mitochondrial DNA depletion syndrome 15

Mitochondrial DNA Depletion Syndrome 15 (MTDPS15)

Mitochondrial DNA Depletion Syndrome 15, also known as hepatocerebral type, is a rare and severe genetic disorder caused by mutations in the TFAM gene. This condition affects multiple body systems, including the liver and brain.

Key Features:

• Severe intrauterine growth restriction
• Neonatal-onset hypoglycemia (low blood sugar)
• Liver dysfunction
• Mitochondrial DNA depletion in the liver and skeletal muscle
• Abnormal mitochondrial morphology in skeletal muscle

Symptoms:

• Congenital or early-onset lactic acidosis (elevated levels of lactic acid in the blood)
• Hypotonia (low muscle tone)
• Severe global developmental delay

Causes:

• Homozygous mutation in the TFAM gene, which is responsible for maintaining mitochondrial DNA.

Other Information:

• Mitochondrial disorders occur when mitochondria, the structures that produce energy for our cells, malfunction.
• This group of diseases is caused by a reduction of the mitochondrial DNA copy number in affected tissues without mutations or rearrangements in the mitochondrial DNA.
• Muscle weakness and exercise intolerance may be responsive to coenzyme Q supplementation.

References:

• [1] (Source 3) - Mitochondrial DNA depletion syndrome-15 (MTDPS15) is caused by homozygous mutation in the TFAM gene.
• [2] (Source 5) - MDS are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content.
• [3] (Source 9) - Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and brain dysfunction.
• [4] (Source 10) - Mitochondrial DNA depletion syndrome (MDS or MDDS), or Alper's disease, is any of a group of autosomal recessive disorders that cause a significant drop in mitochondrial DNA in affected tissues.

Mitochondrial DNA depletion syndrome (MDS) presents with a range of symptoms, primarily affecting infants and young children. The key signs and symptoms include:

• Hypotonia: Affected individuals typically present with hypotonia, which is characterized by low muscle tone [1].
• Lactic acidosis: This condition is marked by an accumulation of lactic acid in the blood, leading to metabolic disturbances [1][5].
• Failure to thrive: Infants and young children with MDS often experience failure to gain weight or grow at a normal rate [1].
• Tubulopathy: The kidneys are affected, leading to tubular dysfunction and impaired renal function [2].
• Microcephaly: Some individuals may have smaller-than-normal head size (microcephaly) [1].
• Progressive muscle stiffness (spasticity): Muscle weakness and stiffness can progress over time, affecting movement and mobility [6][7].
• Exercise intolerance: Affected individuals often experience extreme fatigue and difficulty engaging in physical activities [6][7].
• Difficulty breathing: Respiratory problems may arise due to muscle weakness and impaired lung function [6][7].
• Decline in neurocognitive skills or dementia: As the condition progresses, cognitive decline and even dementia can occur [6][7].
• Vision problems: Some individuals may experience vision difficulties, including droopy eyelids (progressive external ophthalmoplegia) [8].

These symptoms can vary in severity and combination among affected individuals. The progression of MDS can be rapid, leading to significant morbidity and mortality if left untreated.

References: [1] AW El-Hattab · 2013 [5] by AW El-Hattab · 2013 [6] May 1, 2020 [7] Progressive muscle stiffness (spasticity); Exercise intolerance; Extreme fatigue; Difficulty breathing; Decline in neurocognitive skills or dementia; Vision ... [8] Sep 1, 2013

Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) can be diagnosed through various clinical and genetic tests.

• Clinical features: The diagnosis is often established based on the presence of characteristic clinical features, such as liver dysfunction, neurological symptoms, and other systemic manifestations [1].
• Genetic testing: Molecular genetic testing for the TFAM gene can confirm the diagnosis of mitochondrial DNA depletion syndrome 15 [2].
• Mitochondrial genome analysis: This test is also useful in diagnosing mitochondrial DNA depletion syndrome 15, as it can identify mutations in the mitochondrial genome [3].
• Biochemical tests: Biochemical tests may show multiple deficiencies of the respiratory chain complexes with sparing of some complexes, which can suggest the diagnosis of mitochondrial DNA depletion syndrome 15 [4].

It's worth noting that a definitive diagnosis is often made through a combination of clinical evaluation and genetic testing.

References: [1] Clinical resource with information about Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) and its clinical features, TFAM, available genetic ... [2] Genetic tests related with Mitochondrial Dna Depletion Syndrome 15 ; 1, Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), 617156, Autosomal ... [3] by E Mavraki · 2023 · Cited by 34 — Testing for mtDNA depletion​​ MtDNA depletion analysis is a quantitative test to assess mtDNA copy number in a clinically affected post-mitotic ... [4] by DR Carrozzo · 2005 · Cited by 2 — Differential diagnosis​​ It must be suspected especially when the biochemical tests show multiple deficiencies of the respiratory chain complexes with sparing of ...

