GRACILE syndrome

Other Names

FLNMS; Finnish lactic acidosis with hepatic hemosiderosis; Fellman syndrome; Growth Retardation, Aminoaciduria, Cholestasis, Iron overload, Lactic acidosis and Early death; Finnish lethal neonatal metabolic syndrome; Fellman disease; Growth delay-aminoaciduria-cholestasis-iron overload-lactic acidosis-early death syndrome; Growth restriction-aminoaciduria-cholestasis-iron overload-lactic acidosis-early death syndrome GRACILE syndrome is a severe disorder that begins before birth. GRACILE stands for the condition's characteristic features: growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death. Because of the severe health problems caused by GRACILE syndrome, infants with this condition do not survive for more than a few months, and about half die within a few days of birth.

Epidemiology

GRACILE syndrome is found almost exclusively in Finland, where it is estimated to affect 1 in 47,000 infants. At least 32 affected infants have been described in the medical literature.

Cause

GRACILE syndrome is caused by a mutation in the BCS1L gene. The protein produced from this gene is found in cell structures called mitochondria, which convert the energy from food into a form that cells can use. In mitochondria, the BCS1L protein plays a role in oxidative phosphorylation, which is a multistep process through which cells derive much of their energy. The BCS1L protein is critical for the formation of a group of proteins known as complex III, which is one of several protein complexes involved in oxidative phosphorylation.

The genetic change involved in GRACILE syndrome alters the BCS1L protein, and the abnormal protein is broken down more quickly than the normal protein. What little protein remains is able to help form some complete complex III, although the amount is severely reduced, particularly in the liver and kidneys. As a result, complex III activity and oxidative phosphorylation are decreased in these organs in people with GRACILE syndrome. Without energy, these organs become damaged, leading to many of the features of GRACILE syndrome. It is not clear why a change in the BCS1L gene leads to iron accumulation in people with this condition.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

In GRACILE syndrome, growth before birth is slow (intrauterine growth retardation). Affected newborns are smaller than average and have an inability to grow and gain weight at the expected rate (failure to thrive). A characteristic of GRACILE syndrome is excess iron in the liver, which likely begins before birth. Iron levels may begin to improve after birth, although they typically remain elevated. Within the first day of life, infants with GRACILE syndrome have a buildup of a chemical called lactic acid in the body (lactic acidosis). They also have kidney problems that lead to an excess of molecules called amino acids in the urine (aminoaciduria). Babies with GRACILE syndrome have cholestasis, which is a reduced ability to produce and release a digestive fluid called bile. Cholestasis leads to irreversible liver disease (cirrhosis) in the first few months of life. Because of the severe health problems caused by GRACILE syndrome, infants with this condition do not survive for more than a few months, and about half die within a few days of birth.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Cholestasis(Slowed or blocked flow of bile from liver)
• Cirrhosis(Scar tissue replaces healthy tissue in the liver)
• Decreased transferrin saturation
• Elevated hepatic iron concentration(Increased iron concentration in liver)
• Hearing impairment(Deafness)
• Hepatic steatosis(Fatty infiltration of liver)
• Increased serum ferritin(Elevated serum ferritin)
• Intrauterine growth retardation(Prenatal growth deficiency)
• Lactic acidosis(Increased lactate in body)
• Renal Fanconi syndrome

30%-79% of people have these symptoms

• Death in early adulthood

1%-4% of people have these symptoms

• Aminoaciduria(High urine amino acid levels)
• Neonatal hypotonia(Low muscle tone, in neonatal onset)

Diagnosis

The liver histology shows microvesicular steatosis and cholestasis with abundant iron accumulation in hepatocytes and Kupffer cells. The liver iron content slightly decreases with age, concomitantly with increasing liver fibrosis and cirrhosis. Abnormal transaminases and coagulation are noted. There are currently a combination of 55 biochemical and molecular genetics tests that can be completed prior to birth to diagnose GRACILE syndrome. These tests include enzyme assays, deletion/duplication analysis, targeted variant analysis, sequence analysis of select exons, and sequence analysis of the entire coding region.

Treatment

There is no cure for this disease and treatment is based on signs and symptoms. Infants require intesive care,including alkali therapy and supplementations for urinary losses. Standard treatment for lactic acidosis.