GRACILE syndrome is a very rare lethal

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

genetic disorder, one of the Finnish heritage diseases. GRACILE syndrome has also been found in the UK and Sweden, but not nearly as much as in Finland. It is caused by a mutation in the '' BCS1L'' gene and it occurs in approximately 1 out of 50,000 live births in

Finnish people Finns or Finnish people (, ) are a Baltic Finns, Baltic Finnic ethnic group native to Finland. Finns are traditionally divided into smaller regional groups that span several countries adjacent to Finland, both those who are native to these cou ...

. To date, there have only been 32 cases of GRACILE syndrome reported. GRACILE is an

acronym An acronym is a type of abbreviation consisting of a phrase whose only pronounced elements are the initial letters or initial sounds of words inside that phrase. Acronyms are often spelled with the initial Letter (alphabet), letter of each wor ...

for growth retardation,

aminoaciduria Aminoaciduria occurs when the urine contains abnormally high amounts of amino acids. In the healthy kidney, the glomeruli filter all amino acids out of the blood, and the renal tubules then reabsorb over 95% of the filtered amino acids back into ...

(

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

in the urine),

cholestasis Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are: * obstructive type of cholestasis, where there is a mechanical blockage in the duct system that can occur from a gallston ...

iron overload Iron overload is the abnormal and increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress, as elevated intracellular iron levels increase free radical formation via the ...

lactic acidosis Lactic acidosis refers to the process leading to the production of lactate by anaerobic metabolism. It increases hydrogen ion concentration tending to the state of acidemia or low pH. The result can be detected with high levels of lactate and lo ...

and early death. Prior to birth, the growth of the fetus is abnormally slow. This slow growth leads to a smaller than average newborn that has difficulty growing at a normal rate.

Signs and symptoms

People with GRACILE syndrome can have a wide range of symptoms, but that does not mean every person affected will have the same symptoms as one another. It has been determined that 80% - 99% of people with GRACILE syndrome have at least one of these: * Cholestasis *

Cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...

* Decreased transferrin saturation * Elevated hepatic iron concentration * Hearing impairments * Hepatic steatosis * Increased serum ferritin * Intrauterine growth retardation * Lactic acidosis * Renal Fanconi syndrome Other symptoms that happen in a smaller percentage of people with GRACILE syndrome include: * Death in early adulthood * Aminoaciduria * Neonatal hypotonia * Chronic lactic acidosis * Increased serum iron * Increased serum pyruvate

Cause

A point mutation in the BCS1L gene found on chromosome 2 has been determined to be the cause of GRACILE syndrome. The BCS1L gene is responsible for the production of the BCS1L protein found in the mitochondria, which is connected to the process of

oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...

. In particular, the protein is a key contributor in the formation of

Complex III Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...

that is part of the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

. Complex III is still able to be produced, but it is reduced significantly compared to a person without GRACILE syndrome. The deficiency of Complex III is more pronounced in the liver and kidneys, which leads to the symptoms seen in those with GRACILE.

Diagnosis

The liver

histology Histology, also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...

shows microvesicular steatosis and cholestasis with abundant iron accumulation in

hepatocytes A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, bile ...

and

Kupffer cells Kupffer cells, also known as stellate macrophages and Kupffer–Browicz cells, are specialized cells localized in the liver within the lumen of the liver sinusoids and are adhesive to their endothelial cells which make up the blood vessel walls. K ...

. 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 assay Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition. Enzyme units The quantity or concentration of an enzyme can be expressed in molar amounts, as with a ...

s, deletion/duplication analysis, targeted variant analysis, sequence analysis of select exons, and sequence analysis of the entire coding region.

Prognosis

One Finnish study which followed 25 cases from 18 families found that half the infants died within 3 days of birth and the other half died before 4 months of age. Through cases like this, it has been determined that majority of the newborns with GRACILE syndrome will die within the first few months and the rest will die within a few days.

Terminology

* Fellman syndrome * Finnish lactic acidosis with hepatic hemosiderosis * Finnish lethal neonatal metabolic syndrome

References

External links

{{Disorders of TCA and ETC Rare genetic syndromes TCA and ETC metabolism disorders