Mitochondrial energetic impairment in a patient with late‐onset glutaric acidemia Type 2, 2020, Xiao et al

Andy · Aug 18, 2020

Glutaric acidemia type 2 (GA2), also called multiple acyl‐CoA dehydrogenase deficiency, is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism resulting in excretion of multiple organic acids and glycine conjugates as well as elevation of various plasma acylcarnitine species (C4–C18). It is caused by mutations in the ETFA, ETFB, or ETFDH genes which are involved in the transfer of electrons from 11 flavin‐containing dehydrogenases to Coenzyme Q10 (CoQ10) of the mitochondrial electron transport chain (ETC).

We report a patient who was originally reported as the first case with primary myopathic CoQ10 deficiency when he presented at 11.5 years with exercise intolerance and myopathy that improved after treatment with ubiquinone and carnitine. At age 23, his symptoms relapsed despite increasing doses of ubiquinone and he was shown to have biallelic mutations in the ETFDH gene. Treatment with riboflavin was started and ubiquinone was changed to ubiquinol. After 4 months, the patient recovered his muscle strength with normalization of laboratory exams and exercise tolerance. Functional studies on fibroblasts revealed decreased levels of ETFDH as well as of very long‐chain acyl‐CoA dehydrogenase and trifunctional protein α. In addition, the mitochondrial mass was decreased, with increased formation of reactive oxygen species and oxygen consumption rate, but with a decreased spared respiratory capacity, and decreased adenosine triphosphate level.

These findings of widespread dysfunction of fatty acid oxidation and ETC enzymes support the impairment of a larger mitochondrial ETC supercomplex in our patient.
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Paywall, https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.61786
Sci hub, https://sci-hub.tw/10.1002/ajmg.a.61786

Hutan · Aug 18, 2020

He presented at 11.5 years of age with slowly progressive exercise intolerance accompanied by predominantly lower proximal muscle weakness and pain. Development was normal and family history was non- consanguineous with no other neuromuscular or metabolic dis- eases.

Laboratory studies showed elevation in serum creatine kinase and lactate. Urine organic acid analysis detected abnormal metabolites including ethylmalonic acid, methylsuccinic acid, hexanoylglycine, and lactic acid. The plasma acylcarnitine profile exhibited elevations of butyrylcarnitine, pentanoylcarnitine, hexa- noylcarnitine, octanoylcarnitine, and decanoylcarnitine, with no evi- dence of plasma carnitine depletion. Skeletal muscle histochemical studies were notable for ragged-red fibers, reduction in Complex I, I + III, and II + III activity, and a CoQ10 concentration that was 46% of the reference range.

... Empirical treatment with ubiquinone and carnitine were initiated, which led to normalization of creatine kinase and lactate levels, as well as clinical improvement in endurance and strength, including the ability to perform routine activities such as walking between classes without difficulty.
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Paul Fisher's team found that Complexes I, II and III were working ok in people with ME and Warren Tate's team found normal levels of CoQ10 in the cells of people with ME. So this condition doesn't seem to equal ME - but it sounds like a condition worth ruling out.

At 23 years of age, his muscle weakness, myalgia, and extreme fatigue relapsed, limiting head elevation and reducing his exercise
tolerance to a few steps....

Parental testing revealed that the patient's mother is a carrier for the Gln222Pro variant while his father carries the Gly322Cys variant.

Riboflavin supplementation was started at 100 mg daily and then twice daily, and ubiquinone was changed to ubiquinol. After 4 months, the patient had experienced recovery with normalization of his labora- tory exams, exercise tolerance, and self-reported normalization of per- formance status and endurance, including the ability to walk more than a mile without fatigue or shortness of breath.
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I hope everyone with something that looks like this is given the right blood tests and other tests. Interesting that the young man's head elevation was limited.

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Mitochondrial energetic impairment in a patient with late‐onset glutaric acidemia Type 2, 2020, Xiao et al

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Mitochondrial energetic impairment in a patient with late‐onset glutaric acidemia Type 2, 2020, Xiao et al

Andy Committee Member

Hutan Moderator Staff Member

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