NDUFV1-Related Mitochondrial Complex-1 Disorders: A Retrospective Case Series and Literature Review.

BACKGROUND: Pathogenic variants in the NDUFV1 gene disrupt mitochondrial complex I, leading to neuroregression with leukoencephalopathy and basal ganglia involvement on neuroimaging. This study aims to provide a concise review on NDUFV1-related disorders while adding the largest cohort from a single center to the existing literature. METHODS: We retrospectively collected genetically proven cases of NDUFV1 pathogenic variants from our center over the last decade and explored reported instances in existing literature. Magnetic resonance imaging (MRI) patterns observed in these patients were split into three types-Leigh (putamen, basal ganglia, thalamus, and brainstem involvement), mitochondrial leukodystrophy (ML) (cerebral white matter involvement with cystic cavitations), and mixed (both). RESULTS: Analysis included 44 children (seven from our center and 37 from literature). The most prevalent comorbidities were hypertonia, ocular abnormalities, feeding issues, and hypotonia at onset. Children with the Leigh-type MRI pattern exhibited significantly higher rates of breathing difficulties, whereas those with a mixed phenotype had a higher prevalence of dystonia. The c.1156C>T variant in exon 8 of the NDUFV1 gene was the most common variant among individuals of Asian ethnicity and is predominantly associated with irritability and dystonia. Seizures and Leigh pattern of MRI of the brain was found to be less commonly associated with this variant. Higher rate of mortality was observed in children with Leigh-type pattern on brain MRI and those who did not receive mitochondrial cocktail. CONCLUSIONS: MRI phenotyping might help predict outcome. Appropriate and timely treatment with mitochondrial cocktail may reduce the probability of death and may positively impact the long-term outcomes, regardless of the genetic variant or age of onset.

Cell-Surface Biomarkers, C-Reactive Protein and Haematological Parameters for Diagnosing Late Onset Sepsis in Pre-term Neonates.

OBJECTIVE: To compare the diagnostic accuracy of white blood cell-surface biomarkers (CD64, CD11b and HLA-DR), C-reactive protein (CRP) and hematological parameters to diagnose definite sepsis among pre-term neonates presenting with suspected late-onset neonatal sepsis (LONS). DESIGN: This was a prospective, single-gate, diagnostic study in a Level III neonatal unit. Fifty-three neonates (gestation, <34 weeks) with LONS (onset, >72 age), were enrolled. Cell-surface biomarkers, CRP and haematological parameters were assayed at 0 and 48 h after onset. The reference standard was definite sepsis, defined as a positive blood culture with a non-contaminant organism. The index tests (cell-surface biomarkers, CRP and haematological parameters) were compared between subjects with or without 'definite sepsis'. The area under the receiver operator characteristics curves (AUC) generated for each index test at 0 and 48 h was compared. SETTING: Level III neonatal unit in a tertiary care institute. RESULTS: Of 53 enrolled pre-term infants, 24 had definite sepsis. Among all the index tests evaluated, CRP at 48 h had the highest AUC [0.82 (95% confidence interval, 0.69, 0.92)]. The expression of CD11b and HLA-DR was significantly reduced among the septic neonates. Among the cell-surface biomarkers, the maximum AUC was recorded for HLA-DR at 48 [0.68 (95% CI, 0.54, 0.81)]. Comparisons between index tests were not statistically significant. CONCLUSION: C-reactive protein is superior to other sepsis screen biomarkers and white blood cell-surface biomarkers in diagnosing culture-positive LONS among pre-term infants. CD64, CD11b and HLA DR as diagnostic tests in this group have limited discriminatory value. LAY SUMMARY: The diagnosis of neonatal blood stream infections is a challenge. In response to bacterial blood stream infections, white blood cells are known to produce an excess of certain types of specialized proteins on their surface, including CD64, CD11b and HLA-DR. In this study we evaluated the concentration of these cell-surface proteins for diagnosing blood stream infections in pre-mature newborn babies, whose onset of infection was beyond 72 h of life. We compared these tests against standard tests that are currently in clinical use, such as C-reactive protein and blood white cell counts. All tests were performed at the time of initially suspecting the infection and 48 h later. The gold standard against which all these tests were evaluated was blood culture, in which the offending bacteria are grown in specialized laboratory media. Of 53 pre-mature babies with suspected infection, 24 had blood culture-proven infection. Among all tests, C-reactive protein at 48 h had the best ability to distinguish definite infection from no infection. The expression of CD11b and HLA-DR was significantly reduced among infected neonates. We conclude that C-reactive protein is superior to white blood cell-surface proteins and white cell count in diagnosing definite late-onset infections among pre-term infants.