Case report of atypical Leigh syndrome in an adolescent male with novel biallelic variants in NDUFAF5 and review of the natural history of NDUFAF5‐related disorders

Abstract

NDUFAF5 encodes a Complex I assembly factor which is critical to the modification of a core subunit, NDUFS7, in early Complex I factor assembly. Mutations in NDUFAF5 have been previously shown to cause Complex I deficiency leading to mitochondrial respiratory chain impairment. More than 15 individuals affected by variants in NDUFAF5 have been described; however, there is phenotypic heterogeneity within this cohort. Some individuals display features of classical Leigh syndrome with early onset neurodegeneration whereas others live into early adulthood with progressive neurological deficits. Here, we present a clinical report of a 17-year-old African American individual with compound heterozygous mutations in NDUFAF5.The individual presented with childhood onset bilateral optic atrophy and developed progressive neuromuscular decline with relatively preserved cognition over time.

Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype

“…Previous clinical reports of biallelic pathogenic variants in NDUFAF5 included mainly cases of classic Leigh syndrome with early-onset neurodegeneration or cavitating leukoencephalopathy in childhood at the severe end or cases developing progressive neurological deficits in early adulthood 10,11 . Bi et al reported on three siblings with bilateral striatal necrosis and bilateral lesions of the putamen in childhood 12 .…”

Reply

“…Unique manifestations and differences between the prenatal and postnatal presentation of the same genetic disorder have been described previously 10 and are likely to become more prevalent as additional cases are published 11 . Furthermore, variability in the phenotype of the same genetic disorder exists for many conditions, including NDUFAF5 ‐related disorders 3,12,13 . Dr Finsterer mentions other possible abnormalities in individuals with biallelic pathogenic variants in NDUFAF5 , including retinopathy and gastrointestinal abnormalities.…”

Before homozygous NDUFAF5 variants are held responsible for intrauterine death, their pathogenicity must be demonstrated

“…Fifth, impairment of the visual pathways should be discussed. Given that NDUFAF5 variants can manifest phenotypically as Leber hereditary optic neuropathy (LHON) 2 or LHON plus 3 , it would be interesting to know whether optic atrophy was noted at autopsy 4 and whether loss or degeneration of retinal ganglion cells was detected on histological examination of the retina. NDUFAF5 variants can also present with gastrointestinal involvement 5 .…”