GRACILE syndrome

A disorder characterized by growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and premature death. It is caused by alterations in the BCS1L gene that produces a mitochondrial protein essential for energy production in the mitochondria.

GRACILE syndrome is an inherited mitochondrial disease characterized by fetal growth restriction, aminoaciduria (abnormal amount of amino acids in the urine), cholestasis (impaired bile secretion) and iron overload. It is an extremely serious disease with a very short life expectancy.

GRACILE syndrome is caused by the presence of two copies of the mutation c.232A>G (p.Ser78Gly) in the BCS1L gene, which codes for a mitochondrial protein that in the cell is involved in the maintenance of the mitochondrial structure and the assembly of one of the molecular complexes responsible for energy production.

The prevalence of GRACILE syndrome in the general population is less than one case per million population. However, the incidence of the disease is highest in Finland (1/50,000 births) where the c.232A>G variant is especially frequent. Cases of GRACILE have also been reported, with a lower incidence, in Turkey, Sweden, the United Kingdom and Spain.

Symptoms

The first symptoms appear before birth. Fetal size during pregnancy is smaller than usual, with no signs of chronic hypoxia and preterm delivery. The GRACILE-affected neonate develops lactic acidosis and aminoaciduria. Iron overload is seen with increased plasma ferritin and decreased transferrin levels, and iron accumulation in the liver can lead to liver damage. The syndrome gets its name from the symptoms that define it - Growth Retardation, Aminoaciduria, Cholestasis, Iron overload, Lactic acidosis and Early death - or - Growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death.

Disease management

Treatment focuses on alleviating symptoms. Other liver diseases associated with mitochondrial defects such as Pearson's syndrome should be ruled out. Disorders of mitochondrial fatty acid oxidation and Krebs cycle disorders can produce symptoms similar to GRACILE syndrome.

Genes analyzed

BCS1L

Bibliography

Jackson CB, Bauer MF, Schaller A, et al. A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly. Eur J Pediatr. 2016 Apr;175(4):517-25.

A novel mutation in BCS1L associated with tubulopathy.

Ramos-Arroyo MA, Hualde J, Ayechu A, et al. Clinical and biochemical spectrum of mitochondrial complex III deficiency caused by mutations in the BCS1L gene. Clin Genet. 2009 Jun;75(6):585-7.

Visapää I, Fellman V, Vesa J, Dasvarma A, et al. GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet. 2002 Oct;71(4):863-76.