combined malonic and methylmalonic acidemia

Combined Malonic and Methylmalonic Acidemia (CMAMMA)

Combined malonic and methylmalonic acidemia, also known as CMAMMA, is a rare inherited metabolic disorder characterized by the accumulation of certain chemicals in the body. Specifically, it involves elevated levels of malonic acid and methylmalonic acid.

Key Features:

• Elevated levels of malonic acid and methylmalonic acid in the urine
• Higher levels of methylmalonic acid than malonic acid in the urine
• Inherited metabolic disorder, meaning it is passed down from parents to offspring

Causes and Genetics: CMAMMA is caused by biallelic variants in the ACSF3 gene. This genetic mutation affects the body's ability to process certain proteins and fats (lipids) properly.

Symptoms and Effects:

• Varying severity, from mild to life-threatening
• Symptoms may include vomiting, dehydration, weak muscle tone (hypotonia), and other complications

References:

• [1] Combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. [2]
• [3-5] Elevated levels of methylmalonic acid than malonic acid in the urine, although both are elevated.
• [6-8] CMAMMA is a rare genetic disorder caused by ACSF3 biallelic variants that results in impaired protein synthesis and mitochondrial fatty acid synthesis.

Note: The information provided above is based on the search engine's retrieved context and may not be an exhaustive or definitive description of combined malonic and methylmalonic acidemia.

Signs and Symptoms of Combined Malonic and Methylmalonic Acidemia

Combined malonic and methylmalonic acidemia (CMAMMA) is a rare genetic disorder that affects the body's ability to process certain proteins and fats. The signs and symptoms of CMAMMA can vary from mild to life-threatening and may include:

• Vomiting: A common symptom in infants with CMAMMA, vomiting can be severe and persistent.
• Dehydration: Due to excessive vomiting or diarrhea, dehydration is a serious complication that requires immediate medical attention.
• Weak muscle tone (Hypotonia): Infants with CMAMMA may have weak muscles, which can lead to difficulty feeding or breathing.
• Excessive tiredness (Lethargy): Children and adults with CMAMMA may experience persistent fatigue or lethargy.
• Ketoacidosis: A potentially life-threatening condition where the blood becomes too acidic due to the buildup of acids in the body.
• Seizures: In some cases, CMAMMA can cause seizures, which are a serious medical emergency.

Other possible symptoms

• Diarrhea
• Abnormality of metabolism/homeostasis
• Abnormality of the digestive system

It's essential to note that the signs and symptoms of CMAMMA can begin in childhood or even infancy. If you suspect someone has this condition, it's crucial to seek immediate medical attention.

References:

[1] Combined malonic and methylmalonic aciduria (CMAMMA) is a condition characterized by high levels of certain chemicals, known as malonic acid and methylmalonic acid, in the body. A distinguishing feature of this condition is higher levels of methylmalonic acid than malonic acid in the urine, although both are elevated. The signs and symptoms of CMAMMA can begin in childhood. In some children, the buildup of acids causes the blood to become too acidic (ketoacidosis), which can damage the body's tissues and organs. [2]

[3] Combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid.

[4] The clinical phenotypes of CMAMMA are highly heterogeneous and range from asymptomatic, mild to severe symptoms.

[5] Methylmalonic acidemia is an inherited disorder in which the body is unable to process certain proteins and fats (lipids) properly. The effects of methylmalonic acidemia vary from mild to life-threatening.

[6] Clinical Signs and Symptoms; Patient-centred resources for this disease.

[7] The signs and symptoms of CMAMMA can begin in childhood. In some children, the buildup of acids causes the blood to become too acidic (ketoacidosis), which can damage the body's tissues and organs.

[8] Abnormality of metabolism/homeostasis. Dehydration. Dehydration · Abnormality of the digestive system. Diarrhea. Diarrhea · Abnormality of the ...

[9] Infants with this condition typically have drowsiness, vomiting, dehydration, weak muscle tone (hypotonia) and excessive tiredness (lethargy).

[10] In addition to methylmalonic acid, raised malonic acid can be found ...

Diagnostic Tests for Combined Malonic and Methylmalonic Acidemia (CMAMMA)

Combined malonic and methylmalonic acidemia (CMAMMA) is a rare genetic disorder that affects the body's ability to break down certain amino acids. Diagnostic tests play a crucial role in identifying this condition.

• Clinical Genetic Test: A clinical genetic test offered by PreventionGenetics, part of Exact Sciences, can detect combined malonic and methylmalonic acidemia. This test analyzes genes associated with the condition [1].
• Newborn Screening: CMAMMA can be identified through newborn screening programs, which are designed to detect various metabolic disorders in infants [3][4].
• Routine and Biochemical Labs: In addition to newborn screening, routine and biochemical labs can also diagnose CMAMMA by analyzing urine samples for elevated levels of methylmalonic acid and malonic acid [3][4].
• Genetic Testing: Genetic testing, such as next-generation sequencing, can detect single nucleotide and copy number variants in genes associated with methylmalonic aciduria-propionic acidemia (MCPA), which is a related condition to CMAMMA [5][9].

