. While our case report is on a single case, no cases are reported in the literature on using PDE-5 inhibitors for Leigh syndrome or mitochondrial disorders. Hopefully, this example can lead to further research on the role of PDE-5 inhibitors on mitochondrial complex 1 function and their use in the management of mitochondrial disorders with diminished complex 1 function, which includes Leigh syndrome, for which there are no treatments.



 

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