In a male infant, born of consanguineous Egyptian parents, with lethal neonatal complex I deficiency nuclear type 16 (MC1DN16; 618238), Sugiana et al. (2008) identified a homozygous 719T-C transition in exon 7 of the C20ORF7 gene, resulting in a leu229-to-pro (L229P) substitution in a highly conserved region of the protein. The L229P substitution was predicted to alter the secondary structure of the protein. He had intrauterine growth retardation, minor facial dysmorphism, unusual hair patterning, abnormal toes, and a small sacral pit. Cerebral ultrasound showed agenesis of the corpus callosum and ventricular septation. He also had a congenital left diaphragmatic hernia, adrenal insufficiency, and increased lactate in the blood and CSF. He died of cardiorespiratory arrest due to progressive lactic acidosis on day 7. Respiratory-chain enzyme analysis showed marked complex I deficiency in skeletal muscle, liver, and skin fibroblasts of the proband. Prenatal diagnosis of 4 subsequent pregnancies by enzyme and functional analysis of cultured chorionic villus cells identified 2 more affected fetuses.

In 2 adult sibs, born of consanguineous Moroccan parents, who developed symptoms of complex I deficiency (MC1DN16; 618238) with Leigh syndrome (see 256000) in early childhood, Gerards et al. (2010) identified a homozygous 477A-C transversion in exon 5 of the C20ORF7 gene, resulting in a leu159-to-phe (L159F) substitution in the full-length C20ORF7 protein. The mutation was not found in 110 Moroccan and 312 Dutch alleles. Electrophoresis studies of patient leukocytes showed a decrease of mature complex I levels to 30 to 40% of normal controls. The clinically unaffected family members who were heterozygous for the mutation had mature complex I levels of 70 to 90% of normal controls. The sibs were aged 29 and 33 years at the time of the study, but presented with progressive spasticity at age 3, which subsequently developed into an extrapyramidal choreodystonic movement disorder. Delayed mental development also occurred, and both were moderately mentally retarded in their teens. Brain imaging of 1 patient at age 23 showed a small caudate and hyperintense lesions in the basal ganglia. Laboratory studies of 1 sib showed increased lactate in the cerebrospinal fluid, and both sibs had decreased complex I activity in skeletal muscle (36% and 48% of controls, respectively). A third affected sib died at age 36 years. The patients studied were also homozygous for a common hypomorphic P193L variant in the CRLS1 gene (608188), which may have contributed to the phenotype. Gerards et al. (2010) noted the phenotypic overlap with infantile bilateral striatal necrosis (IBSN; 271930), and emphasized the less severe phenotype than that described by Sugiana et al. (2008) (see 612360.0001).

In 5 children from 2 unrelated families of Ashkenazi Jewish origin with Leigh syndrome associated with deficiencies of mitochondrial complexes I and IV (MC1DN16; 618238), Saada et al. (2012) identified a homozygous c.749G-T transversion in exon 7 of the NDUFAF5 gene, resulting in a gly250-to-val (G250V) substitution at a conserved residue. The mutations, which were found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder in the families. Haplotype analysis indicated a founder effect, and 3 heterozygous carriers were found among 869 Ashkenazi Jewish controls, yielding a carrier rate of 1:290 in this population. Transfection of wildtype NDUFAF5 into the fibroblasts of 1 patient restored complex I activity to near normal, while complex IV activity was only partially restored. The patients had typical features of the disorder, with infantile-onset of feeding difficulties, failure to thrive, hypotonia, developmental delay, seizures, and abnormal signals on brain imaging.

In an Ashkenazi Jewish patient (patient 4) with MC1DN16, Simon et al. (2019) identified compound heterozygous mutations in the NDUFAF5 gene: G250V and a c.327G-C transversion in exon 3, resulting in a lys109-to-asn (K109N) substitution. The mutation was identified by whole-exome sequencing. Each parent was heterozygous for one of the mutations. The K109N mutation had an allele frequency of 0.002 in the Ashkenazi Jewish population in the gnomAD database.

