nuclear type mitochondrial complex I deficiency 27

Mitochondrial Complex I Deficiency, Nuclear Type 27

Mitochondrial complex I deficiency, nuclear type 27 (MC1DN27) is a rare genetic disorder caused by mutations in the NDUFAF7 gene. This condition affects the functioning of the mitochondrial respiratory chain complex I, leading to a shortage of energy production in cells.

Clinical Features

The clinical features of MC1DN27 can vary widely among affected individuals. Some common symptoms include:

• Muscle weakness: Progressive muscle weakness and wasting are often seen in patients with MC1DN27.
• Neurological symptoms: Many individuals experience neurological symptoms such as seizures, ataxia, and cognitive decline.
• Endocrine abnormalities: Some patients may exhibit endocrine abnormalities, including hypogonadism and adrenal insufficiency.

Genetic Heterogeneity

Mitochondrial complex I deficiency shows extreme genetic heterogeneity, meaning that mutations in multiple genes can cause this condition. The NDUFAF7 gene is one of the nuclear-encoded genes responsible for encoding a subunit of mitochondrial complex I.

References

• [1] Mitochondrial complex I deficiency, nuclear type 27 (MC1DN27) is an autosomal recessive metabolic disorder characterized by global developmental delay, muscle weakness, and neurological symptoms. [6]
• The NDUFAF7 gene encodes a subunit of mitochondrial complex I, and mutations in this gene can cause MC1DN27. [11]
• Mitochondrial complex I deficiency, nuclear type 27 (MC1DN27) is a rare genetic disorder that affects the functioning of the mitochondrial respiratory chain complex I. [10]

Based on the provided context, here are the signs and symptoms of nuclear type mitochondrial complex I deficiency:

• Acute metabolic acidosis: This is a condition characterized by an excessive accumulation of acidic substances in the body (1).
• Hypertrophic cardiomyopathy: This refers to a thickening of the heart muscle that can lead to problems with the heart's ability to pump blood effectively (3).
• Muscle weakness: Muscle weakness, particularly in the muscles used for movement and other bodily functions, is a common symptom of mitochondrial complex I deficiency (4, 5).
• Hyper-beta-alaninemia: This is an elevated level of beta-alanine in the blood, which can be indicative of mitochondrial dysfunction (4, 6).
• Increased circulating lactate concentration: Elevated levels of lactic acid in the bloodstream are a hallmark of mitochondrial complex I deficiency (4, 6).
• Gastroesophageal reflux: This is a condition characterized by stomach acid flowing back up into the esophagus, which can cause discomfort and other symptoms (4).

It's worth noting that these symptoms can vary greatly from person to person and may not be present in every individual with nuclear type mitochondrial complex I deficiency.

Based on the provided context, here are some diagnostic tests for nuclear type mitochondrial complex I deficiency:

• Genetic testing: Genetic testing can confirm a diagnosis and help identify the underlying cause of the condition. This includes sequencing analysis of the entire coding region, bi-directional Sanger sequence analysis, and massively parallel sequencing (next-generation sequencing) to analyze 221 nuclear-encoded genes implicated in mitochondrial disease [12][15].
• Muscle biopsy: A muscle biopsy can be performed to measure spectrophotometrically the enzyme activity of complex I in a muscle sample [7].
• Clinical Molecular Genetics test: This test, offered by Translational Metabolic Laboratory, uses sequence analysis of the entire coding region and bi-directional Sanger Sequence Analysis to diagnose Mitochondrial complex I deficiency, nuclear type 1 [12].

It's essential to consult with a clinical genetic specialist for an accurate diagnosis. They may also suggest specific genetic testing or other types of tests to help reach a diagnosis [10].

Treatment Options for Nuclear Type Mitochondrial Complex I Deficiency

According to available research, there are several treatment options that have been explored for nuclear type mitochondrial complex I deficiency.

• CoQ10 and B vitamins: Coenzyme Q10 (CoQ10) and a B vitamin are commonly used medications in the starting "mitochondrial treatment cocktail" [1].
• Riboflavin, thiamine, biotin, CoQ10, and carnitine: A variety of treatments have been tried, which may or may not be effective, including riboflavin, thiamine, biotin, CoQ10, and carnitine [11].
• Supportive and preventive approaches: Current treatment for primary mitochondrial disease (PMD), a group of complex genetic disorders that include nuclear type mitochondrial complex I deficiency, revolves around supportive and preventive approaches [3].

It's essential to note that these treatments may not be effective for everyone, and more research is needed to understand their efficacy. Additionally, the effectiveness of these treatments can vary depending on the individual case.

References:

[1] S Parikh · 2009 · Cited by 404 [11] A variety of treatments, which may or may not be effective, include: riboflavin, thiamine, biotin, CoQ10, and carnitine. [3] Primary mitochondrial disease (PMD) is a group of complex genetic disorders that arise due to pathogenic variants in nuclear or mitochondrial genomes.

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 mitochondrial disorders and identifying key clinical features that distinguish it from other conditions.

Key Clinical Features:

• Hypertrophic cardiomyopathy: A hallmark feature of nuclear type mitochondrial complex I deficiency, characterized by thickening of the heart muscle (1).
• Lactic acidosis: Elevated levels of lactic acid in the blood, which can lead to metabolic acidosis and other complications (2).
• 3-methylglutaconic aciduria: Presence of 3-methylglutaconic acid in the urine, a biomarker for mitochondrial disorders (3).
• Hyperammonemia: Elevated levels of ammonia in the blood, which can cause neurological symptoms and seizures (4).

Differential Diagnosis:

• Mitochondrial complex I deficiency, mitochondrial type: A similar condition caused by mutations in the mtDNA, which can present with overlapping clinical features (5).
• Leigh syndrome: A severe neurodegenerative disorder caused by mutations in various genes, including those involved in mitochondrial function (6).
• MELAS syndrome: A mitochondrial disorder characterized by muscle weakness, encephalopathy, lactic acidosis, and stroke-like episodes (7).

Diagnostic Approach:

To diagnose nuclear type mitochondrial complex I deficiency, clinicians should consider the following steps:

1. Clinical evaluation: Assess patients for symptoms such as hypertrophic cardiomyopathy, lactic acidosis, and hyperammonemia.
2. Biochemical testing: Measure levels of 3-methylglutaconic acid in the urine and lactate in the blood to support the diagnosis.
3. Genetic testing: Perform sequencing of the NDUFAF5 gene to confirm mutations associated with this condition.

References:

• (1) Zanette et al., 2021
• (2) Goldstein et al., 2013
• (3) Goldstein et al., 2013
• (4) Weisfeld-Adams et al., 2015
• (5) Flønes et al., 2024
• (6) Kirby et al., 2004