nuclear type mitochondrial complex I deficiency 17

Mitochondrial Complex I Deficiency, Nuclear Type 17 (MC1DN17)

Mitochondrial Complex I Deficiency, Nuclear Type 17 is a rare genetic disorder caused by mutations in the NDUFAF6 gene on chromosome 8q22. This condition affects the mitochondria's ability to produce energy for cells, leading to various clinical symptoms.

Clinical Features

• Developmental Delay: A delay in achieving motor or mental milestones, including motor skills, speech and language, cognitive skills [5].
• Neurodegenerative Disorders: Can range from lethal neonatal disease to adult-onset neurodegenerative disorders [4].
• Mitochondrial Disorder: Characterized by defective oxidative phosphorylation, affecting 1 in 5-10000 live births [4].

Causes and Genetics

• NDUFAF6 Gene Mutation: Homozygous or compound heterozygous mutations in the NDUFAF6 gene cause MC1DN17 [3][8].
• Genetic Heterogeneity: Mitochondrial complex I deficiency can be caused by mutations in both nuclear and mitochondrial genes [14].

Diagnosis and Testing

• Clinical Genetic Specialist: Consultation and evaluation with a clinical genetic specialist is essential for diagnosis.
• Genetic Testing: Specific genetic testing or other types of tests may be suggested to help reach a diagnosis [12].
• Biochemical Signature: MC1DN17 has a distinct biochemical signature, making it a form of mitochondrial disorder [2].

Prevalence and Impact

• Common Mitochondrial Disorder: Complex I deficiency is the most frequent mitochondrial disorder presenting in childhood, accounting for up to 30% of cases [13].
• Wide Array of Clinical Manifestations: MC1DN17 can lead to various clinical manifestations, including Leigh syndrome and MELAS [14].

References: [2] - A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions ... [3] - A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 17 (MC1DN17) is caused by homozygous or compound heterozygous mutation in the NDUFAF6 gene (612392) on chromosome 8q22. [4] - Mitochondrial complex I deficiency, nuclear type 17 is a form of mitochondrial disorder characterized by defective oxidative phosphorylation. It affects 1 in 5-10000 live births and can range in severity from lethal neonatal disease to adult-onset neurodegenerative disorders. [5] - A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills ... [8] - A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 17 (MC1DN17) is caused by homozygous or compound heterozygous mutation in the NDUFAF6 gene (612392) on chromosome 8q22. [12] - 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. Specialists may also suggest specific genetic testing or other types of tests to help reach a diagnosis. [13] - Complex I deficiency is the most frequent mitochondrial disorder presenting in childhood, accounting for up to 30% of cases. As with many mitochondrial disorders, complex I deficiency is characterised by marked clinical and genetic heterogeneity, leading to considerable diagnostic challenges for the clinician, not least because of the involvement of two genomes. [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 ...).

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 amount of acid in the body fluids, which can lead to serious complications if left untreated (4).
• Hypertrophic cardiomyopathy: This is a condition where the heart muscle becomes thickened, leading to problems with the heart's ability to pump blood effectively (4).
• Muscle weakness: Muscle weakness is a common symptom of mitochondrial complex I deficiency, particularly in the muscles used for movement and other physical activities (5, 7).
• Decreased activity of mitochondrial complex I: This is a key feature of mitochondrial complex I deficiency, where the enzyme responsible for generating energy in cells is not functioning properly (5, 7).
• Mitochondrial swelling: Mitochondria are the powerhouses of cells, and swelling can indicate damage to these structures (5).
• Elevated lactate:pyruvate ratio: This is a measure of the balance between lactate and pyruvate in the body, which can be affected by mitochondrial complex I deficiency (5).
• Hyper-beta-alaninemia: This is an elevated level of beta-alanine in the blood, which can be associated with mitochondrial complex I deficiency (5, 7).
• Increased circulating lactate concentration: Lactate levels are often elevated in individuals with mitochondrial complex I deficiency (7).

It's worth noting that these symptoms can vary greatly from person to person and may not be present in all cases of nuclear type mitochondrial complex I deficiency. Additionally, the severity and progression of the disease can also differ significantly among affected individuals.

References: (4) - [4] (5) - [5] (7) - [7]

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

• Genetic testing: This can confirm a diagnosis and help identify the underlying genetic cause of the condition. The Invitae Nuclear Mitochondrial Disorders Panel analyzes nuclear-encoded genes associated with mitochondrial dysfunction, including deficiencies of oxidative phosphorylation and mitochondrial complexes [3].
• Sequence analysis of the entire coding region: This test is offered by Translational Metabolic Laboratory for diagnosing Mitochondrial complex I deficiency, nuclear type 1 [12].
• Bi-directional Sanger Sequence Analysis: This test is also offered by Translational Metabolic Laboratory for diagnosing Mitochondrial complex I deficiency, nuclear type 1 [12].

