However. Most people with genetic metabolic porphyria have characteristic defects that show up on certain brain scans, like holes in the basal ganglia, and are characteristically intense and nervous – similar to someone with a bipolar temperament.

During the dark ages, the other word for bipolar disorder was feudal warlord temperament. Most warlords came to power by being ambitious and obsessive and mad enough to frighten people. Those whose families held power didn’t for instance suffer repeated attacks of madness like someone with severe bipolar disorder. One tends to suspect that genetic metabolic porphyria selected itself into the royal lines. Most royal lineages lived simply, in ways that would not have aggravated porphyria into acute attacks, during their first several generations. Morover, repeated bouts of illess that resembled George VI’s were characteristic of, for example the kings of Wessex, and they just lived with them. The Merovingian kings had repeated attacks of madness, sometimes accompanied by peripheral paralysis. These high aristocratic lines fed into each other, even when the connections can’t be traced.

Hereditary coproporphyria is characateristically milder than variegate porphyria, so would more often be expected to be silent or mild and vague. It is well recognized that through George VI’s generation, royalty did things that aggravated porphyria, from heavy metals in the paint to same in their wine to same in their medicines. People with metabolic porphyria actually can’t take many drugs because heme enzymes are needed to metabolize them, and some block the production of these enzymes. The royal family themselves believed that whatever ailed George VI and his brothers was caused by starvation, dosing with alcohol, and poor cleanliness, all parts of abusive care by their nurse, and all of that would have aggravated genetic metabolic porphyria.

George VI’s repeated attacks of acute digestive symptoms and extreme nervousness were far more characteristic of a typical attack of porphyria than George III’s more severe attacks, that probably were aggravated by his medical care. One time he escaped, went to the seashore, ate porridge, and got well, which pretty much is the strategy that used to work on one of these genetic mutations that has become common in a part of Scandinavia. When these people started going to hospitals they started getting much sicker and dying. Evidently, by the time George VI was in the navy, the royal doctors had absorbed the information that whatever else you do, you do NOT give this family medicine. They kept prescribing rest and milk toast. His attacks were likely caused by conditions on board naval vessels. At the same time as they removed his appendix, he withdrew from the navy, and I guess he never had another acute attack, though his nerves and bad temper were the stuff of legend.

Dora

ACMG’s logic does make sense if you prioritize the prevention of disease for at-risk family members.

Before next-gen sequencing, the way a clinician would know a healthy child was at risk for a medically actionable, adult-onset condition would be if someone else in the family was diagnosed with it. In this situation, there is already an opportunity for all the older at-risk relatives to be warned and the child’s testing can be deferred until s/he is an adult and/or clinical screening begins.

After next-gen sequencing, a child’s incidental finding may inform family members of their risk for a serious disease amenable to screening/treatment before anyone in the family has become sick. It seems preferable to incidentally detect a hereditary disease in a family through a child’s exome sequencing versus after a family member develops an illness that could have been prevented or detected at a stage more responsive to treatment.