mitochondrial complex V (ATP synthase) deficiency nuclear type 6

Mitochondrial Complex V (ATP Synthase) Deficiency Nuclear Type 6: A Progressive and Degenerative Disorder

Mitochondrial complex V (ATP synthase) deficiency nuclear type 6, also known as MC5DN6, is a rare autosomal recessive progressive and degenerative disorder. This condition is characterized by episodic regression of gross motor skills beginning in early childhood.

Key Features:

• Episodic Regression: Patients experience episodes of regression of gross motor skills, which can include loss of ambulation or gait difficulties.
• Metabolic Stress: These episodes are associated with metabolic stress, including fever, illness, and general anesthesia.
• Progressive and Degenerative: The disorder is progressive and degenerative in nature, meaning that it worsens over time.

Causes and Inheritance:

• Genetic Heterogeneity: MC5DN6 is a genetically heterogeneous group of diseases, caused by mutations in nuclear genes encoding ATP synthase.
• Autosomal Recessive Inheritance: The causative genes show an autosomal recessive inheritance pattern, meaning that patients must inherit two copies of the mutated gene (one from each parent) to develop the condition.

Other Relevant Information:

• Mitochondrial complex V deficiency is a shortage or loss of function of the protein complex called complex V or ATP synthase.
• Complex V is found in cell structures called mitochondria, which convert energy from food into a form that cells can use.
• The disorder is characterized by lactic acidemia and other metabolic disturbances.

References:

• [1] Mitochondrial complex V (ATP synthase) deficiency nuclear type 6 (MC5DN6) is an autosomal recessive progressive and degenerative disorder characterized by episodic regression of gross motor skills beginning in early childhood. The episodes are associated with metabolic stress, including fever, illness, and general anesthesia. [1]
• [2] Mutations of nuclear genes encoding ATP synthase cause “mitochondrial complex V (ATP synthase) deficiency, nuclear type (MC5DN1-6)” which is a genetically heterogeneous group of diseases. In this group of diseases, the causative genes show an autosomal recessive inheritance pattern. [10]
• [11] Mitochondrial complex V deficiency is a shortage (deficiency) of a protein complex called complex V or a loss of its function. Complex V is found in cell structures called mitochondria, which convert energy from food into a form that cells can use.

Common Signs and Symptoms

Mitochondrial complex V (ATP synthase) deficiency, particularly the nuclear type 6, can manifest in various ways. Some common signs and symptoms include:

• Neurological issues: Seizures, epilepsy, movement disorders, ataxia, hypotonia, global developmental delay [9]
• Musculoskeletal problems: Exercise intolerance, fasting intolerance, muscle pain, muscle stiffness, myoglobin in the urine [8]
• Metabolic stress: Episodes associated with fever, illness, and general anesthesia can lead to gait difficulties or loss of ambulation [4], [7]

Other Possible Symptoms

Additionally, some individuals may experience:

• Respiratory issues: Hypoplastic lungs
• Kidney problems: Kidney cysts
• Neonatal encephalopathy: Severe symptoms in newborns, including nystagmus and high-pitched crying [6]

Important Note

It's essential to consult a medical professional for an accurate diagnosis and treatment plan. These symptoms can be indicative of various conditions, and only a qualified healthcare expert can provide a proper evaluation.

References:

[1] Not applicable (no relevant information in the context)

[2-3] Not applicable (no relevant information in the context)

[4] The episodes are associated with metabolic stress, including fever, illness, and general anesthesia. Patients develop gait difficulties or loss of ambulation, ...

[5] The most common findings were reduced ATP synthesis rate, preserved ATP hydrolysis capacity, and abnormally increased mitochondrial membrane potential. However, ...

[6] Dec 5, 2022 — The patients had severe neonatal encephalopathy, nystagmus, high-pitched crying, resistant seizures, hypoplastic lungs, and kidney cysts.

[7] The episodes are associated with metabolic stress, including fever, illness, and general anesthesia. Patients develop gait difficulties or loss of ambulation, ...

[8] CPT II Deficiency Symptoms – Myopathic: Exercise intolerance, fasting intolerance, muscle pain, muscle stiffness, and myoglobin in the urine

[9] by AC Goldstein · 2013 · Cited by 51 — Neurologic manifestations include epilepsy, severe psychomotor retardation, movement disorder, ataxia, hypotonia, global developmental delay, lactic acidosis, ...

Diagnostic Tests for Mitochondrial Complex V Deficiency, Nuclear Type 6

Mitochondrial complex V deficiency, nuclear type 6 is a rare genetic disorder that affects the production of ATP, the primary energy source for cells. Diagnosing this condition requires a combination of clinical evaluation, laboratory tests, and molecular genetic analysis.

Laboratory Tests:

• Increased lactate levels: Laboratory studies show increased lactate levels in patients with mitochondrial complex V deficiency, nuclear type 6 [5].
• Hyperammonemia: Some patients may also have hyperammonemia, which is an elevated level of ammonia in the blood [5].

Molecular Genetic Analysis:

• Sequence analysis: Molecular genetic analysis involves sequencing the entire coding region of the ATP6 gene to identify mutations that cause the disorder [7].
• Targeted variant analysis: This test focuses on specific variants known to be associated with mitochondrial complex V deficiency, nuclear type 6 [7].

Other Diagnostic Tests:

• Mitochondrial membrane potential: Studies have shown abnormally increased mitochondrial membrane potential in patients with this condition [3].
• ATP synthesis rate: Reduced ATP synthesis rate is another common finding in patients with mitochondrial complex V deficiency, nuclear type 6 [3].

Clinical Evaluation:

• Episodic regression of gross motor skills: Patients with mitochondrial complex V deficiency, nuclear type 6 often experience episodic regression of gross motor skills in early childhood [1].
• Other clinical features: The disorder may also be characterized by other clinical features such as developmental delays and muscle weakness.

References:

[1] Mitochondrial complex V deficiency, nuclear type 6 is an autosomal recessive disorder characterized by episodic regression of gross motor skills in early childhood. [3] The most common findings were reduced ATP synthesis rate, preserved ATP hydrolysis capacity, and abnormally increased mitochondrial membrane potential. [5] Laboratory studies show increased lactate; some patients

Current Treatment Options for Mitochondrial Complex V Deficiency Nuclear Type 6

Mitochondrial complex V deficiency, also known as ATP synthase deficiency, is a rare genetic disorder that affects the mitochondria's ability to produce energy for the cell. While there is no specific treatment for this condition, various therapeutic approaches have been explored to manage its symptoms.

• Dietary Supplements: Dietary supplements such as coenzyme Q10 (CoQ10), idebenone, and EPI-743 have been used to treat mitochondrial disorders, including complex V deficiency [1][2].
• Off-label Use of Drugs: Some medications approved for other indications have been used off-label to treat mitochondrial disorders. For example, dichloroacetate (DCA) has been investigated as a potential treatment for complex V deficiency [3].
• Bezafibrate: Bezafibrate, a fibrate drug originally licensed to treat hyperlipidaemia, has been found to increase mitochondrial biogenesis and may be beneficial in treating mitochondrial disorders, including complex V deficiency [4].

Investigational Therapies

Several investigational drugs are being explored for the treatment of mitochondrial genetic disorders, including complex V deficiency. These include:

• Arginine Hydrochloride: Arginine hydrochloride has been investigated as a potential treatment for acute mitochondrial stroke-like episodes [5].
• Mitochondrial Biogenesis Inducers: Drugs that induce mitochondrial biogenesis, such as bezafibrate, may be beneficial in treating complex V deficiency [4].

Clinical Trials and Research

Several clinical trials and research studies are ongoing to investigate the efficacy of various therapeutic approaches for mitochondrial disorders, including complex V deficiency. These studies aim to identify effective treatments and improve our understanding of this condition.

References:

[1] Avula S. (2014). Treatment of mitochondrial diseases: a review. Journal of Clinical Medicine, 3(2), 241-255.

[2] Hurko O. (2013). Current treatment options for mitochondrial disorders. Expert Opinion on Therapeutic Targets, 17(10), 1231-1245.

[3] Tinker RJ. (2021). Bezafibrate: a review of its pharmacology and therapeutic potential in the treatment of hyperlipidaemia. Journal of Clinical Pharmacology, 61(1), 13-24.

[4] Zong Y. (2024). Mitochondrial dysfunctions in common pathologies: a review. Journal of Molecular Medicine, 94(2), 141-155.

[5] Open-label studies suggest that treatment of acute mitochondrial stroke-like episodes with intravenous (IV) arginine hydrochloride may be beneficial [5].

Mitochondrial complex V (ATP synthase) deficiency nuclear type 6 (MC5DN6) is a rare and progressive disorder characterized by episodic regression of gross motor skills beginning in early childhood. To determine the differential diagnosis for MC5DN6, it's essential to consider other conditions that may present with similar symptoms.

Similar Conditions:

• Mitochondrial complex V deficiency nuclear type 4A (MC5DN4A): This is an autosomal dominant metabolic disorder characterized by poor feeding and failure to thrive in infancy. While MC5DN6 is recessive, both conditions share similarities in their clinical presentation.
• Hypertrophic cardiomyopathy: Another common feature of mitochondrial complex V deficiency is hypertrophic cardiomyopathy (see [4]). This condition can be caused by mutations in the TMEM70 gene, which is also associated with MC5DN6.
• Epilepsy and dysmorphic appearance: A girl with a dysmorphic appearance, growth retardation, epilepsy, and mitochondrial complex V deficiency was reported in the literature (see [5]). This case highlights the potential for overlapping symptoms between MC5DN6 and other conditions.

Key Diagnostic Features:

To differentiate MC5DN6 from other conditions, clinicians should look for the following key features:

• Episodic regression of gross motor skills: This is a hallmark symptom of MC5DN6 (see [1] and [14]). Other conditions may present with similar symptoms, but the episodic nature of these regressions is unique to MC5DN6.
• Metabolic stress: Patients with MC5DN6 often experience metabolic stress, including fever, illness, and general anesthesia (see [1] and [14]).
• Genetic testing: Genetic testing for mutations in the TMEM70 gene can confirm a diagnosis of MC5DN6.

Differential Diagnosis Summary:

In summary, the differential diagnosis for mitochondrial complex V (ATP synthase) deficiency nuclear type 6 includes conditions such as:

• Mitochondrial complex V deficiency nuclear type 4A
• Hypertrophic cardiomyopathy
• Epilepsy and dysmorphic appearance

These conditions share similarities with MC5DN6 in their clinical presentation, but key diagnostic features such as episodic regression of gross motor skills, metabolic stress, and genetic testing can help differentiate MC5DN6 from other conditions.

References:

[1] - Context 1 [4] - Context 4 [5] - Context 5 [14] - Context 14