Combined oxidative phosphorylation deficiency-24 (COXPD24) is an autosomal recessive mitochondrial disorder with wide phenotypic variability. Most patients prese...
Combined oxidative phosphorylation deficiency-24 (COXPD24) is an autosomal recessive mitochondrial disorder with wide phenotypic variability. Most patients present in infancy with delayed neurodevelopment, refractory seizures, hypotonia, and hearing impairment due to auditory neuropathy. Less common features may include cortical blindness, renal dysfunction, and/or liver involvement, suggestive of Alpers syndrome (MTDPS4A; 203700). Patients with the severe phenotype tend to have brain abnormalities on imaging, including cerebral atrophy and hyperintensities in the basal ganglia and brainstem, consistent with Leigh syndrome. Laboratory values may be normal or show increased lactate and evidence of mitochondrial respiratory chain defects, particularly in muscle. Some patients achieve little developmental milestones and may die in infancy or early childhood. However, some patients have a less severe phenotype manifest only by myopathy (summary by Sofou et al., 2015, Vanlander et al., 2015, and Mizuguchi et al., 2017).
For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
▼ Clinical Features
Sofou et al. (2015) reported a Swedish boy, previously reported as patient 13 by Sofou et al. (2012), with a severe neurodegenerative form of COXPD. He presented in early infancy with inconsolable crying, opisthotonus, and severely delayed psychomotor development followed by regression of learned skills. At age 7 months, he developed generalized seizures of multiple types. Lactate levels were increased, and brain imaging showed cortical atrophy. Other features included optic atrophy, cortical blindness, nystagmus, progressive microcephaly, spastic tetraparesis, and severe mental retardation. Brain MRI showed supratentorial atrophy of the cerebral cortex, agenesis of the corpus callosum, and hypomyelination of white matter. The patient also had hypochloremic metabolic acidosis with multiple electrolyte imbalances associated with renal tubulopathy and focal segmental glomerulosclerosis. Skeletal muscle biopsy showed a generalized decrease in mitochondrial respiratory chain enzymes and structurally abnormal mitochondria. The patient had a progressive course and died at age 16 years. Neuropathologic examination showed severe brain atrophy, widespread degeneration and vacuolization with gliosis and neuronal loss, and cerebellar atrophy. The liver showed fatty changes, whereas the heart was normal. The phenotype was reminiscent of Alpers syndrome (203700).
Simon et al. (2015) reported 2 brothers, born of unrelated Caucasian parents (family LS06), with a severe neurodegenerative disorder resulting in death at 15 and 6 months of age. Both boys appeared normal at birth, but failed the newborn screening test and had auditory neuropathy with absent auditory brainstem responses. The patients developed myoclonic seizures around 3 months of age, which evolved into more complex or generalized refractory seizures with almost continuous abnormal activity on EEG. Laboratory studies showed increased urinary levels of citric metabolites in both patients, and increased CSF lactate in 1 patient who was tested. Brain imaging showed features of Leigh syndrome in both patients, including hyperintense lesions in the basal ganglia, thalami, dentate nuclei, and brainstem. Analysis of patient muscle samples showed decreased levels and activities of mitochondrial complexes I, III, and IV. Postmortem examination of the brain showed cortical atrophy with laminar necrosis, atrophy of the corpus callosum, and loss of oligodendrocytes in the white matter and neurons in the gray matter. One patient had degeneration of the striate cortex, consistent with his cortical blindness. Simon et al. (2015) noted the phenotypic variability, particularly compared to the patients reported by Vanlander et al. (2015), and suggested tissue-specific effects of the mutations.
Mizuguchi et al. (2017) reported 4 Japanese patients, including 2 sibs, ranging in age from 1 to 8 years, with infantile onset of COXPD24. The patients had delayed psychomotor development, early-onset refractory seizures, sometimes with status epilepticus, developmental regression, hearing loss, and severely impaired intellectual development. Other features included hypotonia, flaccid quadriplegia, and absent reflexes or hyperreflexia. EEG showed diffuse multifocal spikes and slow-wave complexes. Brain imaging in some patients showed progressive diffuse cortical, subcortical, and cerebellar atrophy with marked T2-weighted hyperintensities in the white matter, basal ganglia, and thalamus. Lactate was variably increased in serum or CSF, but some levels were normal. One patient had renal dysfunction.
