mitochondrial complex III deficiency nuclear type 4

Mitochondrial complex III deficiency nuclear type 4 (MC3DN4) is a genetic condition that affects the body's ability to produce energy in cells. It is caused by a mutation in the UQCRQ gene, which is located on chromosome 5q31.

Key Features:

• Genetic Cause: MC3DN4 is caused by a homozygous mutation in the UQCRQ gene [5].
• Energy Production: The condition affects the body's ability to produce energy in cells through mitochondrial complex III, leading to impaired cellular function [8].
• Severity: MC3DN4 is considered a severe multisystem disorder, affecting various parts of the body including the brain, kidneys, liver, and skeletal muscles [9].

Symptoms:

While specific symptoms are not mentioned in the provided context, it can be inferred that individuals with MC3DN4 may experience a range of clinical features related to impaired energy production in cells.

• Decreased activity of mitochondrial complex III: This is a direct consequence of the genetic mutation causing MC3DN4 [1].
• Increased circulating lactate concentration: Elevated lactate levels are often associated with impaired cellular respiration, which can occur in individuals with MC3DN4 [1].

References:

[5] Mitochondrial complex III deficiency nuclear type 4 (MC3DN4) is caused by homozygous mutation in the UQCRQ gene (612080) on chromosome 5q31. [8] Complex III (CIII) deficiency is one of the least common oxidative phosphorylation defects associated to mitochondrial disease. CIII constitutes the center of the electron transport chain, and its dysfunction can lead to impaired energy production in cells [8]. [9] Mitochondrial complex III deficiency nuclear types 1–9 (MCIIID) are severe multisystem disorders characterized by impaired mitochondrial function and energy production [9].

Clinical Features and Symptoms

Mitochondrial complex III deficiency, also known as NADH dehydrogenase subcomplex 1 (NDUFS1) deficiency, is a rare genetic disorder that affects the mitochondria's ability to produce energy for the body. The signs and symptoms of this condition can vary in severity and may include:

• Muscle Weakness: People with mitochondrial complex III deficiency often experience muscle weakness, particularly in the muscles used for exercise [2][3].
• Extreme Tiredness (Fatigue): This condition is characterized by extreme tiredness, especially during physical activity or exercise intolerance [2][3].
• Hypotonia: Affected individuals may exhibit decreased muscle tone, leading to a range of symptoms including axial hypotonia [1].
• Ragged-Red Muscle Fibers: A hallmark feature of mitochondrial complex III deficiency is the presence of ragged-red muscle fibers, which are abnormal muscle fibers that contain excessive amounts of mitochondria [1].

Additional Symptoms

In addition to these primary symptoms, people with mitochondrial complex III deficiency may also experience:

• Developmental Delay or Regression: Some individuals may exhibit developmental delays or regression, particularly in areas such as motor skills and eye contact [5].
• Ataxia: This condition can lead to ataxia, which is a lack of coordination and balance.
• Renal Tubulopathy: Affected individuals may experience renal tubulopathy, which affects the kidneys' ability to filter waste from the blood.
• Anemia: Some people with mitochondrial complex III deficiency may develop anemia, which is characterized by low red blood cell count or hemoglobin levels.
• Hearing Loss and Cardiomyopathy: In some cases, this condition can lead to hearing loss and cardiomyopathy, a disease of the heart muscle.

Variable Phenotype

It's essential to note that the phenotype (physical characteristics) of mitochondrial complex III deficiency can vary significantly among affected individuals. Some people may experience mild symptoms, while others may have more severe manifestations [6].

References: [1] Clinical features · Decreased activity of mitochondrial complex III · Increased circulating lactate concentration · Axial hypotonia · Ragged-red muscle fibers. [2] Apr 1, 2014 — People who are mildly affected tend to have muscle weakness (myopathy) and extreme tiredness (fatigue), particularly during exercise (exercise ... [3] Apr 1, 2014 — People who are mildly affected tend to have muscle weakness (myopathy) and extreme tiredness (fatigue), particularly during exercise (exercise ... [5] Affected individuals show hypotonia, failure to thrive, and developmental delay or regression with poor eye contact and loss of motor skills with ataxia. [6] Other associated symptoms are renal tubular disease, skin lesions, diabetes mellitus, proximal muscle weakness, and retinopathy. The phenotype is variable, but ...

