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SDH Deficiency: Causes, Symptoms & Treatment

SDH deficiency is a rare metabolic disorder in which the enzyme succinate dehydrogenase does not function adequately, leading to severe neurological and metabolic complications.

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Things worth knowing about "SDH Deficiency"

SDH deficiency is a rare metabolic disorder in which the enzyme succinate dehydrogenase does not function adequately, leading to severe neurological and metabolic complications.

What is SDH Deficiency?

SDH deficiency (succinate dehydrogenase deficiency) is a very rare inherited metabolic disorder belonging to the group of mitochondrial respiratory chain defects. The enzyme affected, succinate dehydrogenase (also known as Complex II of the mitochondrial respiratory chain), plays an essential role in cellular energy production. A defect in this enzyme means that cells cannot generate sufficient energy in the form of ATP, which particularly affects organs with high energy demands, such as the brain, heart, and muscles.

Causes

SDH deficiency is caused by mutations in the genes encoding the subunits of the succinate dehydrogenase complex. The affected genes include:

SDHA (Subunit A): Most commonly associated with SDH deficiency
SDHB (Subunit B)
SDHC (Subunit C)
SDHD (Subunit D)
SDHAF1 and SDHAF2 (assembly factors)

In most cases, inheritance follows an autosomal recessive pattern, meaning both parents must carry a defective gene copy for the child to be affected. In some cases (e.g., SDHB, SDHC, and SDHD mutations), autosomal dominant inheritance may also occur.

Symptoms

The clinical presentation of SDH deficiency is highly variable, depending on which gene is affected and the severity of the enzyme defect. Common symptoms include:

Neurological symptoms: Developmental delays, hypotonia (reduced muscle tone), leukodystrophy (deterioration of white brain matter), epileptic seizures, and ataxia (balance disorders)
Cardiomyopathy: Disease of the heart muscle that can lead to heart failure
Lactic acidosis: Elevated lactic acid levels in the blood, indicating disturbed energy metabolism
Muscle weakness and easy fatigability
Tumor predisposition: Certain mutations (especially SDHB, SDHC, SDHD) increase the risk of paragangliomas and pheochromocytomas (rare tumors of the nervous system)

Diagnosis

Diagnosis of SDH deficiency involves a multi-step approach:

Blood and urine tests: Detection of lactic acidosis and elevated urinary succinate levels (organic acids)
Enzyme activity measurement: Assessment of succinate dehydrogenase activity in muscle biopsies or fibroblasts
Genetic testing: Molecular genetic analysis of SDHA, SDHB, SDHC, SDHD, SDHAF1, and SDHAF2 genes via sequencing
Neuroimaging: MRI of the brain to detect leukodystrophy or other structural abnormalities

Treatment

There is currently no curative therapy for SDH deficiency. Management is therefore symptomatic and supportive:

Riboflavin (Vitamin B2): High-dose riboflavin supplementation has shown benefit in selected cases, as riboflavin acts as a cofactor for succinate dehydrogenase.
Coenzyme Q10: Frequently used to support mitochondrial function, although evidence remains limited.
Cardiac therapy: Treatment of cardiomyopathy with medications, or heart transplantation in severe cases.
Antiepileptic therapy: For patients with epileptic seizures.
Physiotherapy and occupational therapy: To support motor development and preserve daily functioning.
Regular tumor surveillance: For mutations with increased tumor risk (SDHB, SDHC, SDHD), regular screening examinations are recommended.

Prognosis

The prognosis of SDH deficiency depends strongly on the gene involved, the severity of the enzyme defect, and the time of diagnosis. Severe early-onset forms with pronounced cardiomyopathy or leukodystrophy often carry an unfavorable prognosis. Milder forms, particularly those with later-onset tumor predisposition, can be well managed through regular monitoring. Interdisciplinary care at specialized metabolic centers is strongly recommended.

References

Rutter J, Winge DR, Schiffman JD. Succinate dehydrogenase - Assembly, regulation and role in human disease. Mitochondrion. 2010;10(4):393-401. PubMed PMID: 20226883.
Bezawork-Geleta A, Rohlena J, Dong L, et al. Mitochondrial Complex II: At the Crossroads. Trends in Biochemical Sciences. 2017;42(4):312-325. PubMed PMID: 28185716.
Orphanet: Succinate Dehydrogenase Deficiency. Available at: https://www.orpha.net (accessed 2024).

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