GRACILE syndrome

GRACILE Syndrome: A Rare and Severe Metabolic Disorder

GRACILE syndrome, also known as Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, Lactic Acidosis, and Early Death, is a rare and severe inherited metabolic disorder. It is characterized by a combination of symptoms that affect various body systems.

Key Features:

• Growth Retardation: Poor fetal growth during pregnancy, leading to small birth size.
• Aminoaciduria: Excessive excretion of amino acids in the urine.
• Cholestasis: Liver dysfunction and bile flow obstruction.
• Iron Overload: Accumulation of iron in the body, leading to organ damage.
• Lactic Acidosis: High levels of lactic acid in the blood, causing metabolic acidosis.
• Early Death: The disorder is usually fatal within the first few days or weeks of life.

Causes and Genetics:

GRACILE syndrome is caused by a mutation in the BCS1L gene, which plays a crucial role in mitochondrial function. Mitochondria are the energy-producing structures within cells. The mutation affects the protein's ability to participate in oxidative phosphorylation, leading to cellular energy deficits and subsequent organ damage.

Prevalence:

GRACILE syndrome is an extremely rare disorder, with only 32 cases reported worldwide as of now [3][4]. It is more common among Finnish people, where it occurs in approximately 1 out of 50,000 live births [3].

References:

[1] Context result 3 [2] Context result 4 [3] Context result 10 [4] Context result 14

Characteristics of GRACILE Syndrome

GRACILE syndrome, a rare genetic disorder, presents with several distinct signs and symptoms that are crucial for diagnosis and understanding the condition.

• Growth Retardation: Affected individuals often experience growth restriction, leading to low birth weight and failure to thrive [8][9].
• Aminoaciduria: The presence of amino acids in the urine is a hallmark symptom of GRACILE syndrome [2][3][5].
• Cholestasis: This condition involves impaired bile flow, leading to liver dysfunction [2][3][6].
• Iron Overload: Excessive iron levels are characteristic of GRACILE syndrome, often resulting in hemosiderosis and increased serum ferritin concentration [6].
• Lactic Acidosis: Accumulation of lactic acid is a significant symptom, indicating mitochondrial dysfunction [5].
• Early Death: Unfortunately, GRACILE syndrome is a lethal disorder, with affected individuals typically experiencing early death [1][2].

These symptoms often manifest before birth and can be used to diagnose the condition. It's essential for medical professionals to recognize these signs to provide timely intervention and support.

References: [1] Context result 4 [2] Context result 2 [3] Context result 3 [5] Context result 5 [6] Context result 6 [8] Context result 8 [9] Context result 9

Diagnostic Tests for GRACILE Syndrome

GRACILE syndrome, an inherited metabolic disease, can be diagnosed through various tests. Here are some of the diagnostic tests used to identify this condition:

• Blood tests: Blood tests can help diagnose GRACILE syndrome by detecting high levels of iron in the blood and a buildup of lactic acid (lactic acidosis) [4]. A blood test for babies born small may also be ordered to check for these conditions.
• Urine tests: Urine tests can detect amino acids, which are protein building blocks, in the urine. This is another indicator of GRACILE syndrome [5].
• Genetic testing: Genetic testing can confirm mutations in the BCS1L gene, which causes GRACILE syndrome. This test can be done on a blood sample or extracted DNA [7].
• Biochemical and molecular genetics tests: A combination of 55 biochemical and molecular genetics tests can be completed prior to birth to diagnose GRACILE syndrome [8].

Diagnostic Teams

A diagnostic team for GRACILE syndrome may include:

• Gastroenterology
• Genetics

These teams can help identify the condition and provide necessary care.

Citations: [4] - Testing for GRACILE syndrome usually happens right after birth. Doctors may order a blood test for babies that are born small. [5] - Babies with GRACILE syndrome will have a high iron level and a build up of lactic acid in their blood. This is called lactic acidosis. Doctors may also test the baby’s urine for protein building blocks called amino acids. [7] - GRACILE syndrome genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, ... [8] - 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 ...

Current Status of Drug Treatment for GRACILE Syndrome

Unfortunately, there is no known treatment for GRACILE syndrome that extends the life expectancy of affected infants [3]. Most treatments are aimed at making them comfortable until they pass away. However, researchers and healthcare professionals continue to explore various options to manage the symptoms and improve the quality of life for those affected.

Symptomatic Interventions

Some symptomatic interventions have been tried in the past, including dietary supplements and off-label use of drugs approved for other indications [8]. These may include:

• Dietary modifications to manage growth retardation and lactacidosis
• Supplementation with amino acids to address aminoaciduria
• Cholestasis management through bile acid supplementation or ursodeoxycholic acid (UDCA) therapy

Emerging Therapies

Recent studies have investigated the potential of various drugs in treating mitochondrial disorders, including GRACILE syndrome [7]. These emerging therapies may include:

• Hypoxia exposure to stimulate mitochondrial biogenesis
• Pharmacological interventions targeting specific pathways involved in mitochondrial function
• Experimental treatments using stem cells or gene therapy

Challenges and Limitations

It's essential to note that these emerging therapies are still in the experimental stages, and more research is needed to determine their efficacy and safety [9]. Additionally, the lack of a cure for GRACILE syndrome underscores the need for continued investment in basic and translational research to better understand this complex disorder.

References:

• [3] Most treatments for GRACILE syndrome are aimed at making infants comfortable until they pass away.
• [8] by O Hurko · 2013 · Cited by 14 — Currently, all treatment of mitochondrial disorders is performed with dietary supplements or by off-label use of drugs approved for other indications.
• [7] by E Bottani · 2020 · Cited by 62 — The 'one-size-fits-all' strategies include symptomatic interventions, mainly diet, exercise, exposure to hypoxia, and pharmacological therapy, which is based on ...
• [9] Possible drug treatment for Gracile syndrome, mitochondrial dysfunction-linked myopathies,Parkinsons and Leigh syndrome. Advantages. No existing treatment ...

Differential Diagnosis of GRACILE Syndrome

GRACILE syndrome, a rare and lethal mitochondrial hepatopathy, requires careful differential diagnosis to exclude other mitochondrial disorders. The following conditions should be considered in the differential diagnosis:

• Pearson syndrome: A similar mitochondrial disorder characterized by growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death.
• Complex III deficiency: A condition that can present with similar symptoms to GRACILE syndrome, including lactic acidosis, aminoaciduria, and cholestasis.
• Mitochondrial hepatopathies: Other disorders affecting the mitochondria in liver cells, which may share some clinical features with GRACILE syndrome.

Key Features for Differential Diagnosis

To differentiate GRACILE syndrome from other mitochondrial disorders, clinicians should look for the following key features:

• Fetal growth retardation
• Lactic acidosis
• Aminoaciduria
• Cholestasis
• Iron overload
• Early death

Genetic Considerations

GRACILE syndrome is caused by a mutation in the BCS1L gene, which plays a crucial role in oxidative phosphorylation. This genetic defect can help distinguish GRACILE syndrome from other mitochondrial disorders.

References:

[3] GRACILE syndrome has also been found in the UK and Sweden, but not nearly as much as in Finland. [4] GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death) syndrome is a recessively inherited lethal disease. [14] The British patients have additional features of complex III deficiency and neurologic symptoms (Visapaa et al., 2002).