Diagnostic Tests for Mitochondrial Complex III Deficiency Nuclear Type 4

Mitochondrial complex III deficiency nuclear type 4 can be diagnosed through various genetic tests that analyze the UQCRQ gene. Here are some diagnostic tests mentioned in the search results:

• Genetic Testing: Genetic testing is available to diagnose mitochondrial complex III deficiency nuclear type 4. The test analyzes the UQCRQ gene and can be performed on whole blood or DNA samples.
• PreventionGenetics Test: PreventionGenetics offers a clinical genetic test for conditions, including mitochondrial complex III deficiency nuclear type 4. This test analyzes the UQCRQ gene and is part of Exact Sciences' testing portfolio.
• Invitae Nuclear Mitochondrial Disorders Panel: The Invitae Nuclear Mitochondrial Disorders Panel analyzes nuclear-encoded genes associated with mitochondrial dysfunction, including the UQCRQ gene.
• Intergen Clinical Genetic Test: Intergen offers a clinical genetic test for mitochondrial complex III deficiency nuclear type 4, which analyzes the UQCRQ gene.

Acceptable Specimen Types

For these diagnostic tests, whole blood and DNA samples are acceptable specimen types. It's essential to select the correct test type, such as Family - Trio patient + 2, when ordering these genetic tests.

Laboratory Studies

In addition to genetic testing, laboratory studies may reveal increased serum lactate levels and decreased mitochondrial respiratory complex IV levels, which can be indicative of mitochondrial complex III deficiency nuclear type 4.

References:

• [3] Acceptable specimen types for genetic testing are whole blood and DNA.
• [8] Intergen offers a clinical genetic test for mitochondrial complex III deficiency nuclear type 4.
• [5] Laboratory studies may reveal increased serum lactate levels and decreased mitochondrial respiratory complex IV levels.

Treatment Options for Mitochondrial Complex III Deficiency

Mitochondrial complex III deficiency, a genetic condition affecting the brain, kidneys, liver, heart, and skeletal muscles, requires careful management to alleviate symptoms. While there is no cure, various treatment options can help manage the condition.

• Dietary Supplements: Patients with mitochondrial disorders often benefit from dietary supplements or off-label use of drugs approved for other indications [2][4].
• Coenzyme Q10 (CoQ10): The reduced form of CoQ10 (ubiquinol) is recommended for patients with primary mitochondrial disorders, including complex III deficiency [5].
• Vitamin K-3 and Coenzyme Q10: Patients with complex III deficiency may benefit from vitamin K-3 (40–160 mg/day) or coenzyme Q10 (80–300 mg/day) [8].

Emerging Therapies

Recent studies have explored advanced interventions, such as using healthy mitochondria to replenish or replace damaged mitochondria. These approaches have shown promise in preclinical trials [9].

Mitochondrial Complex III Deficiency Nuclear Type 4 (MC3DN4) Differential Diagnosis

Mitochondrial complex III deficiency, nuclear type 4 (MC3DN4), is a rare genetic disorder that affects the mitochondria's ability to produce energy for the body. The differential diagnosis of MC3DN4 involves ruling out other conditions that may present similar symptoms.

Key Diagnostic Features:

• Complex III Deficiency: A deficiency in the mitochondrial enzyme complex III, which is essential for generating energy (ATP) for the cell.
• Mildly Elevated Transaminase Levels: Slightly elevated levels of transaminases, enzymes involved in amino acid metabolism, can be a diagnostic feature.
• Four Major Forms: MC3DN4 presents with four major forms:
  • Fatal infantile encephalomyopathy
  • Congenital lactic acidosis
  • Hepatic failure
  • Cardiomyopathy

Differential Diagnosis Considerations:

When diagnosing MC3DN4, it is essential to consider other conditions that may present with similar symptoms. These include:

• Mitochondrial DNA-associated Leigh syndrome: A condition caused by mutations in the mitochondrial DNA.
• GRACILE mutation: A genetic mutation that causes postnatal complex III deficiency and hepatopathy.
• MT-CYB mutations: Mutations in the MT-CYB gene can cause isolated complex III deficiency leading to various symptoms.

Diagnostic Approach:

A comprehensive diagnostic approach for MC3DN4 involves:

1. Clinical evaluation: Assessing the patient's medical history, physical examination, and laboratory results.
2. Genetic testing: Identifying mutations in the UQCRB gene associated with MC3DN4.
3. Biochemical tests: Measuring transaminase levels and other biochemical markers to confirm complex III deficiency.

References:

• [1] by S Rahman · 2020 - Differential diagnosis of nuclear gene-encoded Leigh syndrome spectrum includes mitochondrial DNA-associated Leigh syndrome (see Mitochondrial ...).
• [4] by M Mori · 2015 - Mutations in MT-CYB cause isolated complex III deficiency leading to a variety of symptoms including failure to thrive, exercise intolerance, cardiomyopathy, ...
• [7] by JD Weisfeld-Adams · 2015 - Leigh disease encompasses a heterogeneous group of conditions, some of which are caused by autosomal recessively-inherited mutations in nuclear ...