Thiamin-Responsive PDH Deficiency due to a PDHA1 Variant.

Dear Sir,

We read with interest the article by Jauhari et al.[1] about a 21-month-old boy with Leigh syndrome due to the nDNA-variant c.131A>G in the PDHA1 gene who presented with regression of milestones, microcephaly, floppiness, failure to thrive, dysphagia, episodes of respiratory insufficiency, lactic acidosis, and relapses during infections, and responded favorably to thiamine. We have the following comments and concerns.

Because PDHA1-related Leigh syndrome is X-linked, it is conceivable that the mother of the index case is a manifesting carrier (two-thirds of the cases). Was the mother prospectively investigated for clinical or subclinical manifestations of PDH deficiency? Were there any indications that the disease was inherited from the mother’s side? Was the further family history positive for PDH deficiency?

It is unclear what the authors mean with “episodes of encephalopathy.”[1] Did the patient develop stroke-like episodes, which have been occasionally reported in PHD deficiency[2] and usually go along with typical morphological abnormalities on imaging, or do the authors simply mean the recurrent deteriorations triggered by infections? Were magnetic resonance imaging (MRI) and electroencephalogram (EEG) normal during these episodes? Which type of treatment did the patient receive for these conditions?

The patient died suddenly and unexpectedly.[1] Did he ever undergo long-term electrocardiogram recordings? Was echocardiography carried out only once or repeatedly? Was there any indication for seizure activity prior to decease, either clinically or on EEG? Did the patient experience an infectious disease prior to the decease? The authors suspected brain-stem dysfunction resulting in central respiratory insufficiency.[1] Were there any abnormalities on MRI in the medulla oblongata? The individual history was positive for dysphagia.[1] Was dysphagia still present before the decease?

Why did the authors primarily test for hereditary PDH deficiency and not for mitochondrial disorders due to a respiratory chain defect? Which were the clinical manifestations suggesting PDH deficiency?

PDH deficiency may go along with myopathy.[3] Did the patient present with clinical manifestations of myopathy? Did he undergo muscle biopsy?

PDH deficiency is frequently associated with epilepsy.[4] Was the family history positive for epilepsy?

The patient had marked hyperammonemia but normal liver transaminases.[1] How do the authors explain hyperammonemia?

The patient received thiamine and the ketogenic diet simultaneously. How did the authors differentiate which of the two was beneficial?

Overall, this interesting case could be more meaningful by provision of more clinical data, by clinical and genetic investigations of the mother to see if she was a carrier, and by clarification of the cause of sudden death of the index case.

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