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Neonatal Severe Encephalopathy with Lactic Acidosis and Brain Abnormalities

Disease Pathophysiology Research Report

2026-02-10
Falcon MONDO:0060562 Model: Edison Scientific Literature 7 citations

Disease Pathophysiology Research Report

Target disease - Disease Name: Neonatal severe encephalopathy with lactic acidosis and brain abnormalities (NELABA spectrum; mechanistic overlap with NAD(P)HX repair disorders) - MONDO ID: Not confirmed in accessible evidence during this run; likely mapped to NAXE/NAXD-related neurometabolic encephalopathies. - Category: Mendelian

1) Core pathophysiology - Concept and current understanding: In NAD(P)HX-repair deficiency (illustrated by NAXD deficiency), febrile stress and cellular metabolism generate hydrated forms of NADH/NADPH (NADHX/NAD(P)HX) that inhibit multiple dehydrogenases. NAXD (dehydratase) and NAXE (epimerase) normally reconvert these damaged cofactors to functional NAD(P)H. Loss of function leads to accumulation of inhibitory/toxic NAD(P)HX species, impairing mitochondrial respiration and cellular energy production, resulting in lactic acidosis and neuronal vulnerability with encephalopathy and seizures (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4, tuncer2022acasewith pages 4-5). - Dysregulated pathways: Nicotinamide nucleotide metabolism/repair; mitochondrial electron transport/oxidative phosphorylation; cellular response to heat/febrile triggers; redox homeostasis (tuncer2022acasewith pages 2-4, tuncer2022acasewith pages 4-5). - Affected cellular processes: Neuronal energy metabolism, dehydrogenase-dependent pathways, maintenance of NAD(P)H pools; downstream excitability and network instability manifesting as seizures; neurodegeneration with cerebral atrophy on imaging (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4).

2) Key molecular players - Genes/Proteins: NAXD (NAD(P)HX dehydratase; HGNC symbol NAXD). Related pathway gene: NAXE (NAD(P)HX epimerase; HGNC symbol NAXE) by biological analogy, though direct NAXE/NELABA evidence was not accessible in this run (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4, tuncer2022acasewith pages 4-5). - Chemical entities (selected): NADH (reduced nicotinamide adenine dinucleotide), NADPH (reduced nicotinamide adenine dinucleotide phosphate), hydrated derivatives NADHX/NAD(P)HX (damaged cofactors), lactate (reflecting impaired oxidative metabolism and glycolytic flux) (tuncer2022acasewith pages 2-4). - Cell types: Neurons are prominently affected; astrocytes may also be involved given brain energy coupling (inferred from clinical neurodegeneration and seizures) (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4). - Anatomical locations: Cerebrum/forebrain; corpus callosum; basal ganglia/white matter variably involved across cases; spinal cord typically spared in the single detailed case (normal spine MRI) (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4).

3) Biological processes (GO-like annotations) - Nicotinamide nucleotide metabolic process; NAD(P)H regeneration; mitochondrial electron transport chain; cellular respiration; response to heat; regulation of neuron apoptotic processes (inferred from neurodegeneration) (tuncer2022acasewith pages 2-4, tuncer2022acasewith pages 4-5).

4) Cellular components - Mitochondrion; cytosol; neuronal soma and processes in affected cortical/subcortical regions (tuncer2022acasewith pages 2-4).

5) Disease progression - Sequence of events (illustrated by NAXD deficiency): A trigger (often febrile illness) precedes acute deterioration with seizures and encephalopathy; inhibited dehydrogenases and mitochondrial dysfunction provoke lactic acidosis; progressive neurodegeneration manifests with developmental regression and structural brain changes (cerebral atrophy, thin corpus callosum), culminating in high infant mortality in severe cases (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4, tuncer2022acasewith pages 4-5). - Staging: Neonatal/infantile onset with acute metabolic-neurologic crises; intermittent precipitants (fever/infection) superimposed on a chronic energy deficit; progression to severe encephalopathy (tuncer2022acasewith pages 4-5).

6) Phenotypic manifestations - Key clinical phenotypes: Neonatal/early-infantile encephalopathy, myoclonic or refractory seizures, hypotonia and loss of head control, developmental arrest/regression, elevated serum and CSF lactate (mild to moderate), possible cardiomyopathy and skin lesions in broader literature; high mortality in early life (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4, tuncer2022acasewith pages 4-5). - Neuroimaging: Global cerebral atrophy, thin corpus callosum; other series describe basal ganglia and diffuse white/gray matter involvement; absence of diffuse restriction in the index MRI; normal spine MRI (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4). - Triggers: Febrile illness/infection commonly precipitate or exacerbate neurologic decline (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 4-5).

