mitochondrial DNA depletion syndrome 13

Mitochondrial DNA depletion syndrome-13 (MTDPS13) is an autosomal recessive disorder that affects multiple body systems, particularly the nervous system.

Characteristics and Symptoms

• Early infantile onset of encephalopathy: MTDPS13 typically presents with severe brain dysfunction in early infancy.
• Hypotonia: Affected individuals often experience muscle weakness or hypotonia (low muscle tone).
• Lactic acidosis: Elevated levels of lactic acid in the blood are a common feature of this condition.
• Severe global developmental delay: Children with MTDPS13 may exhibit significant delays in achieving motor, speech, and cognitive milestones.

Genetic Basis

MTDPS13 is caused by mutations in the FBXL4 gene, which plays a crucial role in maintaining mitochondrial DNA copy numbers. The disorder is inherited in an autosomal recessive pattern, meaning that affected individuals inherit two copies of the mutated gene (one from each parent).

Clinical Presentation

The clinical presentation of MTDPS13 can vary, but it often includes:

• Failure to thrive
• Neurodevelopmental delays
• Encephalopathy (brain dysfunction)
• Cerebral atrophy (shrinkage of brain tissue)

Overall, mitochondrial DNA depletion syndrome-13 is a severe and debilitating condition that affects multiple body systems. Early diagnosis and management are essential for improving outcomes in affected individuals.

References:

[1] Mitochondrial DNA depletion syndrome-13 is an autosomal recessive disorder characterized by early infantile onset of encephalopathy, hypotonia, ... (Source: 7) [2] An autosomal recessive disorder characterized by early infantile onset of encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. (Source: 8) [3] A rare mitochondrial DNA depletion syndrome characterized by congenital or early-onset lactic acidosis, hypotonia, and severe global developmental delay. (Source: 9)

Mitochondrial DNA depletion syndrome 13 (MDDS13) is characterized by a range of severe symptoms that typically manifest in early infancy.

• Early infantile onset: Symptoms of MDDS13 usually emerge within the first few months of life, often shortly after birth.
• Encephalopathy: Affected individuals may experience brain dysfunction, leading to seizures, developmental delays, and other neurological problems [1].
• Hypotonia: Muscle weakness or low muscle tone is a common feature of MDDS13, making it difficult for infants to feed, grow, and develop normally [4].
• Lactic acidosis: Elevated levels of lactic acid in the blood can lead to metabolic disturbances and other complications [1][4].
• Severe global developmental delay: Infants with MDDS13 often experience significant delays in achieving motor or mental milestones, including speech and language skills [6].
• Dysmorphic facial features: Some individuals may exhibit variable dysmorphic facial features, although this is not a universal characteristic of the condition [5].

It's essential to note that the severity and presentation of MDDS13 can vary among affected individuals. Early diagnosis and intervention are crucial for managing the symptoms and improving outcomes.

References:

[1] Context 1: Mitochondrial DNA depletion syndrome-13 is an autosomal recessive disorder characterized by early infantile onset of encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. [4] Context 4: In MDDS associated with mutations in PEO1/C10orf2 that primarily affect the brain and the liver, symptoms emerge shortly after birth or in early infancy, with hypotonia, symptoms of lactic acidosis, enlarged liver, feeding problems, lack of growth, and delay of psychomotor skills. [5] Context 5: A rare mitochondrial DNA depletion syndrome characterized by congenital or early-onset lactic acidosis, hypotonia, and severe global developmental delay with feeding difficulties and failure to thrive. It is frequently associated with variable dysmorphic facial features. [6] Context 6: A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills ... [13] Context 13: SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome is an inherited disorder that affects the early development of the brain. Signs and symptoms typically appear soon after birth. Most affected children develop severe brain dysfunction and muscle weakness (encephalomyopathy).

Diagnostic Tests for Mitochondrial DNA Depletion Syndrome 13

Mitochondrial DNA depletion syndrome 13 (MDDS13) is a rare genetic disorder that affects the mitochondria, the energy-producing structures within cells. Diagnosing MDDS13 can be challenging, but several diagnostic tests are available to help confirm the condition.

• Real-time polymerase chain reaction (PCR) test: This test is used to analyze mtDNA content (copy number) and is recommended for diagnosing mitochondrial diseases, including MDDS13 [5].
• Mitochondrial genome analysis: This test is ideal for patients with a clinical suspicion of mitochondrial DNA depletion syndrome, including MDDS13 [3].
• Next-generation sequencing (NGS): NGS of the mtDNA genome can be performed to detect deletions and duplications in the mitochondrial DNA, which are associated with mitochondrial diseases like MDDS13 [6].
• Genetic testing: Genetic testing can be used to identify mutations in the FBXL4 gene, which is associated with MDDS13. This test can be performed using various techniques, including PCR and sequencing [2].

