We report a case of hypoplastic left heart syndrome and with subsequent aortopathy and then found to have hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome due to a germline SMAD4 pathologic variant. The patient’s staged palliation was complicated by the development of neoaortic aneurysms, arteriovenous malformations, and gastrointestinal bleeding thought to be secondary to Fontan circulation, but workup revealed a SMAD4 variant consistent with hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome. This case underscores the importance of genetic modifiers in CHD, especially those with Fontan physiology.

Many neuroactive steroids (NS) demonstrate neurotrophic and neuroprotective actions, including protection against apoptosis via Bcl-2 protein. NS are altered in post-mortem brain tissue from subjects with bipolar disorder, and several agents with efficacy in mania elevate NS in rodents. We therefore hypothesized that lithium and valproate may elevate NS, and compensatory NS increases may occur in Bcl-2 knockout mice. NS levels (allopregnanolone, pregnenolone) were determined in frontal cortex by negative ion chemical ionization gas chromatography/mass spectrometry in male Wistar Kyoto rats treated chronically with lithium, valproate, or vehicle. NS were also investigated in heterozygous Bcl-2 knockout mice. Allopregnanolone levels are significantly elevated in lithium-treated (p<0.05), but not in valproate-treated, rats. Pregnenolone levels also tend to be higher following lithium treatment (p=0.09). Knockout of Bcl-2 significantly increases pregnenolone levels in mice (p<0.01), while allopregnanolone levels are unaltered. NS induction may be relevant to mechanisms contributing to lithium therapeutic efficacy and neuroprotection.

Because the genes in all somatic cells of an individual are identical, it is the differential expression of the proteins encoded by particular genes that determines a cell's phenotype. There is now increasing interest in relating the simultaneous expression patterns of multiple proteins to complex biological processes. The goal is to develop ‘expression profiles’ of the proteins that are active within a cell or tissue during a particular condition. The ultimate control of functional protein expression is quite complex and may involve transcriptional, combinatorial, and postranslational mechanisms, as well as differences in protein degradation rates that vary under different conditions. Although mRNA levels do not always predict functional protein levels, they are a useful first step in determining the expression profile.

The evolution of three key technologies offers the promise of obtaining quantitative analysis of gene expression from restricted amounts of nervous system tissue. Laser capture microdissection can accomplish harvesting of identified cell populations from histologically processed tissue.