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Treatment of BOLA3-Associated Multiple Mitochondrial Dysfunctions Syndrome 2 with a Mitochondrial Cocktail

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction
BOLA3 protein is thought to play a role in the biogenesis of mitochondrial iron-sulfur clusters, electron transfer cofactors, and lipids. Biallelic pathogenic variants in BOLA3 are associated with multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia (MMDS2). Currently, there is no established treatment for MMDS2. We propose a treatment for MMDS2 that includes lipoic acid, riboflavin, and ubiquinol.

Case Presentation
This patient was conceived through in vitro fertilization using a sperm donor. Born prematurely at 33 weeks of gestation, he was admitted to the neonatal intensive care unit. By 3 weeks of age, he was consuming full feeds orally and was discharged. At 6 months of age, he experienced global developmental regression, with symptoms including fatigue, loss of head control, weakness, and spasticity. He was first evaluated by a pediatric neurologist at 12 months and by a clinical geneticist at 19 months of age.

Diagnostic Workup
At 16 months of age, brain magnetic resonance imaging revealed symmetric confluent bilateral areas of T2 signal abnormality within the periventricular white matter, diffusely, with peripheral restricted diffusion, suggestive of acute toxic leukoencephalopathy or demyelinating disease. An electroencephalogram was normal. At 21 months of age, exome sequencing revealed biallelic variants of uncertain significance in BOLA3, including a maternally-inherited NM_212552.2:c.82A>C, p.Thr28Pro, and suspected sperm donor-inherited NM_212552.2:c.308_309del. Plasma glycine level was 765 µM (reference range 138-349 µM). Urine organic acid profile revealed several mildly elevated Krebs cycle intermediates. Thus, BOLA3-associated MMDS2 was suspected.

Treatment and Management
At 23 months of age, lipoic acid 100 mg daily (7.7 mg/kg/day) and riboflavin 200 mg daily (15.4 mg/kg/day) were prescribed; however, administration was inconsistent. At 3 years of age, parents were administering lipoic acid 50 mg daily (3.3 mg/kg/day) and an unknown dose of vitamin B12 without riboflavin, at which time the geneticist prescribed lipoic acid 200 mg daily (13.2 mg/kg/day), riboflavin 200 mg daily (13.2 mg/kg/day), and coenzyme Q10 (ubiquinol) 100 mg daily (6.58 mg/kg/day), with subsequent good compliance.  At 4 years and 11 months of age, the dosage of ubiquinol was increased to 100 mg twice daily (10.8 mg/kg/day) because of growth.

Outcome and Follow-Up
At 25 months of age, after beginning treatment with lipoic acid and presumed vitamin B12, the pediatric neurologist reported improvements in head and limb control, as well as the ability to stand with assistance and speak short sentences. At 4 years of age, which was 4 months after adding ubiquinol, the patient exhibited enhanced energy and movement, as evidenced by frequent smiling and laughing, standing up to walk with assistance, grabbing items in the room, and following simple commands during the physical examination. According to the Clinical Global Impressions-Severity (CGI-S) 5-point scoring system, the patient scored a “4” at 3 years and 11 months of age, with a Clinical Global Impressions-Improvement (CGI-I) 7-point score indicating a functional improvement of "2," defined as "much improved." He is now 5 years of age without further episodes of developmental regression.

Discussion
Similar to previous case reports of BOLA3-associated MMDS2, this patient initially experienced developmental regression, leukodystrophy, and elevated plasma glycine. However, this patient has not developed seizures, cardiomyopathy, or elevated baseline blood lactate levels. With the early use of lipoic acid, riboflavin, and ubiquinol, the patient has had continued improvements in development and strength, suggesting clinical recovery without regression.

Conclusion
We advise consideration of a mitochondrial medication regimen consisting of lipoic acid, riboflavin, and ubiquinol for the treatment of MMDS2. Additionally, we encourage the utilization of tools, such as CGI-S and CGI-I, to evaluate the response to intervention for rare neurodegenerative conditions.

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