Novel SCO2 mutation (G1521A) presenting as a spinal muscular atrophy type I phenotype

Abstract

Rare cases of suspected spinal muscular atrophy (SMA) have been found to have cytochrome c oxidase (COX) deficiency. To date, four cases with SMA features have been reported in children with mutations in the synthesis of cytochrome oxidase 2 (SCO2) gene. We report a male neonate who was born hypotonic, with persistent lactic acidosis, spontaneous activity with EMG testing, development of respiratory distress in the first few hours of life, and died at 30 days of age with progressive cardiomyopathy. Testing for survival motor neurone (smn) and NAIP deletions were negative and a skeletal muscle biopsy showed neurogenic features with severe reductions of COX enzymatic and histochemical staining intensity. Post-mortem muscle, heart, and liver biopsies showed severe, moderate, and mild reductions in COX activity, respectively, with parallel findings in the protein content for the mitochondrial DNA (COII) and nuclear DNA (COIV) encoded subunits. DNA sequencing of exon 2 of the SCO2 gene revealed compound heterozygosity with mutations at G1541A (common mutation, E140K) and also at a novel site in the copper binding region (G1521A in the current case (converting a highly conserved cysteine to tyrosine [corrected] (C133Y) [corrected]); mother heterozygous for G1521A; and father heterozygous for G1541A). This case provides strong support that SCO2 mutations can result in neonatal hypotonia with an SMA 1 phenotype. SCO2 mutations should be screened in suspected SMA cases with normal smn mutation analysis and any one of; cardiomyopathy, lactic acidosis, or COX deficiency in muscle.

Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations

“…In addition to the lack of typical mitochondrial disease hallmarks (high lactatemia, muscle histologic anomalies), that type of neuropathy differed from common neuropathies of mitochondrial diseases. [30][31][32][33] The causal link between MT-ATP6/8 mutations and episodic weakness was strengthened by the recurrence of their association in 6 independent families. The phenotype associated with MT-ATP6/8 mutations was homogeneous regarding age at onset of episodic weakness and neuropathy, triggering factors (in particular prolonged sitting), and type of neuropathy (pure motor neuropathy).…”

Analysis of reported SCO2 gene mutations affecting cytochrome c oxidase activity in various diseases

“…Thus, clinical symptoms along with the in silico data suggest that it should be further investigated through functional validation. C133Y, a change of cysteine at the position 133 to tyrosine, is a novel mutation reported in a male neonate case of spinal muscular atrophy with COX deficiency [10]. Post-mortem muscle, heart, and liver biopsies showed severe, moderate, and mild reductions in COX activity, respectively.…”

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

“…These are characterized by congenital hypotonia, progressive postnatal weakness and areflexia with anterior horn cell degeneration. The differential diagnosis includes X-linked infantile SMA with arthrogryposis (XL-SMA) [4,5], SMA due to mitochondrial dysfunction [6][7][8], SMA with pontocerebellar hypoplasia (SMA-PCH/PCH1) [9][10][11][12][13], and SMAwith respiratory distress (SMARD) ( Table 1) [14][15][16]. SMARD1 (or HMN type VI) is probably the second most commonly encountered pediatric from of SMA due to mutations in IGHMBP2 [14].…”