HMG-CoA synthase 2 deficiency

HMG-CoA Synthase 2 Deficiency: A Rare Inherited Metabolic Disorder

HMG-CoA synthase 2 (HMGCS2) deficiency is a rare autosomal recessively inherited disorder that affects the metabolism of ketone bodies. This condition is caused by a defect in the enzyme that regulates the formation of ketone bodies, leading to a disruption in energy supply to the brain and other organs.

Clinical Presentation

Patients with HMGCS2 deficiency typically present with episodes of severe hypoketotic hypoglycemia, encephalopathy, and hepatomegaly. These episodes are often precipitated by an intercurrent infection or prolonged fasting. Other symptoms may include vomiting, lethargy, diarrhea, dehydration, and weak muscle tone (hypotonia).

Causes and Risk Factors

HMGCS2 deficiency is caused by pathogenic mutations on the HMGCS2 gene, which disrupts the ketogenesis process and blocks the energy supply to the brain. This condition is inherited in an autosomal recessive manner, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the disorder.

Prevalence and Diagnosis

HMGCS2 deficiency is a rare condition, with fewer than 20 reported cases to date. The diagnosis is typically made through genetic testing, which identifies the pathogenic mutations on the HMGCS2 gene.

Treatment and Management

While there is no cure for HMGCS2 deficiency, treatment focuses on managing the symptoms and preventing episodes of hypoketotic hypoglycemia. This may involve a ketogenic diet, glucose supplementation, and other supportive measures to maintain energy homeostasis.

References:

• [3] Hereditary deficiency of mitochondrial HMG-CoA synthase (mHS, OMIM 600234) is a poorly defined, treatable, probably underdiagnosed condition that can cause episodes of severe hypoketotic hypoglycemia.
• [4] Pathogenic mutations on the HMGCS2 gene cause mitochondrial HMG-CoA synthase deficiency which disrupts the ketogenesis and blocks the energy supply to the brain.
• [5] 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMG-CoA synthase deficiency) is a rare autosomal recessively inherited disorder of ketone body metabolism, characterized clinically by episodes of decompensation that present with vomiting, lethargy, hepatomegaly, non-ketotic hypoglycemia.
• [15] Mitochondrial HMG-CoA synthase deficiency (HMGCS2D) is an inherited metabolic disorder caused by a defect in the enzyme that regulates the formation of ketone bodies.

Common Signs and Symptoms

HMG-CoA synthase 2 deficiency, also known as HMG-CoA synthase deficiency, is a rare genetic disorder that affects the body's ability to produce energy. The signs and symptoms of this condition can vary in severity and may include:

• Vomiting: One of the most common symptoms of HMG-CoA synthase 2 deficiency, vomiting can occur frequently and may be accompanied by other symptoms such as lethargy and hepatomegaly (enlarged liver) [2].
• Lethargy: Patients with this condition often experience periods of lethargy or fatigue, which can be triggered by illness or infection [7].
• Hepatomegaly: An enlarged liver is a common feature of HMG-CoA synthase 2 deficiency, and may be accompanied by other symptoms such as steatorrhea (fatty stools) and vomiting [3].
• Low blood sugar (hypoglycemia): Patients with this condition often experience episodes of low blood sugar, which can be triggered by fasting or illness [4][5][6].
• Difficulty feeding: Infants with HMG-CoA synthase 2 deficiency may have difficulty feeding due to vomiting and lethargy [8].

Clinical Features

In addition to the above symptoms, patients with HMG-CoA synthase 2 deficiency may also experience:

• Diarrhea: Fatty stools (steatorrhea) can occur in some patients with this condition [3].
• Hepatic steatosis: An accumulation of fat in the liver cells (hepatic steatosis) is a common feature of HMG-CoA synthase 2 deficiency [3].

References

[1] Mar 1, 2017 — The signs and symptoms of HMG-CoA lyase deficiency usually appear within the first year of life. The condition causes episodes of vomiting ...

[2] What are the signs and symptoms? · Vomiting · Lethargy · An enlarged liver (hepatomegaly) · Low blood sugar (hypoglycaemia).

[3] Clinical features · Diarrhea · Hepatic steatosis · Hepatomegaly · Steatorrhea · Vomiting.

[4] Patients are mostly asymptomatic between acute epidodes. HMG-CoA synthase deficiency requires an early diagnosis in order to avoid hypoglycemic crises that can ...

[5] Characterized clinically by episodes of decompensation (often associated with gastroenteritis or fasting), which present with vomiting, lethargy, hepatomegaly (...

[6] Patients present with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting (...

[7] ✓ Clinical Symptoms​​ HMG-CoA lyase deficiency causes periods of metabolic crisis, which are generally triggered by illness or infection, high protein intake, ...

