HSD10 disease: clinical consequences of mutations in the HSD17B10 gene

Abstract The HSD17B10 gene is located on chromosome Xp11.2 and codes for a multifunctional protein called 17β‐hydroxysteroid dehydrogenase type 10 (HSD10). This protein catalyzes the 2‐methyl‐3‐hydroxybutyryl‐CoA dehydrogenation (MHBD) reaction in isoleucine metabolism and is an essential component of mitochondrial RNase P required for the processing of mtDNA transcripts. HSD10 is required for normal mitochondrial maintenance, and complete loss of HSD10 is incompatible with life. Mutations in the HSD17B10 gene have been reported in 19 families. The classical infantile form of what is best named HSD10 disease is characterized by a period of more or less normal development in the first 6‐18 months of life. Some patients showed transient metabolic derangement in the neonatal period, with good clinical recovery but often persistent lactate elevation. Usually from age 6‐18 months affected boys show a progressive neurodegenerative disease course in conjunction with retinopathy and cardiomyopathy leading to death at age 2‐4 years or later. A more severe presentation in the neonatal period with little neurological development, severe progressive cardiomyopathy, and early death, is denoted neonatal form. Juvenile and atypical/asymptomatic forms of HSD10 disease have been recognized. Heterozygous females often show non‐progressive developmental delay and intellectual disability but may also be clinically normal. The pathogenesis is poorly understood but is unrelated to MHBD function. Diagnosis is based on typical abnormalities in urinary organic acid analysis and molecular studies. The same de novo mutation p.R130C was found in over half of patient families; it is associated with the infantile disease form. There is no effective treatment.