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GRACILE Syndrome, Genetic Testing

GRACILE syndrome is a rare autosomal recessive genetic disorder that primarily affects infants. The acronym "GRACILE" stands for Growth Restriction, Aminoaciduria, Cholestasis, Iron overload, Lactic acidosis, and Early death. It is a severe and often fatal condition, and it was first described in the Finnish population. The prevalence of GRACILE syndrome in the general population is less than one case per million population. However, the disease incidence is highest in Finland (1/50.000 births), where the c.232A>G variant is widespread. Cases of GRACILE have also been reported, with a lower incidence, in Turkey, Sweden, the United Kingdom, and Spain.

GRACILE syndrome genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

Critical features of GRACILE syndrome include:

  • Growth Restriction: Affected individuals typically have intrauterine growth restriction, leading to low birth weight and overall growth deficiency.
  • Aminoaciduria: There is increased excretion of amino acids in the urine, indicating impaired kidney function.
  • Cholestasis: GRACILE syndrome is associated with liver dysfunction, resulting in cholestasis (impaired bile flow). This can lead to jaundice and other symptoms related to liver dysfunction.
  • Iron Overload: Excessive iron accumulation in various tissues can contribute to organ damage.
  • Lactic Acidosis: Buildup of lactic acid in the body, indicating impaired cellular respiration and energy production.
  • Early Death: Infants with GRACILE syndrome typically have a short lifespan, and the disorder is often fatal in early infancy.

GRACILE syndrome is caused by mutations in the BCS1L gene, which provides instructions for making a protein involved in the assembly of mitochondrial respiratory chain complex III. Mitochondria are cellular structures responsible for energy production, and disruptions in the respiratory chain can lead to energy deficiencies and the symptoms observed in GRACILE syndrome.

The specific mutations in the BCS1L gene associated with GRACILE syndrome result in the impairment of mitochondrial function, leading to the diverse range of symptoms observed in affected individuals.

There is currently no cure for GRACILE syndrome, and management is typically supportive. Treatment may involve addressing symptoms such as cholestasis, providing nutritional support, and managing complications. Due to the severity of the condition, the prognosis for individuals with GRACILE syndrome is generally poor, and many affected infants do not survive beyond the first few months of life.

Genetic counseling is essential for families affected by GRACILE syndrome to understand the inheritance pattern, assess the risk of having affected children, and explore family planning options. Given the rarity and severity of the disorder, research efforts are ongoing to understand the underlying mechanisms better and develop potential therapeutic approaches.

More Information

The c.232A>G mutation (p.Ser78Gly) results in the substitution of a highly conserved amino acid between species. This has a major impact on the secondary structure of the BCS1L protein since the residue that replaces it differs in polarity, charge, and size. Functional studies have shown reduced stability of the protein.

In addition to the c.232A>G variant, other variants have been described in patients with GRACILE syndrome, such as c.166C>T (p.Arg56Ter), which produces a truncated protein. This variant is also related to mitochondrial complex III deficiency, a disorder of mitochondrial oxidative phosphorylation (which provides energy to the cell), and shares some symptoms with GRACILE, such as lactic acidosis and renal tubulopathy. In some patients, GRACILE syndrome may develop due to a combination of two mutations in the BCS1L gene in compound heterozygosis.

GRACILE syndrome genetic testing analyzes the 2 most frequent pathogenic mutations of the BCS1L gene.

The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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