Infantile Leukoencephalopathy Due to Mitochondrial Complex II Deficiency via the SDHAF1 Gene

Isolated mitochondrial complex II deficiency (also known as succinate dehydrogenase deficiency) has been associated with a diverse clinical spectrum of disease, including cardiomyopathy, Leigh syndrome, infantile leukoencephalopathy, familial paraganglioma, renal cell carcinoma, and gastrointestinal stromal tumor development (Hoekstra and Bayley 2013).

Pathogenic variants in at least three genes (SDHA, SDHB, and SDHAF1) have been linked to infantile leukoencephalopathy (Hoekstra and Bayley 2013; Alston et al. 2012; Renkema et al. 2015). In patients with SDHAF1-related infantile leukoencephalopathy, symptoms generally manifest between 6-20 months following birth, and consist of rapid psychomotor regression, lack of speech development, progression of spastic quadriparesis, and partial loss of postural control with dystonia (Ghezzi et al. 2009; Ohlenbusch et al. 2012). Biochemically, this disease is characterized by elevated levels of blood lactate and pyruvate (Ghezzi et al. 2009). Succinate dehydrogenase holoenzyme quantity and activity are severely reduced in patient muscle and fibroblasts, and proton magnetic resonance spectroscopy (MRS) of the brain often reveals a high succinate peak, indicative of mitochondrial complex II deficiency. A distinctive MRI pattern has also been reported, which is delineated by cerebral hemispheric white matter abnormalities with sparing of the U fibers, corpus callosum involvement with sparing of the outer blades, and involvement of the corticospinal tracts, thalami, and spinal cord (Helman et al. 2016). 

Mitochondrial complex II deficiency, an autosomal recessive disorder, is the result of defects in the assembly or function of the mitochondrial succinate dehydrogenase (complex II) (Hoekstra and Bayley 2013). Complex II consists of four structural subunits (SDHA, SDHB, SDHC, and SDHD), while at least two accessory factors (SDHAF1 and SDHAF2) play roles in complex II assembly. Two additional accessory factors (SDHAF3 and SDHAF4) may also contribute to complex maturation, although their respective roles in this process have been less well defined (Na et al. 2014; Van Vranken et al. 2014).

The single-exon SDHAF1 gene encodes for an LYR-family assembly factor that mediates maturation of SDHB, the iron-sulfur cluster subunit of mitochondrial complex II (Na et al. 2014; Maio et al. 2016). Four pathogenic variants have been reported in the SDHAF1 gene to date, including three missense changes and one nonsense change (Ghezzi et al. 2009; Ohlenbusch et al. 2012).

At this time, due to the limited number of reported cases (<15), the clinical sensitivity of SDHAF1-related mitochondrial complex II deficiency is difficult to estimate. Analytical sensitivity should be high because all pathogenic variants reported are detectable by sequencing.

This test provides full coverage of all coding exons of the SDHAF1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).