Mitochondrial Complex II deficiency: heterozygous loss of function variant in the SDHA gene causing a severe neonatal phenotype.
Biochemical/Metabolic and Therapeutics
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Introduction
Mitochondrial Complex II deficiency (OMIM #252011) accounts for 2–4% of mitochondrial oxidative phosphorylation defects and is characterized by multisystem involvement with clinical presentations including Leigh syndrome, leukoencephalopathy, optic atrophy, and cardiomyopathy with highly variable severity and age of onset. This condition is caused by biallelic loss of function pathogenic variants in four structural subunit genes (SDHA, SDHB, SDHC, and SDHD) and two assembly factors genes (SDHAF1, SDHAF2). Defects involving the flavoprotein-encoding SDHA gene are the most commonly reported and predominantly associated with Leigh syndrome phenotype. Interestingly, this gene is also a tumor suppressor, and inactivating germline mutations are associated with hereditary paraganglioma-pheochromocytoma syndromes with autosomal dominant inheritance.
Case Presentation
A female proband presented at the age of 4 months following a cardiac arrest of unknown etiology and subsequent end-organ failure. MRI of the brain revealed a high burden of infarcts in various vascular distributions including brainstem (entire pons), thalami, basal ganglia, and throughout her cerebrum and cerebellum. Notably, MRI was significant for white matter signal abnormalities outside the areas of infarction. Echocardiogram did not identify any structural abnormalities. Prenatal history was significant for intrauterine growth restriction; family history was significant for a high degree of consanguinity (331Mb regions of homozygosity; 11.49% autosomal genome). Up to her initial presentation, the proband had been growing and developing well. However, after this event she experienced developmental regression in her motor skills and ability to feed, and has since made only minimal developmental progresses; at 20 months of age she is only able to roll over and doesn’t say any words.
Diagnostic Workup
The proband’s multi-system involvement and family history were suspicious for an underlying genetic etiology; a mitochondrial disorder with recessive inheritance was high in the differential diagnosis. Whole exome sequencing with mitochondrial DNA analysis was subsequently performed and identified a heterozygous pathogenic variant in the SDHA gene (c.91C>T; p.Arg31*). Further analysis of this gene on genome sequencing backbone was performed, and did not identify secondary deep intronic variants or copy number variations. The variant was confirmed to be inherited from the proband’s unaffected mother. RNA sequencing of the SDHA gene is pending at this time.
Discussion
The loss of function variant identified in the proband and her mother has been previously reported in the heterozygous state in patients with hereditary cancer syndromes; in addition, the variant has been reported in compound heterozygosity in one patient with Leigh syndrome. This is the first report of this variant in the heterozygous state in a patient with a clinical phenotype consistent with Mitochondrial Complex II deficiency. Autosomal dominant inheritance of Mitochondrial Complex II deficiency has been reported in 6 individuals from 3 independent families to date. The variants identified were missense (c.1351C>T, p.Arg451Cys; c.1984C>T, p.Arg662Cys) and had a dominant negative effect on FAD binding to SDHA. The variant identified in our proband would be the first loss of function variant linked to an autosomal dominant inheritance causing a severe phenotypic presentation in the neonatal period. This condition has highly variable expressivity, preventing an accurate prediction of the proband’s young mother (20 years old) phenotypic trajectory, and putting her at risk to develop features consistent with both Mitochondrial Complex II deficiency and hereditary cancer syndromes later in life.
Conclusion
Although RNA sequencing is pending at this time, the patient’s phenotype is highly suggestive of an autosomal dominant case of Mitochondrial Complex II deficiency. This case also highlights the complexity of genetic counseling and surveillance in patients found to harbor monoallelic variants in the SDHA gene, that could be at risk for hereditary cancer syndromes as well as mitochondrial disorders.
Mitochondrial Complex II deficiency (OMIM #252011) accounts for 2–4% of mitochondrial oxidative phosphorylation defects and is characterized by multisystem involvement with clinical presentations including Leigh syndrome, leukoencephalopathy, optic atrophy, and cardiomyopathy with highly variable severity and age of onset. This condition is caused by biallelic loss of function pathogenic variants in four structural subunit genes (SDHA, SDHB, SDHC, and SDHD) and two assembly factors genes (SDHAF1, SDHAF2). Defects involving the flavoprotein-encoding SDHA gene are the most commonly reported and predominantly associated with Leigh syndrome phenotype. Interestingly, this gene is also a tumor suppressor, and inactivating germline mutations are associated with hereditary paraganglioma-pheochromocytoma syndromes with autosomal dominant inheritance.
Case Presentation
A female proband presented at the age of 4 months following a cardiac arrest of unknown etiology and subsequent end-organ failure. MRI of the brain revealed a high burden of infarcts in various vascular distributions including brainstem (entire pons), thalami, basal ganglia, and throughout her cerebrum and cerebellum. Notably, MRI was significant for white matter signal abnormalities outside the areas of infarction. Echocardiogram did not identify any structural abnormalities. Prenatal history was significant for intrauterine growth restriction; family history was significant for a high degree of consanguinity (331Mb regions of homozygosity; 11.49% autosomal genome). Up to her initial presentation, the proband had been growing and developing well. However, after this event she experienced developmental regression in her motor skills and ability to feed, and has since made only minimal developmental progresses; at 20 months of age she is only able to roll over and doesn’t say any words.
Diagnostic Workup
The proband’s multi-system involvement and family history were suspicious for an underlying genetic etiology; a mitochondrial disorder with recessive inheritance was high in the differential diagnosis. Whole exome sequencing with mitochondrial DNA analysis was subsequently performed and identified a heterozygous pathogenic variant in the SDHA gene (c.91C>T; p.Arg31*). Further analysis of this gene on genome sequencing backbone was performed, and did not identify secondary deep intronic variants or copy number variations. The variant was confirmed to be inherited from the proband’s unaffected mother. RNA sequencing of the SDHA gene is pending at this time.
Discussion
The loss of function variant identified in the proband and her mother has been previously reported in the heterozygous state in patients with hereditary cancer syndromes; in addition, the variant has been reported in compound heterozygosity in one patient with Leigh syndrome. This is the first report of this variant in the heterozygous state in a patient with a clinical phenotype consistent with Mitochondrial Complex II deficiency. Autosomal dominant inheritance of Mitochondrial Complex II deficiency has been reported in 6 individuals from 3 independent families to date. The variants identified were missense (c.1351C>T, p.Arg451Cys; c.1984C>T, p.Arg662Cys) and had a dominant negative effect on FAD binding to SDHA. The variant identified in our proband would be the first loss of function variant linked to an autosomal dominant inheritance causing a severe phenotypic presentation in the neonatal period. This condition has highly variable expressivity, preventing an accurate prediction of the proband’s young mother (20 years old) phenotypic trajectory, and putting her at risk to develop features consistent with both Mitochondrial Complex II deficiency and hereditary cancer syndromes later in life.
Conclusion
Although RNA sequencing is pending at this time, the patient’s phenotype is highly suggestive of an autosomal dominant case of Mitochondrial Complex II deficiency. This case also highlights the complexity of genetic counseling and surveillance in patients found to harbor monoallelic variants in the SDHA gene, that could be at risk for hereditary cancer syndromes as well as mitochondrial disorders.