GRACILE syndrome (ORPHA:53693)
An inherited lethal mitochondrial disorder characterized by fetal growth restriction (GR), aminoaciduria (A), cholestasis (C), iron overload (I), lactacidosis (L), and early death (E).
Epidemiology
The typical GRACILE syndrome is prevalent in Finland, where it has an incidence of about 1/50,000 births. It has also rarely been found in Sweden and the U.K.
Clinical description
Fetal growth restriction appears early during the pregnancy without signs of chronic hypoxia. Because of small fetal size, the pregnancies are usually interrupted a few weeks before the estimated due date (median 38 gestational weeks). The newborn infant is small for gestational age (birth weight approximately 1,700 g) and develops fulminant lactic acidosis (median pH 7.02, lactate 12.8 mmol/l) during the first day of life. In metabolic screening, marked aminoaciduria is found due to renal proximal tubulopathy of Fanconi type. Iron overload is illustrated by increased plasma ferritin and decreased transferrin concentrations and accumulation of iron in the liver. Further signs of hepatopathy are cholestasis with steatosis, fibrosis and cirrhosis. No dysmorphic features are noted. No distinct cerebral abnormalities have so far been found, however in some infants, EEG has been abnormal, maybe as a result of severe metabolic acidosis. The hearing response assessed with BAEP has been abnormal.
Etiology
GRACILE syndrome is caused by a mutation in BCS1L, located on chromosome 2q35, encoding a protein essential in the assembly of complex III in the mitochondrial respiratory chain. In Finnish patients, the disease is caused by one homozygous mutation (c.232A>G) leading to an amino acid change (Serine on position 78 to Glycine) in the BCS1L protein. Several recently discovered mutations in the gene can cause variable phenotypes ranging from neonatal GRACILE-like hepatopathy and tubulopathy to those presenting during infancy or childhood with encephalopathy and psychiatric disorders.
Diagnostic methods
GRACILE syndrome is suspected if an infant is severely small for gestational age, develops hypoglycemia and lactic acidosis, has tubulopathy and increased ferritin levels and shows signs of liver dysfunction. Iron overload is illustrated by increased plasma ferritin and decreased transferrin concentrations and accumulation of iron in the liver. In patients of Finnish descent, the diagnosis is confirmed by assessing the single-nucleotide polymorphism (accredited method in HUS-LAB, Helsinki). In other patients, the entire BCS1L gene should be sequenced. Respirometry should be performed in a mitochondrial laboratory.
Differential diagnosis
Other mitochondrial hepatopathies such as Pearson syndrome should be excluded. Disorders of mitochondrial fatty acid oxidation and Krebs cycle disorders may also mimic GRACILE syndrome.
Antenatal diagnosis
In families with a previous case of GRACILE syndrome or renal tubulopathy, encephalopathy, liver failure, the causative BCS1L mutation can be investigated antenatally.
Genetic counseling
GRACILE syndrome is inherited autosomal recessively so genetic counseling should be offered to affected families. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for the disease and treatments are purely symptomatic. Infants require intensive care, including alkali therapy and supplementation of urinary losses. Lactic acidosis responds only slightly to treatment.
Prognosis
The prognosis is life threatening with half of infants decease during the first days of life and the other half not living past 4 months of age, mainly because of energy depletion.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Pr Vineta FELLMAN