Urbach-Wiethe disease · Grey Matter

Urbach-Wiethe disease (lipoid proteinosis) is a rare inherited disorder of the skin and mucous membranes that, in some patients, calcifies both amygdalae and so provides the clearest human evidence of what the amygdala does for fear.

Urbach-Wiethe disease. Urbach-Wiethe disease (lipoid proteinosis) is a rare inherited disorder of the skin and mucous membranes that, in some patients, calcifies both amygdalae and so provides the clearest human evidence of what the amygdala does for fear.

It is recessive and caused by loss-of-function mutations in the ECM1 gene, which encodes a protein of the extracellular matrix. Its first sign is usually a hoarse voice in infancy, from deposits in the larynx, followed by waxy skin lesions and beaded papules along the eyelids. In a subset of patients, deposits in the medial temporal lobes calcify the amygdala on both sides while sparing most surrounding tissue, a natural lesion confined to that structure.

The patient SM showed what that lesion removes. With both amygdalae destroyed, she handled snakes and spiders, felt little fear in a haunted house or during frightening films, and had trouble recognising fear in faces, while her intelligence and memory were normal.

Fear from inside the body remained. When SM and two other patients with the disease inhaled air enriched with carbon dioxide, they felt panic, which shows that fear of an internal threat can arise without the amygdala, through brainstem and insula circuits.

Not every patient develops amygdala calcification, and the neurological and emotional features vary widely between those who do.

Questions: What does a person without amygdalae fail to feel, and what can they still feel? The patient SM, whose amygdalae were destroyed by Urbach-Wiethe disease, showed almost no fear of external threats: she handled snakes and spiders, found a haunted house entertaining and reported little fear in frightening situations, while feeling other emotions normally. Yet when she and two other patients with the same lesion inhaled air with 35 % carbon dioxide, they felt intense panic, more than most healthy volunteers. The amygdala is therefore needed to turn threats from the world into fear, while fear from the body's own alarm (suffocation sensed by the brainstem) can arise without it.