Mitochondrial DNA depletion syndrome (MDDS) is a rare genetic disorder characterized by a significant reduction in the amount of mitochondrial DNA, leading to impaired cellular energy production.

Current Drug Treatments

While there are no specific FDA-approved treatments for MDDS, several drugs have been investigated as potential therapeutic options. These include:

• Deoxyribonucleosides: Administration of deoxyribonucleosides or inhibition of their catabolism has been explored as a pharmacological approach to treat MDDS [2][4].
• Bezafibrate: This fibrate drug increases mitochondrial biogenesis and has been investigated in the treatment of MDDS [8].

Emerging Therapies

Researchers are also exploring other emerging therapies that may be broadly applicable across various forms of MDDS. These include:

• Dietary modulation: Modifying dietary intake to provide essential nutrients and cofactors is being studied as a potential therapeutic approach.
• Cofactor supplementation: Supplementing patients with specific cofactors, such as vitamins and minerals, has been investigated as a treatment option [5].
• Nucleoside therapy: Nucleoside therapy involves supplementing patients with exogenous deoxypyrimidines, which is being explored as a promising experimental treatment for TK2 deficiency [3].

Other Treatment Options

In some cases of MDDS, other treatment options may be considered, including:

• Dietary modification
• Cofactor supplementation
• Liver transplantation
• Stem cell transplantation

It's essential to note that these treatments are still under investigation and not all have been proven effective in treating MDDS. Further research is needed to determine the most effective treatment strategies for this condition.

References:

[1] Avula, S., et al. (2014). Treatment options for mitochondrial DNA depletion syndrome. [Context 1]

[2] Ramón, J., et al. (2021). Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome. Hum. Mol. Genet. [Context 2]

[3] Dombi, E., et al. (2024). Nucleoside therapy is a promising experimental treatment for TK2 deficiency. [Context 3]

[4] López-Gómez, C., et al. (2022). Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome. [Context 4]

[5] El-Hattab, AW., et al. (2013). Other treatment options for some MDS include dietary modulation, cofactor supplementation, liver transplantation, and stem cell transplantation. Assessment of... [Context 5]

[6] Ramón, J., et al. (2021). Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches to more complex treatments. [Context 9]

[7] Tinker, RJ., et al. (2021). Bezafibrate is a fibrate drug that increases mitochondrial biogenesis [38]. It was originally licensed in 1978 to treat hyperlipidaemia and... [Context 8]

Mitochondrial DNA (mtDNA) depletion syndrome (MDDS) is a group of genetic disorders characterized by decreased mtDNA copy number in affected tissues. The differential diagnosis of MDDS involves considering various conditions that present with similar clinical features.

Similarities with other conditions:

• Muscle weakness or "floppiness": This symptom can also be seen in RRM2B-related encephalomyopathic MDS (result 3) and hepatocerebral mitochondrial DNA depletion syndrome (MTDPS, result 4).
• Reeding of the hair: This feature is also associated with MTDPS (result 4).
• Cardiomyopathy: Mitochondrial DNA depletion syndrome can present with heart disease, similar to other conditions such as complex I and II assembly defects (result 9).

Key differences:

• Age of onset: Infantile-onset MDDS due to RRM2B deficiency typically presents in early infancy, whereas MTDPS often presents later in childhood or adolescence (results 3 and 4).
• Clinical features: The clinical presentation of MDDS can vary depending on the underlying genetic defect. For example, RRM2B-related encephalomyopathic MDS is characterized by severe neurological impairment, while MTDPS may present with hepatocerebral involvement (results 3 and 4).

Other conditions to consider:

• Mitochondrial leukoencephalopathy: This condition can also present with similar clinical features, including muscle weakness and cardiomyopathy (result 9).
• Complex I and II assembly defects: These genetic disorders can also lead to mitochondrial dysfunction and present with similar symptoms (result 9).

Prognosis:

The prognosis for MDDS is generally poor, with most affected children dying in childhood due to intercurrent infections (result 1). However, the prognosis can vary depending on the underlying genetic defect and the severity of the clinical presentation.

References: [1] Prognosis is poor, with most affected children dying in childhood, most commonly from an intercurrent infection [24–30]. [3] Infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. [4] Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to ... [9] Causes of mitochondrial leukoencephalopathy include deficiencies of complex I and II assembly, defects of iron–sulphur cluster and lipoic acid ...