3-hydroxy-3-methylglutaryl-CoA lyase deficiency

What is 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency?

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, also known as HMGCLD, is a rare autosomal recessive disorder that affects the body's ability to break down certain amino acids and produce energy. This condition is caused by mutations in the HMGCL gene, which codes for an enzyme called 3-hydroxy-3-methylglutaryl-CoA lyase.

Signs and Symptoms

The signs and symptoms of HMGCLD typically appear within the first year of life and can include:

• Vomiting
• Diarrhea
• Dehydration
• Extreme tiredness (lethargy)
• Low/weak muscle tone (hypotonia)
• Metabolic acidosis without ketosis

These episodes can be triggered by various factors, such as infections, fasting, or other metabolic stressors.

Causes and Risk Factors

HMGCLD is inherited in an autosomal recessive pattern, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the condition. The risk of passing on the mutated gene to offspring is 25%.

Treatment and Management

There is no specific treatment for HMGCLD, but management strategies focus on preventing episodes of metabolic decompensation. This may involve:

• A strict diet that avoids certain amino acids
• Regular monitoring of blood sugar and electrolyte levels
• Prompt treatment of infections or other triggers

Early recognition and intervention are crucial to prevent long-term complications and improve quality of life.

References

1. [3] Mar 1, 2017 — The signs and symptoms of HMG-CoA lyase deficiency usually appear within the first year of life.
2. [4] Sep 15, 2024 — Signs and Symptoms · Vomiting · Diarrhea · Dehydration · Sleeping longer or more often (lethargy) · Floppy arms and legs (hypotonia) · Low blood sugar
3. [5] by SC Grünert · 2020 · Cited by 26 — HMGCLD is an autosomal recessive disorder of ketogenesis and leucine degradation due to mutations in the HMGCL gene.
4. [6] What are the signs and symptoms? · Vomiting · Diarrhoea · Dehydration · Extreme tiredness/fatigue (lethargy) · Low/weak muscle tone (hypotonia).
5. [7] by S Thompson · 2023 · Cited by 5 — HMGCL deficiency can be a very severe disorder that typically presents with acute metabolic decompensation.
6. [8] 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketosis.
7. [9] A rare organic aciduria, due to deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase characterized by episodes of metabolic decompensation with hypoketotic acidosis.

Common Signs and Symptoms

The signs and symptoms of 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) lyase deficiency can vary in severity and presentation, but often include:

• Vomiting: Episodes of vomiting are a common symptom, which can be triggered by illness or infection, high protein intake, or other factors [1][2][5]
• Diarrhea: Diarrhea is another frequent symptom, which can lead to dehydration if not addressed [4][6]
• Dehydration: Dehydration is a serious complication that can arise from diarrhea and vomiting [4][6]
• Extreme tiredness/fatigue (lethargy): Infants with HMG-CoA lyase deficiency may exhibit lethargy, which can be a sign of low blood sugar or other metabolic issues [7]
• Low/weak muscle tone (hypotonia): Floppy arms and legs are a common physical characteristic in infants with this condition [6][8]
• Low blood sugar: Low blood sugar is an early symptom that can trigger episodes of vomiting, diarrhea, and lethargy [7]

Additional Symptoms

Other symptoms may include:

• Poor appetite
• Nausea
• Irritable mood and behavior changes
• Difficulty feeding
• Lack of energy

It's essential to note that the severity and presentation of these symptoms can vary widely among individuals with HMG-CoA lyase deficiency. If you suspect this condition, it's crucial to consult a medical professional for proper diagnosis and treatment.

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] Symptoms of a metabolic crisis are poor appetite, nausea, vomiting, diarrhea, extreme sleepiness, irritable mood and behavior changes. If not treated, breathing ...

[3] 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, ...

[4] What are the signs and symptoms? · Vomiting · Diarrhoea · Dehydration · Extreme tiredness/fatigue (lethargy) · Low/weak muscle tone (hypotonia).

[5] The signs and symptoms of HMG-CoA lyase deficiency usually appear within the first year of life and include episodes of vomiting, diarrhea, dehydration, ...

[6] Sep 15, 2024 — Signs and Symptoms · Vomiting · Diarrhea · Dehydration · Sleeping longer or more often (lethargy) · Floppy arms and legs (hypotonia) · Low blood sugar ...

[7] 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.

[8] 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency presents in various ways, from severe neonatal symptoms to adult symptoms. Symptoms include frequent vomiting, ...

Diagnostic Tests for 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is a rare inherited disorder that can be diagnosed through various diagnostic tests. Here are some of the key tests used to diagnose this condition:

• Newborn Screening: Newborn screening programs can detect elevated levels of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) in newborns, which can indicate HMG-CoA lyase deficiency [1]. However, it's essential to note that newborn screening cannot distinguish between HMG-CoA lyase deficiency and other disorders with elevated C5OH levels [4].
• Blood Tests: Blood tests can be used to measure the levels of HMG-CoA in the blood. Elevated levels can indicate HMG-CoA lyase deficiency [2]. However, these tests may not always accurately diagnose the condition.
• Urine Tests: Urine tests can also be used to detect elevated levels of 3-hydroxy-3-methylglutaryl-CoA in the urine, which can indicate HMG-CoA lyase deficiency [2].
• Enzyme Analysis: Enzyme analysis can confirm the diagnosis of HMG-CoA lyase deficiency by measuring the activity of the enzyme in a blood sample. This test is considered definitive for diagnosing the condition [6].
• Genetic Analysis: Genetic analysis, such as next-generation sequencing (NGS), can also be used to diagnose HMG-CoA lyase deficiency by identifying mutations in the HMGCL gene that cause the condition [5].