It's worth noting that the diagnosis of mitochondrial complex I deficiency can be challenging due to its genetic and clinical heterogeneity. A consultation and evaluation with a clinical genetic specialist are recommended to determine the best course of action [10]. Additionally, there may be inconsistencies in treatment and preventive care regimens, as noted by the Mitochondrial Medicine Society [13].

References:

[3] The Invitae Nuclear Mitochondrial Disorders Panel analyzes nuclear-encoded genes that are associated with mitochondrial dysfunction, including but not limited to deficiencies of oxidative phosphorylation, deficiencies of mitochondrial complexes, primary coenzyme Q10 deficiency, and multiple mitochondrial dysfunction syndromes.

[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. Specialists may also suggest specific genetic testing or other types of tests to help reach a diagnosis.

[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 condition caused by mutations in the NDUFS4 gene, can be challenging to treat. While there is no cure, various treatments may help alleviate symptoms and improve quality of life.

• Riboflavin: Also known as vitamin B2, riboflavin has been used to treat complex I deficiency. It plays a crucial role in energy production within the mitochondria.
• Thiamine: Thiamine, or vitamin B1, is another essential nutrient that can help alleviate symptoms of complex I deficiency.
• Biotin: Biotin, a B-complex vitamin, has been used to treat various mitochondrial disorders, including complex I deficiency.
• CoQ10: Coenzyme Q10 (CoQ10) is an antioxidant that helps generate energy within the mitochondria. It may be beneficial in treating complex I deficiency.
• Carnitine: L-carnitine is a nutrient that plays a crucial role in energy production and can help alleviate symptoms of complex I deficiency.

Emerging Therapies

Researchers are exploring new therapies to treat mitochondrial disorders, including complex I deficiency. These emerging treatments may include:

• Dietary supplements: Certain dietary supplements, such as CoQ10 and carnitine, may be beneficial in treating complex I deficiency.
• Exercise therapy: Regular exercise can help improve energy production within the mitochondria and alleviate symptoms of complex I deficiency.

Current Challenges

While these treatments show promise, there are currently limited evidence-based treatment options available for mitochondrial respiratory chain dysfunction. Further research is needed to develop effective therapies for complex I deficiency and other mitochondrial disorders.

References:

• [1] McFarland et al. (2004) - Isolated complex I deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.
• [2] Kirby et al. (2004) - Complex I deficiency is a significant contributor to mitochondrial dysfunction.
• [3] S Parikh (2009) - CoQ10 and B vitamins are commonly used medications in treating mitochondrial diseases.
• [4] O Hurko (2013) - Dietary supplements and off-label use of drugs approved for other indications are currently the only treatment options available for mitochondrial disorders.

Differential Diagnosis of Nuclear Type Mitochondrial Complex I Deficiency 17

Mitochondrial complex I deficiency, particularly the nuclear-encoded type 17 (NDUFAF6), presents a diagnostic challenge due to its genetic heterogeneity and overlapping clinical features with other mitochondrial disorders. The differential diagnosis for this condition involves considering various factors and conditions that may mimic or co-occur with mitochondrial complex I deficiency.

Key Conditions to Consider:

• Leigh Syndrome: A severe neurodegenerative disorder caused by mutations in the NDUFS1, NDUFA9, or NDUFB11 genes, which are also associated with mitochondrial complex I deficiency.
• MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes): A condition characterized by recurrent episodes of encephalopathy, lactic acidosis, and stroke-like episodes, often caused by mutations in the MT-ND1 or MT-ND5 genes.
• Cavitating Leukodystrophy: A rare neurodegenerative disorder that can present with similar clinical features to mitochondrial complex I deficiency, such as developmental regression and seizures.

Diagnostic Approaches:

To establish a diagnosis of nuclear type mitochondrial complex I deficiency 17 (NDUFAF6), clinicians should consider the following approaches:

1. Genetic Testing: Whole exome sequencing (WES) or whole genome sequencing (WGS) can help identify mutations in the NDUFAF6 gene.
2. Biochemical Analysis: Enzyme assays and biochemical tests can confirm complex I deficiency and rule out other mitochondrial disorders.
3. Clinical Evaluation: A thorough clinical evaluation, including a detailed medical history, physical examination, and assessment of cognitive and motor function, is essential to establish the diagnosis.

References:

• [13] Clinical resource with information about Mitochondrial complex 1 deficiency nuclear type 17 and its clinical features, NDUFAF6, 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
• [14] 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.
• [15] Mitochondrial diseases are amongst the most genetically and phenotypically diverse groups of inherited diseases. The vast phenotypic overlap with other disease entities together with the absence of reliable biomarkers act as driving forces for the integration of unbiased methodologies early in the diagnostic algorithm, such as whole exome sequencing (WES) and whole genome sequencing (WGS).