Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings

Abstract

Pyruvate dehydrogenase (PDH) deficiency is one of the most common causes of congenital lactic acidosis. Correlations between the genetic defect and neuroimaging findings are lacking. We present conventional and diffusion-weighted MRI findings in a 7-day-old male neonate with PDH deficiency due to a mosaicism for the R302H mutation in the PDHA1 gene. Corpus callosum dysgenesis, widespread increased diffusion in the white matter, and bilateral subependymal cysts were the main features. Although confirmation of PDH deficiency depends on specialized biochemical analyses, neonatal MRI plays a role in evaluating the pattern and extent of brain damage, and potentially in early diagnosis and clinical decision making.

The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients

“…2). Seven subjects were reported to have normal imaging findings; all had E1α deficiency [80,110,125,137,145,147,156,163]. Ventriculomegaly was the most frequent abnormality, affecting 65 patients (35%) in whom an abnormal brain imaging finding was reported.…”

“…PDHA1 gene mutations have been subdivided broadly into 1) missense point mutations, with loss of PDC catalytic activity only; 2) deletions or exon skipping mutations, resulting in loss of E1α mRNA and protein; and 3) deletions, missense or nonsense mutations, resulting in loss of E1α protein without loss of E1α mRNA (unstable E1α) [10,23,138,147,154,170,172,178]. Despite the variable nature of these mutations, we found it difficult to draw sharp distinctions between specific mutations of the PDC and the natural history of the disease, although mutations affecting position 378 in PDHA1 may be particularly lethal.…”

MRI Features of 4 Female Patients With Pyruvate Dehydrogenase E1 alpha Deficiency

“…However, the neurological presentation of PDHA1 deficiency is variable, and often differs between males and females [1–5]. Imaging features in males with PDHA1 deficiency are well recognized, and include subependymal cysts [8]; agenesis of the corpus callosum [2]; or a Leigh-like picture frequently accompanied by leukoencephalopathy [2, 8–10]. Females with PDHA1 deficiency often have a more severe clinical phenotype [1–4].…”

Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency

“…PDHA1 mosaicism was reported in six males [7], [8], [9], [10], [11], [12], [13] and one female patient [14] with different types of mutations (see Table 1 for details). Mosaic mutations may attenuate the clinical phenotype, as observed in surviving males with exonic mutations that resulted in skipping of exons 5 and 6 [9], [11].…”