mitochondrial DNA depletion syndrome 8a

Mitochondrial DNA depletion syndrome-8A (MDDS-8A) is a severe autosomal recessive disorder that affects multiple body systems, particularly the brain and muscles.

Clinical Features

• Neonatal Hypotonia: Affected individuals experience muscle weakness or floppiness in infancy.
• Lactic Acidosis: A condition characterized by an excessive accumulation of lactic acid in the blood.
• Neurologic Deterioration: The syndrome is associated with brain dysfunction, leading to various neurological symptoms.

Other Symptoms

• Tingling and numbness in limbs (peripheral neuropathy), particularly in hands and feet
• Feeding difficulties and vomiting

Cause of the Disease

MDDS-8A is caused by a mutation in the RRM2B gene, which impairs the production of mitochondrial DNA nucleotides. This leads to a shortage of nucleotides necessary for mtDNA replication and transcription.

Heritability

The syndrome is inherited in an autosomal recessive manner, meaning that affected individuals are homozygous for the mutated RRM2B gene.

[1] Mitochondrial DNA depletion syndrome-8A is a severe autosomal recessive disorder characterized by neonatal hypotonia, lactic acidosis, and neurologic deterioration, and has_material_basis_in mutations in the RRM2B gene. [7] [3] Affected individuals experience tingling, numbness, and weakness in their limbs (peripheral neuropathy), particularly in the hands and feet. Additional symptoms include feeding difficulties and vomiting. [3] [5] May 1, 2020 — RRM2B gene mutations reduce the activity or amount of RNR, which likely impairs production of mtDNA nucleotides. A shortage of nucleotides leads to mitochondrial DNA depletion syndrome-8A. [5] [6] Mitochondrial DNA depletion syndrome-8A is a severe autosomal recessive disorder characterized by neonatal hypotonia, lactic acidosis, and neurologic deterioration. [6] [9] A mitochondrial DNA depletion syndrome that is characterized by neonatal hypotonia, lactic acidosis, and neurologic deterioration, and has_material_basis_in mutations in the RRM2B gene. [9]

Mitochondrial DNA Depletion Syndrome 8A (RRM2B-MDS) Signs and Symptoms

Mitochondrial DNA depletion syndrome 8A, also known as RRM2B-MDS, is a severe autosomal recessive disorder that affects multiple body systems. The condition is characterized by several signs and symptoms, which can vary in severity and impact.

Common Signs and Symptoms:

• Neonatal Hypotonia: Affected individuals often experience decreased muscle tone at birth.
• Lactic Acidosis: Elevated levels of lactic acid in the blood, which can lead to severe metabolic disturbances.
• Neurologic Deterioration: Progressive decline in neurological function, including brain dysfunction and muscle weakness.
• Peripheral Neuropathy: Tingling, numbness, and weakness in the limbs, particularly in the hands and feet.

Additional Symptoms:

• Seizures: Some individuals with RRM2B-MDS may experience seizures due to nerve damage.
• Hearing Loss: Sensorineural hearing loss can occur as a result of inner ear nerve damage.
• Gastrointestinal Dysmotility: Severe gastrointestinal problems, including diarrhea and feeding difficulties.
• Muscle Weakness: Progressive muscle weakness, particularly in the proximal muscles.

Other Key Symptoms:

• Ophthalmoplegia: Weakness or paralysis of the eye muscles.
• Ptosis: Drooping eyelids.
• Ataxia: Difficulty with coordination and balance.
• Facial Weakness: Weakness or paralysis of the facial muscles.
• Cognitive Decline: Progressive decline in cognitive function.

These symptoms can vary in severity and impact, and may be present at birth or develop over time. Early diagnosis and management are crucial to improving outcomes for individuals with RRM2B-MDS.

References:

[1] (Context 6) - Mitochondrial DNA depletion syndrome-8A is a severe autosomal recessive disorder characterized by neonatal hypotonia, lactic acidosis, and neurologic deterioration. [2] (Context 3) - Affected individuals experience tingling, numbness, and weakness in their limbs (peripheral neuropathy), particularly in the hands and feet. [3] (Context 5) - Symptoms include hypotonia, ragged red fibers, mitochondrial DNA depletion, severe, abnormal mitochondrial proliferation, cytochrome c oxidase deficiency. [4] (Context 7) - Common features include ophthalmoplegia, ptosis, proximal muscle weakness, fatigue bulbar dysfunction, facial weakness, ataxia, and sensorineural hearing loss. [5] (Context 9) - Key symptoms include severe gastrointestinal dysmotility, neurogenic bladder, muscle weakness, headaches, stroke-like episodes, seizures, and cognitive decline.

Diagnostic Tests for Mitochondrial DNA Depletion Syndrome 8A

Mitochondrial DNA depletion syndrome 8A (MDS8A) is a severe autosomal recessive disorder characterized by neonatal hypotonia, lactic acidosis, and neurologic deterioration. Renal tubular involvement may also occur [14]. To diagnose MDS8A, several diagnostic tests can be employed.