Ontology-grounded annotations for knowledge base use - Genes/Proteins (HGNC): NAXD (HGNC:23340). Related pathway: NAXE (HGNC:17359) [note: not evidenced in this run]. (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4) - GO Biological Processes: nicotinamide nucleotide metabolic process; cellular respiration; mitochondrial electron transport chain; response to heat (tuncer2022acasewith pages 2-4, tuncer2022acasewith pages 4-5). - GO Cellular Components: mitochondrion; cytosol (tuncer2022acasewith pages 2-4). - Cell types (CL): neurons; astrocytes (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4). - Anatomical structures (UBERON): brain (cerebrum), corpus callosum; basal ganglia (variable) (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4). - Chemical entities (CHEBI): NADH; NADPH; lactate; NAD(P)HX (hydrated NAD(P)H; label) (tuncer2022acasewith pages 2-4). - Phenotypes (HPO): Neonatal encephalopathy; Seizures; Lactic acidosis; Developmental regression; Generalized hypotonia; Abnormal corpus callosum morphology; Cerebral atrophy (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4, tuncer2022acasewith pages 4-5).

Expert opinions and treatment attempts - Expert interpretation from the case report emphasizes that “mitochondrial cocktail” therapies (e.g., L-carnitine, CoQ10, thiamine, riboflavin, vitamin E) may be reasonable empirical interventions when NAXD deficiency is suspected; literature has suggested niacin (vitamin B3) as a potential adjunct in nicotinamide repair defects, and a longer survival in a case receiving vitamin therapy than an affected sibling was noted in prior reports cited by the authors, although definitive efficacy remains unproven (tuncer2022acasewith pages 2-4, tuncer2022acasewith pages 4-5).

Relevant statistics and data (from accessible source) - Biochemistry: Mildly elevated serum and CSF lactate were documented (serum ~2.7 mmol/L; CSF ~1.6 mmol/L; reference 0.4–1.4) (tuncer2022acasewith pages 1-2). - Outcomes: Despite seizure control on antiepileptics and supportive measures including a mitochondrial cocktail, the reported infant died by 18 months, underscoring severity (tuncer2022acasewith pages 1-2).

Evidence items (with URLs and dates) - Tuncer GÖ, Randa NC, Aydin S, Aksoy A. A Case with NAD(P)HX Dehydratase (NAXD) Deficiency: A Newly Defined Mutation in a Novel Neurodegenerative Disorder. Molecular Syndromology. Published online Feb 8, 2022. DOI: 10.1159/000520553. URL: https://doi.org/10.1159/000520553 (tuncer2022acasewith pages 1-2, tuncer2022acasewith pages 2-4, tuncer2022acasewith pages 4-5).

Limitations - The disease label supplied (NELABA) is classically associated with NAXE deficiency in the literature, but our tool-accessible full-text evidence here centers on NAXD deficiency, a mechanistically related NAD(P)HX-repair disorder with overlapping neonatal encephalopathy, lactic acidosis, and brain MRI abnormalities. We therefore present a mechanistic and phenotypic synthesis grounded in this accessible primary source and highlight where inferences are made. Additional 2023–2024 reviews and OMIM/MONDO entries would allow fuller NAXE-specific mapping in an updated report.

References

  1. (tuncer2022acasewith pages 1-2): Gökçen Oz Tuncer, Nadide Cemre Randa, Seren Aydin, and Ayşe Aksoy. A case with nad(p)hx dehydratase (naxd) deficiency: a newly defined mutation in a novel neurodegenerative disorder. Molecular Syndromology, 13:1-5, Feb 2022. URL: https://doi.org/10.1159/000520553, doi:10.1159/000520553. This article has 7 citations and is from a peer-reviewed journal.

  2. (tuncer2022acasewith pages 2-4): Gökçen Oz Tuncer, Nadide Cemre Randa, Seren Aydin, and Ayşe Aksoy. A case with nad(p)hx dehydratase (naxd) deficiency: a newly defined mutation in a novel neurodegenerative disorder. Molecular Syndromology, 13:1-5, Feb 2022. URL: https://doi.org/10.1159/000520553, doi:10.1159/000520553. This article has 7 citations and is from a peer-reviewed journal.

  3. (tuncer2022acasewith pages 4-5): Gökçen Oz Tuncer, Nadide Cemre Randa, Seren Aydin, and Ayşe Aksoy. A case with nad(p)hx dehydratase (naxd) deficiency: a newly defined mutation in a novel neurodegenerative disorder. Molecular Syndromology, 13:1-5, Feb 2022. URL: https://doi.org/10.1159/000520553, doi:10.1159/000520553. This article has 7 citations and is from a peer-reviewed journal.