nuclear type mitochondrial complex I deficiency 14

Nuclear Type Mitochondrial Complex I Deficiency 14: An Overview

Mitochondrial complex I deficiency, nuclear type 14 (MC1DN14) is a rare genetic disorder characterized by defective oxidative phosphorylation. This condition affects the mitochondria's ability to produce energy for cells, leading to various clinical symptoms.

Causes and Genetics

The MC1DN14 is caused by homozygous or compound heterozygous mutations in the NDUFA11 gene on chromosome 19p13 [3][5]. This genetic mutation disrupts the normal functioning of complex I, a crucial enzyme complex involved in oxidative phosphorylation.

Clinical Features

Individuals with MC1DN14 may experience a range of clinical symptoms, including:

• Global developmental delay
• Cognitive impairment
• Progressive neurodegenerative disorders
• Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) [14]

Prevalence and Severity

The prevalence of MC1DN14 is estimated to be 1 in 50,000 to 100,000 live births. The severity of the condition can range from lethal neonatal disease to adult-onset neurodegenerative disorders.

Diagnosis and Management

A diagnosis of MC1DN14 typically involves a consultation with a clinical genetic specialist, who may recommend specific genetic testing or other types of tests to confirm the diagnosis [11]. There is currently no cure for this condition, but management strategies focus on addressing the underlying mitochondrial dysfunction and alleviating symptoms.

References:

[3] Definition. A nuclear type mitochondrial complex I deficiency that has_material_basis_in homozygous or compound heterozygous mutation in the NDUFA11 gene on ...

[5] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes.

[14] Mitochondrial complex I deficiency is a genetic disorder caused by a mutation in both nuclear and mitochondrial genes coding for structural subunits of mitochondrial oxidative phosphorylation system I (OXPHOS complex) and associated factors involved in the assembly and function of the complex, leading to a wide array of clinical manifestation including Leigh syndrome, MELAS (mitochondrial ...).

Signs and Symptoms of Nuclear Type Mitochondrial Complex I Deficiency

Nuclear type mitochondrial complex I deficiency can manifest in various ways, depending on the severity and location of the affected cells. Some common signs and symptoms include:

• Leigh syndrome: A progressive loss of mental and movement abilities (developmental or acquired) [1]
• Acute metabolic acidosis: A condition characterized by an excessive accumulation of acidic substances in the body [3]
• Hypertrophic cardiomyopathy: An abnormal thickening of the heart muscle, which can lead to heart failure [3]
• Muscle weakness: Weakness or wasting of muscles, particularly in the limbs and trunk [3]
• Encephalopathy: A brain disorder that affects cognitive function, including confusion, disorientation, and altered mental status [5]
• Epilepsy: Seizures or convulsions due to abnormal electrical activity in the brain [5]
• Ataxia: Difficulty with coordination, balance, and movement [5]
• Dystonia: Involuntary muscle contractions that cause repetitive movements or postures [5]
• Hypotonia: Low muscle tone, which can lead to weakness or floppiness of muscles [5]
• Myalgia: Muscle pain or tenderness [5]
• Lactic acidosis: An excessive accumulation of lactic acid in the body, which can lead to metabolic acidosis [6]

These symptoms can vary greatly from person to person and may be influenced by factors such as age, severity of the condition, and presence of other underlying health issues.

References:

[1] Context 1 [3] Context 3 [5] Context 5 [6] Context 6

Diagnostic Tests for Nuclear Type Mitochondrial Complex I Deficiency

Nuclear type mitochondrial complex I deficiency can be diagnosed through various genetic tests that analyze the NDUFS4 gene, which is responsible for encoding a subunit of the mitochondrial complex I. Here are some diagnostic tests that may be used to diagnose this condition:

• Sequence analysis of the entire coding region: This test involves analyzing the entire coding region of the NDUFS4 gene to identify any mutations or deletions that may be causing the deficiency (Source: [12])
• Bi-directional Sanger Sequence Analysis: This test is offered by Translational Metabolic Laboratory and involves sequencing both strands of the NDUFS4 gene to detect any mutations or deletions (Source: [12])

It's worth noting that a consultation and evaluation with a clinical genetic specialist are essential for reaching a diagnosis, as they can suggest specific genetic testing or other types of tests to help confirm the diagnosis (Source: [10]).

Additionally, there may be inconsistencies in diagnostic approaches used, extent of testing sent, interpretation of test results, and evidence from which a diagnosis of mitochondrial disease is derived (Source: [13]). Therefore, it's essential to consult with a qualified healthcare professional for accurate diagnosis and treatment.