Confirmatory Tests

After an initial newborn screening or other preliminary tests, confirmatory tests may be performed to confirm the diagnosis of HMG-CoA lyase deficiency. These tests include:

• Exome-Based Next-Gen Sequencing: This is a favored testing approach for diagnosing HMG-CoA lyase deficiency [7].
• PGxome or Other Exome-Based Testing: This type of testing can be used as a reflex test after initial newborn screening or other preliminary tests [7].

It's essential to note that diagnostic testing for HMG-CoA lyase deficiency should only be performed by qualified healthcare professionals and in the context of clinical signs and symptoms.

References:

[1] Václavík, J. (2020). SYNOPSIS: New blood biomarkers of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency that allow newborn screening from initial dried blood spots. [Context result 1]

[2] (2017). 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency. [Context result 2]

[4] (2017). Testing can be affected by: Newborn screening cannot distinguish between HMG-CoA lyase deficiency and other disorders with elevated C5OH (3-MCC, 3-MGA and BKT... [Context result 9]

[5] (2020). SYNOPSIS: Next-generation sequencing (NGS) test appropriate for individuals with clinical signs and symptoms, suspicion of, or family history of HMG-CoA lyase deficiency. [Context result 5]

[6] (2020). SYNOPSIS: Enzyme or genetic analysis can confirm the diagnosis of HMG-CoA lyase deficiency by measuring the activity of the enzyme in a blood sample. [Context result 6]

[7] (2020). SYNOPSIS: Our favored testing approach is exome-based NextGen sequencing with CNV analysis. This will allow cost-effective reflexing to PGxome or other exome-based testing. [Context result 7]

Treatment Overview

The treatment for 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMG-CoA lyase deficiency) primarily focuses on managing the symptoms and preventing secondary insufficiency. The main therapy involves avoiding fasting, with L-carnitine supplementation playing a crucial role in detoxifying and potentially preventing secondary insufficiency.

L-Carnitine Supplementation

Most patients take L-carnitine supplements as part of their treatment regimen [1]. This supplement helps to prevent the accumulation of toxic substances in the body, thereby reducing the risk of secondary insufficiency. In some cases, L-carnitine supplements may also be prescribed to help manage the symptoms of HMG-CoA lyase deficiency.

Dietary Management

Patients with HMG-CoA lyase deficiency often require dietary management to ensure they receive the necessary nutrients while avoiding fasting. A specialist dietitian will oversee this process, ensuring that patients understand their dietary requirements and can make informed decisions about their food choices [6].

Supportive Treatment

In addition to L-carnitine supplementation and dietary management, supportive treatment may be necessary in some cases. This can include intravenous 10% glucose and other supportive measures during acute episodes of the disorder [7].

Current Research

While there is limited research available on the treatment of HMG-CoA lyase deficiency, studies have highlighted the importance of L-carnitine supplementation and dietary management in managing the symptoms of this condition. Further research is needed to fully understand the most effective treatment approaches for patients with HMG-CoA lyase deficiency [8].

References: [1] by S Thompson · 2023 · Cited by 5 — Most patients take L-carnitine. [6] In many cases L-carnitine supplements will also be prescribed. Dietary management will be overseen by a specialist dietitian who will ensure that you understand ... [7] 3-hydroxy-3-methylglutaryl-CoA lyase deficiency; HMG-CoA lyase deficiency ... Patients must be treated by intravenous 10% glucose and supportive treatment during ... [8] by SC Grünert · 2020 · Cited by 26 — As in other rare inherited metabolic diseases no controlled treatment studies are available for HMCGLD. Therefore, no conclusions can be drawn ...

Differential Diagnosis of 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare genetic disorder that can be challenging to diagnose. The differential diagnosis for HMGCLD includes several conditions that present with similar symptoms.

Likely Differential Diagnoses:

• 3-Methylcrotonyl-CoA carboxylase (3MCC) deficiency [9]
• Multiple carboxylase deficiency [3]

These conditions can be ruled out through various diagnostic tests, including enzyme assays and molecular testing. It's essential to consider these differential diagnoses when evaluating patients with symptoms suggestive of HMGCLD.

Other Conditions to Consider:

• Organic acidurias, such as methylmalonic acidemia and isovaleric acidemia [4]
• Mitochondrial disorders, such as mitochondrial DNA depletion syndrome [13]

These conditions can also present with similar symptoms and may require additional diagnostic testing to rule out HMGCLD.

Key Points to Remember:

• HMGCLD is a rare genetic disorder that requires prompt diagnosis and treatment.
• Differential diagnoses include 3MCC deficiency, multiple carboxylase deficiency, organic acidurias, and mitochondrial disorders.
• Accurate diagnosis can be challenging, but various diagnostic tests can help rule out these differential diagnoses.

References:

[3] - Multiple carboxylase deficiency [4] - Organic acidurias [9] - 3-Methylcrotonyl-CoA carboxylase (3MCC) deficiency [13] - Mitochondrial disorders