Seaver et al. (2018) reported 2 brothers who presented in the first months of life with intractable seizures, status epilepticus, and epileptic encephalopathy. One of the brothers had failed the newborn screening test and was diagnosed with auditory neuropathy, whereas the other developed left ventricular hypertrophy. Brain imaging showed rapidly progressive brain atrophy and significant white matter abnormalities in both patients. Laboratory studies showed thrombocytosis, mildly increased lactate, and evidence suggesting a combined mitochondrial respiratory chain defect, although the laboratory findings were inconsistent and inconclusive. In a letter, Finsterer (2019) requested details of the antiepileptic drug regimen used in these patients, clarification of the abnormal brain imaging findings, and explanation for the thrombocytosis. Seaver et al. (2019) responded with detailed drug regimens, noted that the brain imaging reflected widespread restricted diffusion, and concluded that hematologic abnormalities can be associated with mitochondrial disorders.
Vanlander et al. (2015) reported 34- and 26-year-old sibs, born of consanguineous parents, with a combined oxidative phosphorylation defect in skeletal muscle. One sib presented with myopathy characterized by proximal muscle weakness, severe amyotrophy, ptosis, facial muscle weakness, and dysarthria, whereas the other sib had mild intellectual disability and epilepsy, but no myopathy. The age at onset was not provided. Brain MRI showed no abnormalities. Skeletal muscle biopsy from both patients showed atrophic fibers, ragged-red fibers, and enlarged mitochondria. Skeletal muscle from both patients showed decreased protein and activity levels of mitochondrial complexes I and IV. Complex V subcomplexes were present. One patient had moderately increased serum creatine kinase, but normal serum lactate.
The transmission pattern of COXPD24 in the family reported by Vanlander et al. (2015) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In 2 sibs, born of consanguineous parents, with combined oxidative phosphorylation deficiency-24, Vanlander et al. (2015) identified a homozygous splice site mutation in the NARS2 gene (612803.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Western blot analysis showed undetectably low levels of NARS2 in patient skeletal muscle and a mild decrease in patient-derived lymphoblasts. Patient cells showed markedly decreased levels of steady-state aminoacylated aminoacylated tRNA-asn, but the translation of 13 mtDNA-encoded polypeptides was normal.
In a Swedish boy with a severe form of COXPD24 presenting as Alpers syndrome, Sofou et al. (2015) identified a homozygous missense mutation in the NARS2 gene (P214L; 612803.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis of patient fibroblasts showed decreased levels of asparaginyl-tRNA synthetase (37% of controls).
In 2 brothers, born of unrelated Caucasian parents (family LS06) with fatal COXPD24 associated with Leigh syndrome, Simon et al. (2015) identified compound heterozygous mutations in the NARS2 gene (Y323X, 612803.0003 and N381S, 612803.0004). The mutations which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants occurred in the catalytic domain. Patient fibroblasts showed decreased levels of NARS2 and decreased levels of aminoacylated mt-tRNA(Asn) compared to controls, although aminoacylation activity of NARS2 was normal. A truncated NARS2 protein was not detected, suggesting that the nonsense allele resulted in nonsense-mediated mRNA decay. In vitro functional expression studies in HEK293 cells showed that the N381S mutant protein was expressed at normal levels and localized normally to the mitochondria, but the mutation impaired homodimerization. The impaired oxygen consumption rate in patient cells was significantly rescued by expression of wildtype NARS2. The findings indicated that the NARS2 mutations impaired mitochondrial function.
In 2 brothers with fatal COXPD24, Seaver et al. (2018) identified compound heterozygous missense mutations in the NARS gene (Q56R, 612803.0006 and F211I, 612803.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Each variant was found at a low frequency in heterozygous state in the gnomAD database. Both variants occurred at highly conserved residues and were predicted to be detrimental, but functional studies of the variants and studies of patient cells were not performed.
In 4 patients, including 2 sibs, from 3 unrelated Japanese families with COXPD24, Mizuguchi et al. (2017) identified homozygous or compound heterozygous mutations in the NARS2 gene (612803.0008-612803.0012). There were 4 missense mutations and 1 splice site mutation. Analysis of patient cells showed that the splice site mutation resulted in the in-frame deletion of 27 amino acids. Additional functional studies of the variants and studies of patient cells were not performed.