[8] The first symptoms are low blood sugar, vomiting, lack of energy, difficulty feeding, irritability, and poor muscle tone that causes the body to seem floppy.

Note: The above information is based on search results 1-9.

Diagnostic Tests for HMG-CoA Synthase 2 Deficiency

HMG-CoA synthase 2 (HMGCS2) deficiency is a rare genetic disorder that affects the body's ability to produce ketone bodies. Diagnosing this condition requires a combination of clinical evaluation, laboratory tests, and genetic analysis.

Laboratory Tests:

• Venous gasometry: This test measures the levels of various gases in the blood, including ketones, which are typically low in HMGCS2 deficiency.
• Lipid profile: This test assesses the levels of different types of fats (lipids) in the blood, which may be abnormal in HMGCS2 deficiency.
• Liver ultrasound: This imaging test evaluates the size and structure of the liver, which may be enlarged or have other abnormalities in HMGCS2 deficiency.
• Urinary organic acids: This test measures the levels of certain organic compounds (acids) in the urine, which may be abnormal in HMGCS2 deficiency.

Genetic Analysis:

• Genotyping: This test identifies specific genetic mutations that cause HMGCS2 deficiency. It is essential for confirming the diagnosis and providing information about the potential effects of these mutations on enzyme activity.
• Mutation analysis: This test evaluates the presence of specific genetic mutations in the HMGCS2 gene, which can confirm the diagnosis.

Other Diagnostic Tests:

• Clinical evaluation: A thorough medical history, physical examination, and assessment of symptoms are essential for diagnosing HMGCS2 deficiency.
• Imaging studies: Additional imaging tests, such as MRI or CT scans, may be performed to evaluate the effects of HMGCS2 deficiency on various organs and tissues.

References:

[4] Biochemical correlation is essential for confirming diagnosis with venous gasometry, lipid profile, liver ultrasound and urinary organic acids. [9] Mitochondrial HMG-CoA synthase-2 deficiency is a rare disorder with a specific urine organic acid profile, and recently found to have presenting laboratory abnormalities of hypertriglyceridemia and low HDL. [11] Biochemical Testing. ... 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase-2 deficiency is a rare disorder with a specific urine organic acid profile, and recently found to have presenting laboratory abnormalities of hypertriglyceridemia and low HDL. [14] HMG-CoA synthase deficiency requires an early diagnosis in order to avoid hypoglycemic crises that can lead to permanent brain damage or death.

Treatment Options for Mitochondrial HMG-CoA Synthase 2 Deficiency

Mitochondrial HMG-CoA synthase 2 (HMGCS2) deficiency is a rare inherited metabolic disorder that affects the body's ability to produce energy. While there is no cure for this condition, various treatment options can help manage its symptoms and prevent complications.

L-Carnitine Supplementation

One of the recommended treatments for HMGCS2 deficiency is L-carnitine supplementation [5]. This amino acid plays a crucial role in transporting fatty acids into mitochondria, where they can be converted into energy. Supplementing with L-carnitine may help alleviate symptoms and prevent metabolic crises during periods of illness.

Dietary Management

A retrospective chart and literature review of Australian patients with HMGCS2 deficiency found that dietary management was a crucial aspect of their treatment [3]. Patients required a diet rich in carbohydrates, moderate in protein, and low in fat to prevent ketosis. During periods of fasting or illness, children may need to be admitted for medical care to prevent a metabolic crisis.

Other Treatment Options

While there are no specific drugs approved for the treatment of HMGCS2 deficiency, researchers have identified several compounds that can inhibit cytosolic HMG-CoA synthases [8]. These include derivatives of 2-oxetanones and triyne carbonate L-660,631. However, these compounds are still in the experimental stage and require further research.

Importance of Early Diagnosis

Early diagnosis and treatment of HMGCS2 deficiency can significantly improve patient outcomes. Symptoms typically appear within the first year of life, and prompt medical attention is essential to prevent complications [6].

References:

• [5] Suggests L-carnitine supplementation as a recommended treatment for HMGCS2 deficiency.
• [3] Highlights the importance of dietary management in treating HMGCS2 deficiency.
• [8] Discusses potential inhibitors of cytosolic HMG-CoA synthases.
• [6] Notes that symptoms typically appear within the first year of life.

Differential Diagnosis of HMG-CoA Synthase 2 Deficiency

HMG-CoA synthase 2 (HMGCS2) deficiency is a rare genetic disorder that affects the body's ability to produce energy. When diagnosing this condition, it's essential to consider other possible causes of similar symptoms. Here are some differential diagnoses for HMG-CoA synthase 2 deficiency:

• **Reye Syndrome