Sometimes your licked before you’ve even started

The first issue of Neuron for 2022 got off to a rather depressing start, with two papers stating that the die was cast before you leave the uterus.

The first concerned Huntington’s chorea a hereditary movement disorder which doesn’t begin for decades after birth (like many hereditary disorders).  Or does it?

Well over 10,000 papers have been written to figure out why mutations in the huntingtin protein produces neurodegeneration, primarily in a small set of neurons deep in the brain.

Now that we know the genetic cause, it is possible to study people with the mutation long before they get sick.  One finding is a thin tract of axons connecting the two hemispheres (the corpus callosum).

So a transgenic mouse was created with a typical huntingtin mutation (111 glutamines in a row instead of the normal 7 for the mouse).  Even in utero axons forming the corpus callosum were shorter and fewer.  This was due to defects in bundling of microtubules in the axon growth cone.  It was due to a deficiency not of huntingtin but of a microtubule binding protein called NUMA1 (Nuclear Mitotic Apparatus 1) whose function we thought we knew in the mitotic spindle.  Giving NUMA1 reversed the axonal defect (in tissue culture).   So the problems with Huntington’s chorea go back to fetal life.

Even worse, 4 human fetuses of 13 weeks gestation (presumably aborted because the parents didn’t want a child with the gene, showed also sorts of abnormalities in the developing brain Science vol. 369 pp. 771 – 772, 787 -792 ’20 ].  Read it if you wish, I found it rather creepy.

The second paper is on congenital hydrocephalus [ Neuron vol. 110- pp. 12 – 15 ’22 ].  Several parent child trios were sequenced, and damaging mutations were found in 25% of the probands.  All of them were regulators of neural stem cell fate.  So the ventricles got big (that’s hydrocephalus after all), because there weren’t enough neurons to keep them small.

Even worse, the most consistent macroscopic (e.g. visible) finding in schizophrenia is large ventricles.  Were they doomed from birth?

If that isn’t depressing enough here’s a Supreme Court Justice holding forth on COVID19 in children. “We have over 100,000 children, which we’ve never had before, in serious condition, and many on ventilators” due to the coronavirus.  Presumably the Justice believes in science as many of her party claim.