Additional Testing

If a mitochondrial disorder is suspected based on clinical symptoms or family history, additional genetic testing may be recommended to confirm the diagnosis [8]. This can include tests such as:

• Mitochondrial DNA deletion and duplication testing: This test should be performed in cases of suspected mitochondrial disease via NGS of the mtDNA genome, especially if there are deletions or duplications in the mitochondrial DNA [6].
• Genetic Testing Registry: The Genetic Testing Registry is a database that provides information on genetic tests available for various conditions, including MDDS13 [7].

Clinical Features and Diagnosis

The diagnosis of FBXL4-related mtDNA depletion syndrome (including MDDS13) is established in a proband by identification of biallelic pathogenic mutations in the FBXL4 gene [2]. Clinical features of MDDS13 can vary widely, but may include symptoms such as muscle weakness, fatigue, and developmental delays.

References:

[1] Clinical resource with information about Mitochondrial DNA depletion syndrome 13 and its clinical features, FBXL4, available genetic tests from US and labs ...

[2] by M Almannai · 2017 · Cited by 17 — Diagnosis/testing. The diagnosis of FBXL4-related mtDNA depletion syndrome is established in a proband by identification of biallelic pathogenic ...

[3] Nov 13, 2023 — Is ideal for patients with a clinical suspicion of mitochondrial DNA depletion syndrome. Also includes mitochondrial genome analysis.

[4] Integrated disease information for Mitochondrial Dna Depletion Syndrome 13 including associated genes, mutations, phenotypes, pathways, drugs, ...

[5] Common tests for diagnosing mitochondrial disease · Real-time polymerase chain reaction (PCR) test used to analyze mtDNA content (copy number)

[6] Jan 1, 2024 — mtDNA deletion and duplication testing should be performed in cases of suspected mitochondrial disease via NGS of the mtDNA genome, especially ...

[7] May 1, 2017 — Genetic Testing Information. Genetic Testing Registry: Mitochondrial DNA depletion syndrome 13 From the National Institutes of Health. Genetic ...

[8] If a mitochondrial disorder is suspected based on clinical symptoms or family history, additional genetic testing may be recommended to confirm the diagnosis.

[9] A clinically heterogeneous group of mitochondrial disorders characterized by a reduction of the mitochondrial DNA copy number in affected tissues without ...

Current Drug Treatments for Mitochondrial DNA Depletion Syndrome

Unfortunately, there is no cure for mitochondrial DNA depletion syndromes (MDS). However, various treatments are being explored to manage the symptoms and provide supportive care.

• Nucleoside bypass therapy: This experimental treatment aims to restore normal levels of deoxyribonucleotides (dNTPs) in mitochondria. It has shown promise in some patients with mitochondrial DNA depletion syndrome [8].
• CoQ10 and B vitamins: These supplements are commonly used as part of a "mitochondrial treatment cocktail" [4]. Coenzyme Q10 (CoQ10) is particularly important, as it plays a crucial role in the electron transport chain/oxidative phosphorylation process.
• Deoxyribonucleosides or inhibition of their catabolism: This pharmacological approach has been proposed as a potential treatment for mitochondrial DNA depletion syndrome [6].

It's essential to note that these treatments are still experimental and may not be effective for everyone. A comprehensive evaluation by a healthcare professional is necessary to assess the degree of involvement of different systems in affected individuals.

References: [4] Avula S (2014) - CoQ10 and B vitamins as part of a mitochondrial treatment cocktail. [6] Ramón J (2021) - Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome. [8] Dombi E (2024) - Nucleoside therapy is a promising experimental treatment for TK2 deficiency.

The differential diagnosis for mitochondrial DNA depletion syndromes (MDDS) is very broad and should be undertaken by a multidisciplinary team [3]. This includes other hepatocerebral mitochondrial depletion syndromes, such as those caused by mutations in the POLG, MPV17 or TWNK genes [4].

Some of the key conditions to consider in the differential diagnosis of MDDS include:

• Infantile-onset MDDS due to RRM2B deficiency, which is a severe disorder with characteristic clinical features and extremely poor prognosis [5].
• Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS), caused by defects in mitochondrial DNA maintenance, leading to liver failure and neurological symptoms [6].
• Multiple mtDNA deletions and decreased mtDNA copy number leading to mtDNA depletion, which can occur secondary to a primary nuclear gene defect [8].

It's also worth noting that mitochondrial disease presenting in childhood is characterized by clinical, biochemical, and genetic complexity [10]. Therefore, a comprehensive evaluation of the patient's medical history, physical examination, laboratory tests, and genetic analysis is essential for accurate diagnosis.

References: [3] The differential diagnosis for mitochondrial DNA depletion syndromes is very broad and should be undertaken by a multidisciplinary team. [4] Differential diagnosis includes the other hepatocerebral mitochondrial depletion syndromes, namely due to mutations in the POLG, MPV17 or TWNK genes. [5] Infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. [6] Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological symptoms. [8] Multiple mtDNA deletions and decreased mtDNA copy number leading to mtDNA depletion can both occur secondary to a primary nuclear gene defect. [10] Mitochondrial disease presenting in childhood is characterized by clinical, biochemical, and genetic complexity.