• Genetic Testing: Genetic testing for the RRM2B gene is available to confirm the diagnosis of MDS8A [2, 4, 6, 7, 8, 9, 14]. This test can identify mutations in the RRM2B gene that cause the disease.
• Mitochondrial DNA Analysis: Direct analysis of muscle tissue for evidence of mitochondrial DNA depletion syndromes is also possible [13]. Test results may indicate a nuclear DNA abnormality.
• Clinical Evaluation: A clinical evaluation by a specialist, such as a geneticist or a pediatrician, is essential to diagnose MDS8A. This involves assessing the patient's medical history, performing a physical examination, and ordering diagnostic tests.

Additional Diagnostic Tests

Other diagnostic tests that may be used to support the diagnosis of MDS8A include:

• Blood Tests: Blood tests can help identify lactic acidosis and other metabolic abnormalities associated with MDS8A.
• Imaging Studies: Imaging studies, such as MRI or CT scans, may be performed to evaluate the extent of neurologic involvement.

Specialist Referrals

If you suspect that your child has MDS8A, it is essential to consult a specialist, such as a geneticist or a pediatrician. A primary care physician (PCP) can help you get specialist referrals, order diagnostic tests, and coordinate providers as you build a healthcare team [12].

Current Drug Treatments for Mitochondrial DNA Depletion Syndrome

According to available information, currently, all treatment of mitochondrial disorders, including mitochondrial DNA depletion syndrome (MDS), is performed with dietary supplements or by off-label use of drugs approved for other indications [7][3]. This approach may help alleviate symptoms and slow disease progression but does not provide a cure.

Experimental Treatments

Research has shown that nucleoside therapy is a promising experimental treatment for TK2 deficiency, which is associated with MDS. This treatment involves supplementing patients with exogenous deoxypyrimidines to support mitochondrial DNA maintenance [2].

Limitations and Future Directions

It's essential to note that there is currently no curative treatment available for MDS. The syndrome can be fatal in infancy or early childhood, highlighting the need for further research into effective treatments [10]. As of now, patients are advised to consult with a healthcare professional for medical advice and treatment [6].

References

• [1] AZ Lim (2021) - RRM2B mitochondrial DNA maintenance defects should be suspected in individuals with suggestive findings of the two common phenotypes.
• [2] E Dombi (2024) - Nucleoside therapy is a promising experimental treatment for TK2 deficiency, where patients are supplemented with exogenous deoxypyrimidines.
• [3] O Hurko (2013) - Currently, all treatment of mitochondrial disorders is performed with dietary supplements or by off-label use of drugs approved for other indications.
• [4] O Hurko (2013) - Currently, all treatment of mitochondrial disorders is performed with dietary supplements or by off-label use of drugs approved for other indications.
• [5] May 1, 2020 - RRM2B-MDS is a severe condition that begins in infancy and affects multiple body systems. It is associated with brain dysfunction combined with muscle weakness.
• [6] Please consult with a healthcare professional for medical advice and treatment. Print. Disease Overview. Any mitochondrial DNA depletion syndrome in which the ...
• [7] Currently, all treatment of mitochondrial disorders is performed with dietary supplements or by off-label use of drugs approved for other indications.
• [8] Apr 28, 2024 - There is currently no curative treatment available. Nucleoside therapy is a promising experimental treatment for TK2 deficiency, where patients ...
• [9] Sep 20, 2023 - A loss of thymidine phosphorylase activity and the resulting buildup of thymidine disrupt the usual maintenance and repair of mtDNA. As a result ...
• [10] MDS can be fatal in infancy or early childhood, with no curative treatment currently available. The syndrome impairs mtDNA-encoded protein synthesis and energy ...

Mitochondrial DNA depletion syndrome 8A (MTDPS8A) has a differential diagnosis that includes other mitochondrial dystonia syndromes, such as Mitochondrial DNA depletion syndrome 16A (Hepatic type) (MTDPS16A). This is because both conditions are characterized by mitochondrial dysfunction and can present with similar symptoms.

Other conditions to consider in the differential diagnosis of MTDPS8A:

• Mitochondrial DNA depletion syndrome 16A (Hepatic type): This condition, also known as POLG2 variant syndrome, presents with liver dysfunction and is caused by mutations in the POLG2 gene. Like MTDPS8A, it is characterized by mitochondrial DNA depletion.
• Other mitochondrial dystonia syndromes: These are a group of conditions that affect the mitochondria and can present with symptoms such as muscle weakness, fatigue, and neurological problems.

Key points to consider:

• Mitochondrial dysfunction is a common thread among these conditions
• Symptoms can be similar, making differential diagnosis challenging
• Genetic testing may be necessary to confirm the diagnosis

[Citations]

• [6] POLG2 variant syndrome: Mitochondrial DNA depletion syndrome 16A (Hepatic type) (MTDPS16A)
• [8] Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075, AR, 3.