In a Chinese girl (paatient 16) with Leigh syndrome associated with mitochondrial deficiencies of complexes I and IV (MC1DN16; 618238), Tong et al. (2018) identified compound heterozygous mutations in the NDUFAF5 gene: a c.836T-G transversion, resulting in a met279-to-arg (M279R) substitution, and a c.145C-G transition, resulting in an arg49-to-gly (R49G; 612360.0005) substitution. The mutations were identified with trio whole-exome sequencing, and both parents were shown to be mutation carriers. Functional studies were not performed.

In 2 Taiwanese patients with MC1DN16, Simon et al. (2019) identified mutations in the NDUFAF5 gene. Patient 2 was homozygous for the c.836T-G transversion (c.836T-G, NM_024120), resulting in the M279R substitution. The parents were shown to be carriers by Sanger sequencing. Patient fibroblasts showed decreased protein levels of NDUFAF5 and the complex I subunit NDUFS3 (603846). Oxygen consumption studies in patient fibroblasts showed low basal respiration and high extracellular acidification rate, indicative of a respiratory chain defect. Patient 1 was compound heterozygous for M279R and a c.155A-C transversion resulting in a lys52-to-thr (K52T; 612360.0006) substitution at a conserved residue. The mutations were identified by whole-exome sequencing. The M279R mutation was not found in 220 Taiwanese alleles. The M279R mutation was present in the East Asian population in the gnomAD database at a frequency of 1/1100, with no homozygotes reported, and the K52T mutation was present in the East Asian population in the gnomAD database at a frequency of 1/1600, with no homozygotes reported.

For discussion of the c.145C-G transition in the NDUFAF5 gene, resulting in an arg49-to-gly (R49G) substitution, that was found in compound heterozygous state in a patient with mitochondrial deficiencies of complexes I and IV (MC1DN16; 618238) by Tong et al. (2018), see 612360.0004.

For discussion of the c.155A-C transversion in the NDUFAF5 gene, resulting in a lys52-to-thr (K52T) substitution, that was found in compound heterozygous state in a patient (patient 1) with deficiencies of mitochondrial complexes I and IV (MC1DN16; 618238) by Simon et al. (2019), see 612360.0004.

In a Caucasian patient (patient 3) with deficiencies of mitochondrial complexes I and IV (MC1DN16; 618238), Simon et al. (2019) identified compound heterozygous mutations in the NDUFAF5 gene: a c.327G-C transversion (c.327G-C, NM_024120) in exon 3, resulting in a lys109-to-asn (K109N) substitution, and a c.223-907A-C splicing mutation in intron 1 (612360.0008). The K109N mutation had an allele frequency of 0.0007 in the non-Finnish European population in the gnomAD database. The mutations were identified by a combination of whole-exome and whole-genome sequencing, and the parents were shown to be carriers. Amplification and sequencing of RNA from patient fibroblasts and maternal blood showed that the c.327G-C transversion results in abnormal splicing with skipping of exon 3, leading to a frameshift and early termination. Amplification and sequencing of RNA from patient fibroblasts and paternal blood showed that the splice site mutation results in the inclusion of a 258-bp cryptic exon. Patient fibroblasts showed NDUFAF5 mRNA levels decreased to 25 to 40% of normal.

For discussion of the K109N mutation that was found in compound heterozygous state in an Ashkenazi Jewish patient (patient 4) with MC1DN16 by Simon et al. (2019), see 612360.0003.

For discussion of the c.223-907A-C splicing mutation (c.223-907A-C, NM_024120) in intron 1 of the NDUFAF5 gene that was found in compound heterozygous state in a patient (patient 3) with deficiencies of mitochondrial complexes I and IV (MC1DN16; 618238) by Simon et al. (2019), see 612360.0007.