The GRACILE syndrome, a neonatal lethal metabolic disorder with iron overload

Abstract

GRACILE syndrome (Fellman syndrome, MIM 603358), an autosomal recessive metabolic disorder of the Finnish disease heritage, has been diagnosed in 25 infants of 18 families. The incidence is at least 1/47,000 in Finland. The main findings are fetal growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload (liver hemosiderosis, hyperferritinemia, hypotransferrinemia, increased transferrin iron saturation, and free plasma iron), profound lactic acidosis, and early death. The pathophysiology of the metabolic disturbance is unsolved. No significant deficiency of complex III activity of respiratory chain has been found, although we recently showed that the underlying genetic cause is a missense mutation (S78G) in the BCS1L gene and other mutations in that gene have been associated with complex III deficiency. BCS1L encodes a mitochondrial protein, acting as a chaperone in the assembly of complex III. Iron accumulation in liver, a typical feature being less abundant with increasing age, might be a primary abnormality or a secondary phenomenon due to liver dysfunction. In order to decrease the iron overload, three infants have been repeatedly treated with apotransferrin followed by exchange transfusion. Improvement in iron biochemistry occurred, but no clear beneficial effect on the clinical condition was found. Further studies will elucidate the role of iron in the pathophysiology of the disease.