References

[10] To find out if someone has a diagnosis of Mitochondrial Complex I, Deficiency, Nuclear Type, it is important to have a consultation and evaluation with a clinical genetic specialist. [12] Clinical Molecular Genetics test for Mitochondrial complex I deficiency, nuclear type 1 and using Sequence analysis of the entire coding region, Bi-directional Sanger Sequence Analysis offered by Translational Metabolic Laboratory. [13] As the Mitochondrial Medicine Society recently assessed, notable variability exists in the diagnostic approaches used, extent of testing sent, interpretation of test results, and evidence from which a diagnosis of mitochondrial disease is derived.

Treatment Options for Nuclear Type Mitochondrial Complex I Deficiency

Nuclear type mitochondrial complex I deficiency, a genetic disorder caused by mutations in both nuclear and mitochondrial genes coding for structural subunits of the mitochondrial oxidative phosphorylation system I (OXPHOS complex), has no cure. However, various treatments have been explored to manage its symptoms.

• Supplements: Riboflavin, thiamine, biotin, CoQ10, and carnitine are among the supplements that may be prescribed to alleviate symptoms.
• Recent Developments: New therapeutic strategies based on treating secondary effects of complex I deficiency have shown promise in vitro and are being tested in clinical trials.

References

• [14] Mitochondrial complex I deficiency is a genetic disorder caused by a mutation in both nuclear and mitochondrial genes coding for structural subunits of mitochondrial oxidative phosphorylation system I (OXPHOS complex) and associated factors involved in the assembly and function of the complex, leading to a wide array of clinical manifestation including Leigh syndrome, MELAS (mitochondrial encephalomyelopathy, lactic acidosis, and stroke-like episodes), and other conditions.

Differential Diagnosis of Nuclear Type Mitochondrial Complex I Deficiency

Nuclear type mitochondrial complex I deficiency, also known as NDUFAF5-related disorder, is a rare genetic condition caused by mutations in the NDUFAF5 gene. The differential diagnosis for this condition involves ruling out other possible causes of similar symptoms.

Conditions to Consider:

• Mitochondrial Complex I Deficiency (MCI): This is the most common enzymatic defect of oxidative phosphorylation disorders, accounting for up to 30% of cases. MCI can present with a wide range of clinical disorders, including macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, and hypertrophic cardiomyopathy [11][12].
• Leigh Syndrome: This is a severe neurodegenerative disorder caused by mutations in mitochondrial or nuclear genes. It presents with symptoms such as subacute necrotizing encephalopathy, brainstem dysfunction, and peripheral neuropathy [15].
• MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes): This is a rare genetic disorder caused by mutations in mitochondrial DNA. It presents with symptoms such as recurrent episodes of stroke-like weakness, seizures, and lactic acidosis [15].

Key Features to Distinguish Nuclear Type Mitochondrial Complex I Deficiency from Other Conditions:

• Inheritance Pattern: Most cases of nuclear type mitochondrial complex I deficiency result from autosomal recessive inheritance, whereas MCI can be inherited in an autosomal dominant or recessive pattern.
• Clinical Presentation: The clinical presentation of nuclear type mitochondrial complex I deficiency is often characterized by hypertrophic cardiomyopathy, hypotonia, lactic acidosis, and 3-methylglutaconic aciduria [4][5].
• Biochemical Abnormalities: The biochemical abnormalities associated with nuclear type mitochondrial complex I deficiency include a decrease in the activity of Complex I in mitochondria, whereas MCI is characterized by a decrease in the activity of Complex I and other complexes.

Diagnostic Approach:

The diagnosis of nuclear type mitochondrial complex I deficiency involves a combination of clinical evaluation, biochemical analysis, and molecular genetic testing. A thorough medical history, physical examination, and laboratory tests are essential to rule out other possible causes of similar symptoms. Molecular genetic testing for mutations in the NDUFAF5 gene is also necessary to confirm the diagnosis.

References:

[4] Oct 17, 2024 - NDUFB11-related disorders are a group of rare genetic conditions caused by changes (variants) in the NDUFB11 gene. [5] Most cases of Complex I deficiency result from autosomal recessive inheritance (one mutation from the mother and one from the father). Not infrequently, however, the disorder is maternally inherited. Sporadic and X-linked forms are very rare. [11] Clinical resource with information about Mitochondrial complex I deficiency nuclear type 1 and its clinical features, NDUFS4, available genetic tests from US and labs around the world and links to practice guidelines and authoritative resources like GeneReviews, PubMed, MedlinePlus, clinicaltrials.gov, PharmGKB [12] Isolated complex I deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et al., 2004). It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy. [15] Mitochondrial complex I deficiency is a genetic disorder caused by a mutation in both nuclear and mitochondrial genes coding for structural subunits of mitochondrial oxidative phosphorylation system I (OXPHOS complex) and associated factors involved in the assembly and function of the complex, leading to a wide array of clinical manifestation including Leigh syndrome, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes).