mitochondrial complex II deficiency

Mitochondrial complex II deficiency, also known as CII deficiency, is a rare mitochondrial disease caused by a deficiency of mitochondrial complex II.

• This condition affects the mitochondria's ability to produce energy for the body's cells [3].
• It is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype [1].
• The clinical features can vary widely among affected individuals, but some common symptoms include:
  • Poor growth and failure to thrive [5][9]
  • Severe spastic quadriplegia (a condition characterized by muscle stiffness and weakness) [2][4][5]
  • Cognitive impairment and developmental delays [2][4][5]
  • Dystonia (a movement disorder that causes involuntary muscle contractions) [5]
• In some cases, the disease can also cause psychomotor regression in infants, which is a decline in physical and mental development [5].
• Mitochondrial complex II deficiency accounts for approximately 2% of mitochondrial disease diagnoses [6].

It's worth noting that this condition is rare and affects a small number of people worldwide. The exact prevalence of the disease is not well established, but it is considered to be relatively rare compared to other mitochondrial diseases.

References: [1] Context result 1 [3] Context result 3 [4] Context result 2 [5] Context result 5 [6] Context result 6

Mitochondrial Complex II Deficiency Signs and Symptoms

Mitochondrial complex II deficiency can manifest in various ways, ranging from severe life-threatening symptoms in infancy to muscle disease beginning later in life.

• Severe Life-Threatening Symptoms: In some cases, the condition can lead to severe symptoms in infancy, including feeding difficulties, decreased activity of mitochondrial complex II, increased circulating lactate concentration, and increased serum pyruvate [5].
• Muscle Disease: The condition can also manifest as a muscle disease, characterized by exercise intolerance, fasting intolerance, muscle pain, muscle stiffness, and myoglobin in the urine [6].
• Developmental Regression: Some patients may experience developmental regression, distal muscle wasting (distal amyotrophy), easy fatigability, hyperactive deep tendon reflexes, and other symptoms [8].

Common Symptoms

The signs and symptoms of mitochondrial complex II deficiency can vary greatly from person to person. However, some common symptoms include:

• Decreased activity of mitochondrial complex II
• Increased circulating lactate concentration
• Increased serum pyruvate
• Feeding difficulties in infancy
• Muscle pain and stiffness
• Exercise intolerance
• Fasting intolerance
• Myoglobin in the urine

References

[1] The signs and symptoms of mitochondrial complex II deficiency can vary greatly from severe life-threatening symptoms in infancy to muscle disease beginning later in life. [5] Decreased activity of mitochondrial complex II · Increased circulating lactate concentration · Increased serum pyruvate · Feeding difficulties in infancy. [6] CPT II Deficiency Symptoms – Myopathic: Exercise intolerance, fasting intolerance, muscle pain, muscle stiffness, and myoglobin in the urine [8] What are the signs and symptoms? · Developmental regression · Distal muscle wasting (distal amyotrophy) · Easy fatigability · Hyperactive deep tendon reflexes

Diagnostic Approaches for Mitochondrial Complex II Deficiency

Mitochondrial complex II deficiency, also known as succinate dehydrogenase complex subunit a (SDHA) deficiency, is a rare genetic disorder that affects the body's mitochondria. The diagnostic approaches for this condition involve a combination of clinical evaluation, laboratory tests, and genetic analysis.

Clinical Evaluation

A thorough medical and family history, along with a complete physical examination, are essential in diagnosing mitochondrial complex II deficiency [4]. A neurological examination may also be performed to assess the presence of any neurological symptoms [4].

Laboratory Tests

Initial laboratory tests such as lactate, pyruvate, urine organic acids, and plasma amino acids can guide clinicians toward possible mitochondrial disease [5]. Measurement of complex II activity in muscle is considered the most reliable means of diagnosis [14][15].

Genetic Analysis

Genetic testing, including exome sequencing, genome sequencing, and mitochondrial sequencing, can simultaneously analyze nuclear DNA and mtDNA to identify mutations in the SDHA gene [3]. However, in many cases, the underlying gene mutations cannot be identified [6].

Other Diagnostic Tests

Other diagnostic tests may include brain MRIs to detect symptoms characteristic of Leigh syndrome, electromyography (EMG) to detect myopathies, and blood tests to assess the presence of any metabolic disorders [10].

Importance of Experienced Centers

It is essential that these diagnostic tests are performed in a center with experience in mitochondrial disease diagnosis. The major diagnostic feature is the presence of fibers deficient for COX activity, which represents poor activity of complex IV of the respiratory chain [11].

References:

• [1] Mitochondrial Medicine Society's assessment on diagnostic approaches
• [3] PF Chinnery · 2021 · Cited by 456 — Such testing includes exome sequencing, genome sequencing, and mitochondrial sequencing which can simultaneously analyze nuclear DNA and mtDNA.
• [4] A review of your medical and family history. · A complete physical examination. · A neurological examination. · A ...
• [5] Initial laboratory tests such as lactate, pyruvate, urine organic acids, and plasma amino acids can guide the clinician toward possible mitochondrial disease.
• [6] Complex II deficiency can be caused by mutations in the SDHA, SDHB, SDHD, or SDHAF1 genes. In many cases the underlying gene mutations cannot be identified.
• [10] Mitochondrial complex II deficiency affects the body's mitochondria and can have a variety of presentations.
• [11] The testing should include a variety of histochemical functional assays and be performed in a centre with experience in mitochondrial disease diagnosis.

Treatment Options for Mitochondrial Complex II Deficiency

Mitochondrial complex II deficiency, also known as succinate dehydrogenase (SDH) deficiency, is a rare genetic disorder that affects the mitochondria's ability to produce energy. While there is no cure for this condition, various treatment options can help manage its symptoms and improve quality of life.

Medications

Several medications have been explored as potential treatments for mitochondrial complex II deficiency:

• Acipimox: This medication aims to increase cellular mitochondrial concentration by targeting the enzyme acetyl-CoA carboxylase (ACC) [5].
• Bezafibrate: Another medication that has shown promise in treating mitochondrial diseases, including complex II deficiency, by increasing mitochondrial biogenesis and function [5].
• Omaveloxolone: This drug targets the transcription factor PGC-1α to increase mitochondrial biogenesis and function [5].
• REN001: A small molecule that aims to increase mitochondrial concentration and improve energy production in cells [5].

Supplements

In addition to medications, certain supplements have been investigated as potential treatments for mitochondrial complex II deficiency:

• Coenzyme Q10 (CoQ10): This antioxidant has shown some clinical benefit in treating mitochondrial diseases, including complex II deficiency [3-5].
• Riboflavin: Also known as vitamin B2, riboflavin may have a clinical benefit in some cases of complex II deficiency [9].

Supportive Therapy

While there is no cure for mitochondrial complex II deficiency, supportive therapy can help manage symptoms and improve quality of life. This may include:

• Dietary supplements: Providing essential nutrients to support energy production and overall health.
• Off-label use of drugs: Using medications approved for other indications to treat specific symptoms or complications associated with complex II deficiency.

It's essential to consult with a healthcare professional for personalized advice and treatment, as each individual's situation may vary.

Mitochondrial complex II deficiency, also known as succinate dehydrogenase deficiency, is a rare inborn error of metabolism that can present with a wide range of symptoms and signs.

Key Features to Consider:

• Encephalomyopathy: A neurological disorder characterized by brain dysfunction, which can manifest as seizures, developmental delay, or even coma [3].
• Failure to thrive: Prolonged inability to gain weight or grow at an expected rate, often accompanied by lethargy and poor appetite [4].
• Muscle weakness: Weakness or wasting of muscles, particularly in the proximal limbs [7].
• Respiratory failure: In severe cases, patients may experience respiratory distress or failure due to impaired mitochondrial function [8].

Differential Diagnosis:

When considering a diagnosis of mitochondrial complex II deficiency, it is essential to rule out other conditions that can present with similar symptoms. These include:

• Pyruvate dehydrogenase complex (PDHC) deficiency: A rare genetic disorder characterized by severe infantile-onset disease, often presenting with encephalopathy and failure to thrive [9].
• Mitochondrial myopathies: A group of disorders affecting the muscle tissue, which can manifest as weakness, wasting, or pain [7].
• Other mitochondrial diseases: Such as Kearns-Sayre syndrome, MELAS syndrome, or NARP syndrome, which can present with a range of symptoms including encephalopathy, muscle weakness, and respiratory failure [8].

Diagnostic Workup:

The initial diagnostic workup for persons suspected to have mitochondrial complex II deficiency should include an examination of the blood pH, lactate, pyruvate, creatine phosphokinase, and other relevant biochemical markers [2]. Further investigation may involve genetic testing, muscle biopsy, or imaging studies to confirm the diagnosis.

References:

[1] RW Taylor · 1996 · Cited by 82 [2] Initial diagnostic workup of persons with complex II deficiency should include an examination of the blood pH, lactate, pyruvate, creatine phosphokinase, and ... [3] Complex II Deficiency Long Name: Succinate dehydrogenase deficiency Symptoms: Encephalomyopathy and various manifestations, including failure to thrive, ... [4] Symptoms: Encephalomyopathy and various manifestations, including failure to thrive, developmental delay, hyoptonia, lethargy, respiratory failure, ataxia, ... [5] by BC Ürey · 2023 · Cited by 2 — Succinate dehydrogenase deficiency, also known as mitochondrial complex II deficiency, is a rare inborn error of metabolism, accounting for ... [6] The syndrome was called “mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency” and attributed to altered metabolism of iron-sulfur (Fe-S) ... [7] What are the symptoms of mitochondrial disease? · Poor growth. · Muscle weakness, muscle pain or a low muscle tone. · Vision and/or hearing loss. · Developmental ... [8] by CL Alston · 2012 · Cited by 143 — Background Isolated complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses ... [9] by JD Weisfeld-Adams · 2015 · Cited by 54 — Several patients with pyruvate dehydrogenase complex deficiency, classically described as a severe infantile-onset disease, have been ...