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 effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

genetic disorder, one of the

Finnish heritage disease A Finnish heritage disease is a genetic disease or disorder that is significantly more common in people whose ancestors were ethnic Finns, natives of Finland and Sweden ( Meänmaa) and Russia ( Karelia and Ingria). There are 36 rare diseases regar ...

s. 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 ( fi, suomalaiset, ) are a 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 ...

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

acronym An acronym is a word or name formed from the initial components of a longer name or phrase. Acronyms are usually formed from the initial letters of words, as in ''NATO'' (''North Atlantic Treaty Organization''), but sometimes use syllables, as ...

for

growth retardation Delayed milestone, also called developmental delays, is used to describe the condition where a child does not reach one of these stages at the expected age. However, in most cases, a wide variety of ages can be considered normal, and not a cause fo ...

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 t ...

(

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

in the urine),

cholestasis Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malignan ...

iron overload Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatosi ...

lactic acidosis Lactic acidosis is a medical condition characterized by a build-up of lactate (especially -lactate) in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates ...

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, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...

* 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 cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...

. 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 that 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 which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...

shows

microvesicular steatosis Steatosis, also called fatty change, is abnormal retention of fat (lipids) within a cell or organ. Steatosis most often affects the liver – the primary organ of lipid metabolism – where the condition is commonly referred to as fatty liver dis ...

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, b ...

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. Ku ...

. 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 any ...

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

Rare syndromes TCA and ETC metabolism disorders {{genetic-disorder-stub