Rauschenberger et al. (2010) found that development and severity of symptoms in HSD10 disease are unrelated to residual enzymatic activity. They reported a male infant with a severe form of the disorder who had absent neurologic development and died of progressive hypertrophic cardiomyopathy at age 7 months. Genetic analysis identified a hemizygous mutation in the HSD17B10 gene (D86G; ); patient fibroblasts showed about 30% residual enzymatic activity. Another boy with a hemizygous HSD17B10 variant (Q165H) had failure to thrive in infancy but had normal cognitive and motor development up to age 8 years, despite his fibroblasts having no detectable MHBD activity. The findings indicated that the clinical effects of this disorder cannot be attributed to the accumulation of toxic metabolites in the isoleucine pathway or other metabolic effects, suggesting that an isoleucine-restricted diet is unlikely to provide therapeutic benefit. Fibroblasts from the individual with the Q165H variant had mostly normal-appearing mitochondria, but 27% showed depletion of cristae. In contrast, fibroblasts from the patient with the D86G or R130C ( ) mutations showed abnormal morphology in 65 to 85% of mitochondria. These findings indicated that HSD10 is required for normal mitochondrial integrity, and that this function is not correlated with residual enzyme activity. Conditional knockout of the Hsd17b10 gene in mouse noradrenergic neurons resulted in a significant number of abnormal mitochondria, and knockdown of the gene in Xenopus caused increased apoptosis in cells. Rauschenberger et al. (2010) concluded that HSD10 disease is not a classic organic aciduria, and that the clinical manifestations result from defects in mitochondrial function.
The fetal adrenal cortex lacks expression of the enzyme early on, thus mineralocorticoids (. aldosterone ) and glucocorticoids (. cortisol ) cannot be synthesized. This is significant because cortisol induces type II pneumocytes of the lungs to synthesize and secrete pulmonary surfactant ; without pulmonary surfactant to reduce the alveolar surface tension , premature neonates may die of neonatal respiratory distress syndrome . If delivery is unavoidable (. because of placental abruption , or pre-eclampsia / HELLP syndrome ), then glucocorticoids (. cortisol) can be administered.