Recommended Diagnostic Tests

The American College of Medical Genetics recommends diagnostic testing for the ACSF3 gene to identify potential genetic changes that may be causing CMAMMA. This type of testing can inform prognosis and guide treatment decisions [8].

Treatment Options for Combined Malonic and Methylmalonic Acidemia

Combined malonic and methylmalonic acidemia (CMAMMA) is a rare inborn error of metabolism characterized by elevations of urine malonic acid (MA) and methylmalonic acid (MMA). While there are no specific drug treatments available, various interventions can help manage the condition.

• L-Carnitine: Patients with CMAMMA may be treated with L-carnitine to remove excess toxic acylcarnitine species from the mitochondria. This detoxification is crucial in reducing the accumulation of harmful substances in the body.
• Gene Therapy: Research has been conducted on gene therapy as a potential treatment for CMAMMA. However, more studies are needed to fully understand its efficacy and safety.
• Dietary Management: A well-planned diet can help manage the condition by reducing the intake of certain nutrients that may exacerbate the symptoms.
• Bacteria-reducing measures: Certain bacteria-reducing measures may also be employed to help manage the condition.

Current Research and Guidelines

Recent studies have focused on developing clinical practice recommendations for the kidney management of CMAMMA. These guidelines aim to provide healthcare professionals with evidence-based advice on specific aspects of kidney care for patients with this condition.

• Carglumic Acid: Carglumic acid has been studied as a potential treatment for methylmalonic acidemia and propionic acidemia, which are related conditions.
• hLB-001: Gene therapy with hLB-001 has been investigated in pediatric patients with severe methylmalonic acidemia.

Conclusion

While there is no specific drug treatment available for combined malonic and methylmalonic acidemia, various interventions can help manage the condition. Further research is needed to fully understand the efficacy and safety of these treatments.

References:

• [1] Waters PJ, Buhas D, et al. Combined malonic and methylmalonic aciduria due to ACSF3 mutations: benign clinical course in an unselected cohort.
• [8] Mar 15, 2019 — Patients with CMAMMA may be treated with L-carnitine to remove excess toxic acylcarnitine species from the mitochondria.
• [14] Methylmalonic acidemias (MMAs) are rare inherited metabolic diseases with multiorgan involvement.

Combined Malonic and Methylmalonic Aciduria (CMAMMA) is a rare inborn error of metabolism characterized by the elevation of both malonic acid (MA) and methylmalonic acid (MMA) in body fluids, with higher levels of MMA than MA [8]. The differential diagnosis of CMAMMA involves distinguishing it from other conditions that present with elevated levels of both malonic and methylmalonic acids.

Key Conditions to Consider:

• Malonic Aciduria due to ACSF3 mutations: This condition is similar to CMAMMA but has a distinct genetic cause [9].
• Methylmalonic Acidemia (MMA) or Methylmalonic Aciduria: This is a separate metabolic disorder characterized by elevated methylmalonic acid levels, often caused by defects in the MMUT gene or other genes involved in the intracellular cobalamin pathway [12][13].
• Propionic Acidaemia (PA): Another rare inherited metabolic disease that can present with similar symptoms to CMAMMA [15].

Clinical Presentation and Diagnostic Considerations:

CMAMMA typically presents in childhood with symptoms such as metabolic acidosis, developmental delay, dystonia, and failure to thrive. In adulthood, it may manifest as seizures, memory loss, and other neurological symptoms [4]. The differential diagnosis of raised methylmalonic acid entails a range of diseases, including CMAMMA, MMA, PA, and others.

Genetic Considerations:

Mutations in the ACSF3 gene have been associated with CMAMMA. This genetic information is crucial for accurate diagnosis and management of the condition [14].

References:

• [8] Combined malonic and methylmalonic aciduria; Nutritional vitamin B12 deficiency; Methylmalonic acidemia (MMA) or methylmalonic aciduria, simply, is the elevation of methylmalonic acid in the blood and/or the urine (generally it is seen in both).
• [9] Feb 11, 2019 — CMAMMA is also distinguishable from the other condition with increases of both malonic and methylmalonic acids: malonic aciduria due to ACSF3 mutations.
• [12] The differential diagnosis of raised methylmalonic acid entails a range of diseases. Specifically, methylmalonic acid can be raised due to a defect in MMUT or one of the genes distal in the intracellular cobalamin pathway, causing the MMA subtypes discussed in these guidelines, or due defects more proximal in the intracellular cobalabin pathway.
• [13] Diagnosis (and differential diagnosis) Clinical signs and symptoms - conditions raising the suspicion of MMA/PA. Clinical signs and symptoms of MMA/PA are nonspecific. Patients may present with acute or chronic symptoms at any age (Table 3). Some of the signs and symptoms are common, others are uncommon and a few are only described in single cases.
• [14] Alfares A, Nunez LD, Al-Thihli K, et al. Combined malonic and methylmalonic aciduria: exome sequencing reveals mutations in the ACSF3 gene.
• [15] Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic diseases. Six years ago, a detailed evaluation of the available evidence on diagnosis and management of these disorders has been published for the first time. The article received considerable attention, …