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GRACILE syndrome

ORPHA53693
Synonym(s) Fellman disease
Growth delay - aminoaciduria - cholestasis - iron overload - lactic acidosis - early death
Growth restriction - aminoaciduria - cholestasis - iron overload - lactic acidosis - early death
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10 -
OMIM
UMLS
  • C1864002
MeSH
  • C537934
MedDRA -

Summary

GRACILE syndrome is an inherited lethal mitochondrial disorder characterized by fetal growth restriction (GR), aminoaciduria (A), cholestasis (C), iron overload (I), lactacidosis (L), and early death (E).

The typical GRACILE syndrome (caused by the homozygous c.232A>G mutation in the BCS1L gene) 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.

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 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. To date, the only neurological abnormality reported is abnormal hearing response.

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, (all of which can be seen in renal tubulopathy - encephalopathy - liver failure; see this term), as well as the mildest phenotype, seen in Björnstad syndrome (see this term).

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. In other patients, the entire BCS1L gene should be sequenced. Respirometry should be performed in a mitochondrial laboratory.

Other mitochondrial hepatopathies such as Pearson syndrome (see this term) should be excluded. Disorders of mitochondrial fatty acid oxidation and Krebs cycle disorders (see these terms) may also mimic GRACILE syndrome.

In families with a previous case of GRACILE syndrome or renal tubulopathy - encephalopathy - liver failure, the causative BCS1L mutation can be investigated antenatally.

GRACILE syndrome is inherited autosomal recessively so genetic counseling should be offered to affected families.

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.

The prognosis is poor with half of infants dying during the first days of life and the other half not living past 4 months of age, mainly because of energy depletion.

Expert reviewer(s)

  • Pr Vineta FELLMAN

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