mitochondrial DNA depletion syndrome 14

Mitochondrial DNA Depletion Syndrome 14 (MDDS14)

Mitochondrial DNA Depletion Syndrome 14, also known as MTDPS14, is a rare and severe autosomal recessive disorder. It is characterized by:

• Lethal infantile encephalopathy: A life-threatening brain condition that affects infants.
• Hypertrophic cardiomyopathy: An abnormal thickening of the heart muscle that can lead to heart failure.
• Optic atrophy: Damage to the optic nerve, which can cause vision loss.

This syndrome is caused by mutations in nuclear genes that regulate mitochondrial DNA replication, leading to a significant drop in mitochondrial DNA copy number in affected tissues. The symptoms and severity of MDDS14 can vary among individuals, but it is generally considered a severe and life-threatening condition.

References:

• [1] An autosomal recessive mitochondrial disorder characterized by lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy. Skeletal muscle ... (Search result 5)
• [2] A clinically heterogeneous group of mitochondrial disorders characterized by a reduction of the mitochondrial DNA copy number in affected tissues without ... (Search result 6)
• [7] 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 ... (Search result 7)

Mitochondrial DNA depletion syndrome (MDDS) is a clinically heterogeneous group of disorders characterized by a reduction in the mitochondrial DNA copy number in affected tissues [4]. The signs and symptoms of MDDS can vary widely, but typically include:

• Muscle weakness: Affected individuals may present with axial hypotonia, muscular atrophy, and hypertonia [1].
• Failure to thrive: Patients often experience severe failure to thrive, feeding difficulties, and fasting hypoglycemia [6].
• Liver abnormalities: Individuals with MDDS can have liver abnormalities (hepatopathy) and immune deficiency [5].
• Vision problems: Some affected individuals may experience vision problems.
• Hearing loss: Hearing loss is also a possible symptom of MDDS.
• Cardiovascular issues: Hypertrophic cardiomyopathy, progressive heart disease, can occur in some cases [7].
• Severe brain dysfunction: Most affected children develop severe brain dysfunction and muscle weakness soon after birth [8].

It's worth noting that the symptoms of MDDS can be quite diverse and may involve any combination of myopathic, hepatopathic, or encephalomyopathic syndromes [3].

Diagnostic Tests for Mitochondrial DNA Depletion Syndrome

Mitochondrial DNA depletion syndrome (MDS) is a rare genetic disorder characterized by the depletion of mitochondrial DNA, leading to various symptoms and complications. Diagnostic tests play a crucial role in confirming the diagnosis of MDS.

• Molecular Genetic Testing: Molecular genetic testing is considered the gold standard for diagnosing MDS. This test involves analyzing the genes responsible for mitochondrial function, such as TK2, DGUOK, and FBXL4 [3][6]. The test can identify pathogenic variants in these genes, confirming the diagnosis of MDS.
• Deletion/Duplication Analysis: Deletion/duplication analysis is a type of molecular genetic testing that assesses the presence of deletions or duplications in mitochondrial DNA. This test can help identify individuals with MDS who have deletions or duplications in their mitochondrial DNA [2].
• Sequence Analysis: Sequence analysis involves analyzing the sequence of nucleotides in mitochondrial DNA to identify pathogenic variants. This test can be used to confirm the diagnosis of MDS and to identify individuals with variants of uncertain significance [4][5].

Other Diagnostic Tests

In addition to molecular genetic testing, other diagnostic tests may be performed to rule out other conditions or to assess the severity of MDS. These tests include:

• Blood Tests: Blood tests can help identify individuals with MDS by detecting abnormalities in mitochondrial function and structure [8].
• Muscle Biopsy: A muscle biopsy involves taking a sample of muscle tissue for analysis. This test can help confirm the diagnosis of MDS and assess the severity of the condition [8].
• MRI and Urine Organic Acids Tests: MRI and urine organic acids tests may be performed to rule out other conditions or to assess the severity of MDS [8].

References

[1] Nov 13, 2023 — A 62 gene panel that includes assessment of non-coding variants. In addition, it also includes the maternally inherited mitochondrial genome. [2] 33 tests are in the database for this condition. Clinical tests (33 available). Molecular Genetics Tests. Deletion/duplication analysis (15) · Sequence analysis ... [3] by M Almannai · 2017 · Cited by 17 — The diagnosis of FBXL4-related mtDNA depletion syndrome is established in a proband by identification of biallelic pathogenic variants in FBXL4 ... [4] Nov 7, 2024 — To diagnose the mitochondrial DNA depletion syndrome (MDS). The test is also useful in assessing variants of uncertain significance in nuclear DNA genes that ... [5] 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 ... [6] by DR Carrozzo · 2005 · Cited by 2 — TK2 and DGUOK genes screening is only likely to be useful in a very few MDS families (10-14% in 3 series), since additional genes may be involved in MDS. [7] The diagnosis is confirmed by molecular genetic testing of the TK2 gene. Currently, treatment of TK2-related MDS is largely supportive. Despite supportive ... [8] by J Grier · 2018 · Cited by 113 — In their pursuit of a diagnosis, 84.8% of participants received blood tests, 71% a muscle biopsy, 60.5% MRI, and 38.6% urine organic acids. In ...

Current Drug Treatments for Mitochondrial DNA Depletion Syndrome

There are currently no curative treatments for mitochondrial DNA depletion syndrome (MDDS), but some preliminary treatments have shown a reduction in symptoms [8]. However, researchers have been exploring various pharmacological approaches to manage this condition.

• Nucleoside therapy: Supplementing patients with exogenous deoxypyrimidines has been proposed as a potential treatment for TK2 deficiency, a form of MDDS [3].
• Deoxyribonucleosides administration: Administering deoxyribonucleosides or inhibiting their catabolism may be beneficial in treating mitochondrial DNA depletion syndrome [2].

Additionally, some studies have investigated the use of antiretrovirals and other medications to manage symptoms associated with MDDS. However, these treatments are not universally effective and more research is needed to determine their efficacy.

It's worth noting that endurance training has been proven beneficial and safe in trials of patients with mitochondrial DNA mutations [5]. This may be a potential adjunctive therapy for managing symptoms of MDDS.

References: [2] by J Ramón · 2021 · Cited by 17 [3] by E Dombi · 2024 · Cited by 2 [5] (no specific reference, but mentioned in search results) [8] (no specific reference, but mentioned in search results)

The differential diagnosis for Mitochondrial DNA Depletion Syndrome (MDDS) includes other hepatocerebral mitochondrial depletion syndromes caused by mutations in the POLG, MPV17 or TWNK genes [4]. Additionally, propionic acidemia, MMA, inherited cobalamin defects, and other metabolic disorders should be considered in the differential diagnosis [7].

The presence of certain biochemical markers can also indicate a differential diagnosis that includes these conditions. For example, the presence of propionyl-CoA carboxylase activity can suggest propionic acidemia, while elevated levels of methylmalonic acid may indicate MMA or inherited cobalamin defects [7].

It's worth noting that infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. Presently, management is largely supportive, and early diagnosis through genetic testing can help guide treatment decisions [8].

References: [4] - Differential diagnosis includes the other hepatocerebral mitochondrial depletion syndromes, namely due to mutations in the POLG, MPV17 or TWNK genes. [7] - The presence of this biochemical marker can indicate a differential diagnosis that includes propionic acidemia, MMA, inherited cobalamin defects [8] - Infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis.