NAD(P)HX Dehydratase Deficiency

Mendelian MONDO:0034121 Pathograph 22 Show in embeddings browser Inborn Errors of Metabolism

NAD(P)HX dehydratase (NAXD) deficiency, also catalogued as PEBEL2, is an autosomal recessive metabolite repair disorder. NAD(P)H is chemically fragile: spontaneous hydration, accelerated by heat, converts it into redox-inactive NAD(P)HX derivatives that inhibit dehydrogenases. NAXD is the ATP-dependent enzyme that reverses this damage. When it fails, the damaged cofactors accumulate and mitochondrial function degrades. The clinically distinctive feature is that the disease is largely silent until a trigger arrives. A trivial febrile illness precipitates rapid, often irreversible neurological deterioration with brain oedema, leukoencephalopathy, seizures, lactic acidosis and characteristic skin lesions, and children commonly die during or shortly after the first crisis. A single adult case was precipitated at 32 by mild head trauma rather than fever, which widens the trigger set beyond hyperthermia. Which tissues fail depends on which NAXD isoform the variants hit: variants affecting both the cytosolic and mitochondrial isoforms give the neurological picture, while variants restricted to the mitochondrial isoform give myopathy, neuropathy and cardiac disease without seizures or skin lesions. Niacin-based treatment has partly relieved symptoms but is not curative.

Ask OpenScientist

Ask a research question about NAD(P)HX Dehydratase Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
7
Pathophys.
13
Phenotypes
3
Gaps
22
Pathograph
1
Genes
1
Medical Actions
2
Subtypes
2
Differentials
1
Models
8
References
1
Deep Research
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive; affected individuals carry biallelic NAXD variants, both truncating and missense.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:30576410 SUPPORT Human Clinical
"Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case."
States recessive inheritance across the founding case series.
PMID:34161859 SUPPORT Human Clinical
"Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 (PEBEL2; MIM# 618321), caused by biallelic pathogenic variants in the NAD(P)HX dehydratase (NAXD) is a rare metabolite repair disorder."
Independently states biallelic inheritance and gives the OMIM identifier recorded in external_assertions.
◆

Subtypes

2
Combined cytosolic and mitochondrial isoform deficiency (neurological presentation)
Variants affecting both the cytosolic and the mitochondrial NAXD isoform. These patients present with neurological deterioration, seizures and skin lesions. This is the presentation the disease was first described from.
Show evidence (1 reference)
PMID:35866541 SUPPORT Human Clinical
"NAXD deficiency patients with variants that affect both the cytosolic and mitochondrial isoforms present with neurological defects, seizures and skin lesions."
Defines this subtype by isoform involvement and names its clinical signature.
Mitochondrial-isoform-restricted deficiency (myopathic and cardiac presentation)
Variants that spare the cytosolic isoform, because the cytosolic isoform is initiated from an alternative start codon in exon 2 while exon 1 encodes the mitochondrial propeptide. These patients present with myopathy, moderate neuropathy and cardiac disease, and characteristically lack the skin lesions, seizures and neurological degeneration of the combined form.
Show evidence (1 reference)
PMID:35866541 SUPPORT Human Clinical
"Interestingly, patients with NAXD variants exclusively affecting the mitochondrial isoform present with myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration."
Defines this subtype and, importantly, states the negative findings that separate it from the combined form.
?

Discussions and Knowledge Gaps

3
Is the precipitant of a NAXD crisis specifically hyperthermia, or any metabolic stress?
KNOWLEDGE GAP naxd_trigger_set_beyond_fever
Attached to
environmental#Mild head trauma pathophysiology#Trigger-Precipitated Neurometabolic Crisis
The mechanism as usually stated is temperature-driven: heat accelerates NAD(P)H hydration, and the characterised mutant enzymes are thermolabile. That explanation predicts fever and nothing else. But the one adult case was precipitated by mild head trauma, with no fever reported as the trigger. If the real precipitant is any acute rise in metabolic demand, then surveillance advice built around antipyresis is incomplete, and the thermolability finding is a partial explanation rather than the mechanism. A single case cannot settle this, which is why it is recorded as a gap.
Proposed experiments
Non-thermal metabolic stress in NAXD patient fibroblasts
naxd_nonthermal_stress_fibroblasts
Compare NAD(P)HX accumulation in patient and control fibroblasts under thermal stress against non-thermal stresses at matched metabolic demand, to test whether temperature is necessary or merely sufficient.
Readouts
NAD(P)HX accumulation under non-thermal stress
pathophysiology#Accumulation of Damaged NAD(P)HX Cofactors
Direction: INCREASED
Interpretation: Accumulation without hyperthermia would show the trigger set is broader than heat.
Does cytosolic NAD(P)HX repair specifically protect the brain, and mitochondrial repair specifically protect muscle?
KNOWLEDGE GAP naxd_isoform_phenotype_split
Attached to
has_subtypes#Mitochondrial isoform has_subtypes#Combined isoform
The subtype split in this entry is drawn from a review's cataloguing of published cases by variant position, not from an experiment. The proposed interpretation, that cytosolic repair protects from neurological damage while muscle is more sensitive to mitochondrial damage, is the reviewers' own inference from that catalogue and is offered as a suggestion. With roughly a dozen published patients the split rests on small numbers, and no isoform-specific knockout or rescue experiment has tested it.
Show evidence (1 reference)
PMID:35866541 SUPPORT INDIRECT Human Clinical
"This suggests that cytosolic NAD(P)HX repair may protect from neurological damage, whereas muscle fibres may be more sensitive to mitochondrial NAD(P)HX damage."
The hypothesis itself, quoted with the hedges the authors used. Indirect because it is an inference from a case catalogue rather than a measured result.
How much of the NAXD phenotype is obligate, given patients who lack both the febrile trigger and the skin eruption?
CONTROVERSY naxd_phenotypic_diversity_incomplete_triad
Attached to
phenotypes#Cutaneous necrosis pathophysiology#Trigger-Precipitated Neurometabolic Crisis
The clinical picture is usually stated as a triad: fever trigger, skin eruption, neurological crisis. Two published cases break it. One 7-month-old with a novel homozygous NAXD variant had neither a preceding fever nor any skin lesion, and his authors concluded the cases show phenotypic diversity. Another patient had prominent skin findings after immunization with no fever at all. Meanwhile the largest cohort puts skin manifestations at 31%, so the eruption is a minority finding rather than a defining one. This matters practically: a diagnostic heuristic built on the triad will miss patients, and the entry curates the skin phenotypes without asserting that they are obligate.
Show evidence (2 references)
PMID:36158054 SUPPORT Human Clinical
"Unlike the cases reported in the literature, our patient had neither preceding fever nor skin lesion during follow-up."
The case that breaks both halves of the triad at once.
PMID:39887790 SUPPORT INDIRECT Human Clinical
"Skin manifestations were observed in 31% of patients with whole cell NAXD and NAXE deficiencies."
Quantifies the skin eruption as a minority finding. Graded INDIRECT because the denominator pools NAXD with NAXE, so the figure is not an NAXD-specific frequency.
⚙

Pathophysiology

7
Biallelic NAXD Loss of Function
Biallelic NAXD variants reduce or abolish ATP-dependent NAD(P)HX dehydratase activity. Two characterised missense substitutions produce a thermolabile enzyme with reduced Vmax and increased KM, which is a mechanistically satisfying fit to a disease whose crises are precipitated by fever: the residual enzyme is least able to work exactly when demand for repair is highest.
Genetic context NAXD hgnc:25576 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns NAXD (hgnc:25576). hgnc:25576 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: LOSS_OF_FUNCTION
Downstream
Failure of NAD(P)HX Repair Reduced dehydratase activity leaves hydrated cofactor derivatives unrepaired.
Show evidence (1 reference)
PMID:30576410 SUPPORT In Vitro
"Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity."
Direct enzymological demonstration of loss of function, including the thermolability that links the molecular defect to the febrile trigger.
Failure of NAD(P)HX Repair
NAD(P)H is spontaneously hydrated into redox-inactive NAD(P)HX, and heat accelerates the reaction. NAXD is the enzyme that reverses it. Without NAXD, the repair cycle does not close.
NAD+ metabolic process GO:0019674 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal NAD+ metabolic process (GO:0019674). GO:0019674 is a biological process from the Gene Ontology. ⚠ ABNORMAL
ATP-dependent NAD(P)H-hydrate dehydratase activity GO:0047453 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ATP-dependent NAD(P)H-hydrate dehydratase activity (GO:0047453). GO:0047453 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Accumulation of Damaged NAD(P)HX Cofactors Unrepaired derivatives accumulate in the cell.
Show evidence (3 references)
PMID:30576410 SUPPORT Other
"Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors"
States that physical stress, and specifically high temperature, damages the nicotinamide nucleotide cofactors. Quoted to stop short of the bracketed formulae, which the reference validator strips before matching.
PMID:35866541 SUPPORT Other
"The central cofactors NAD(P)H are prone to damage by hydration, resulting in formation of redox-inactive derivatives designated NAD(P)HX."
Names the damage reaction (hydration) and the product, completing the chemistry the previous item begins.
PMID:30576410 SUPPORT Other
"The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX."
States NAXD's role as the repair enzyme, which is what is lost.
Accumulation of Damaged NAD(P)HX Cofactors
Patient fibroblasts contain highly elevated S-NADHX, R-NADHX and cyclic NADHX. That lentiviral transduction with wild-type NAXD abolishes the accumulation is the step that makes this causal rather than correlative.
Experimental models
NAXD patient dermal fibroblasts PRIMARY CELL CULTURE The fibroblasts carry the patient genotype and show the accumulated cofactors directly; wild-type NAXD transduction abolishes it.
Downstream
Mitochondrial Respiratory Chain Dysfunction Damaged cofactors impair mitochondrial energy metabolism.
Inhibition of De Novo Serine Synthesis The second, non-mitochondrial consequence of the same accumulation.
Show evidence (2 references)
PMID:30576410 SUPPORT In Vitro
"Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX."
The direct measurement of accumulated damaged cofactors in patient cells.
PMID:30576410 SUPPORT In Vitro
"NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD."
Genetic complementation establishes that the accumulation is caused by the NAXD defect rather than accompanying it.
Inhibition of De Novo Serine Synthesis
A branch that does not run through the mitochondrion. In NAXD knockout cells grown on galactose the mitochondrial signs were only subtle, while metabolomics showed strong inhibition of the cytosolic de novo serine synthesis pathway, and the same inhibition was present in NAXD patient fibroblasts. This matters for how the disease is read: it means the mitochondrial arm is not the whole account of what damaged cofactor does to a cell.
L-serine biosynthetic process GO:0006564 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased L-serine biosynthetic process (GO:0006564). GO:0006564 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:39789421 SUPPORT In Vitro
"Surprisingly, the galactose-grown NAXDko cells displayed only subtle signs of mitochondrial impairment, whereas metabolomic analyses revealed a strong inhibition of the cytosolic, de novo serine synthesis pathway in those cells as well as in NAXD patient-derived fibroblasts."
Establishes the serine-synthesis branch in both NAXD knockout cells and NAXD patient fibroblasts, and records that the mitochondrial signs were subtle in the same experiment.
Mitochondrial Respiratory Chain Dysfunction
Patient fibroblasts and muscle show impaired mitochondrial function and are selectively vulnerable to metabolic stress: they fail in galactose and azide media, which force oxidative phosphorylation, but not in glucose, which permits glycolysis. Proteomics in both paediatric and adult cases shows reduced respiratory complexes I and IV and reduced mitoribosome, with mitochondrial apoptotic pathways upregulated.
oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Increased circulating lactate concentration Impaired oxidative phosphorylation shifts metabolism toward lactate.
Increased CSF lactate The same shift measured in cerebrospinal fluid.
Cardiomyopathy Cardiac muscle is one of the two organs the founding series identifies as vulnerable, the other being brain.
Trigger-Precipitated Neurometabolic Crisis A compromised oxidative capacity fails when demand rises.
Show evidence (2 references)
PMID:30576410 SUPPORT In Vitro
"Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production."
Reports the mitochondrial dysfunction and the substrate-conditional vulnerability that localises it to oxidative phosphorylation.
PMID:36834994 SUPPORT Human Clinical
"The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of..."
Names the specific complexes affected, and shows the signature is shared between the adult and paediatric presentations.
Trigger-Precipitated Neurometabolic Crisis
The defining clinical event. A trivial fever, infection or illness, or in one adult a mild head trauma, precipitates rapid deterioration. This is the node the whole entry turns on, because it is where a chronic biochemical vulnerability becomes an acute, often fatal, event.
Downstream
Progressive Neurodegeneration
Show evidence (2 references)
PMID:35866541 SUPPORT Human Clinical
"Recently, pathogenic variants in both the NAXD and NAXE genes were associated with rapid deterioration and death after an otherwise trivial fever, infection, or illness in young patients."
States the trigger-and-crisis pattern and its outcome.
PMID:30576410 SUPPORT Human Clinical
"Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death."
The founding case series, establishing both the febrile trigger and the two organ outcomes.
Progressive Neurodegeneration
Progressive neurological deterioration with brain oedema and leukoencephalopathy on imaging. Deterioration is stepwise, tied to crises, rather than smoothly progressive.
Downstream
Cerebral edema
Leukoencephalopathy
Seizure
Developmental regression
Cutaneous necrosis
Skin erosion
Show evidence (2 references)
PMID:34161859 SUPPORT Human Clinical
"It is characterized by progressive neurological deterioration usually associated with a febrile illness."
States the progressive neurological course and its association with febrile illness.
PMID:30576410 SUPPORT Human Clinical
"The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death."
Places the neurodegeneration within the metabolite-repair framework and names the two vulnerable organs.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for NAD(P)HX Dehydratase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

13
Cardiovascular 1
Cardiomyopathy HP:0001638 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomyopathy (HP:0001638). HP:0001638 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36158054 SUPPORT Human Clinical
"Prominent features of NAXD deficiency are progressive neurological deterioration after fever, cardiomyopathy, skin lesions, and premature death."
Names cardiomyopathy among the prominent features of NAXD deficiency.
PMID:30576410 SUPPORT Human Clinical
"Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death."
The founding series records cardiac failure as one of the two crisis outcomes.
Integument 3
Cutaneous necrosis HP:0033126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is flexural erosive plaques progressing to blistering and necrosis, annotated with Cutaneous necrosis (HP:0033126). HP:0033126 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39887790 SUPPORT Human Clinical
"The characteristic skin eruption comprises well-demarcated erythematous and erosive plaques progressing to blistering and necrosis, predominantly affecting flexural surfaces."
Describes the eruption in the terms this phenotype records, including the progression to necrosis that the binding names.
PMID:34161859 SUPPORT Human Clinical
"The other common findings include skin lesions, elevated serum or cerebrospinal fluid lactate levels, and brain neuroimaging abnormalities."
Independently lists skin lesions among the common findings.
Skin erosion HP:0200041 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin erosion (HP:0200041). HP:0200041 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39887790 SUPPORT Human Clinical
"The characteristic skin eruption comprises well-demarcated erythematous and erosive plaques progressing to blistering and necrosis, predominantly affecting flexural surfaces."
The erosive plaque stage of the same eruption, recorded separately because erosion and necrosis are different findings at different points in the crisis.
Sparse hair HP:0008070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse hair (HP:0008070). HP:0008070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34161859 SUPPORT Human Clinical
"We report on an additional individual with characteristic findings of PEBEL2, and an additional finding of sparse scalp hair."
The single-patient observation, quoted with the authors' own framing that it is an addition to the known phenotype.
Metabolism 3
Cerebral edema HP:0002181 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral edema (HP:0002181). HP:0002181 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34161859 SUPPORT Human Clinical
"Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 (PEBEL2; MIM# 618321), caused by biallelic pathogenic variants in the NAD(P)HX dehydratase (NAXD) is a rare metabolite repair disorder."
Brain oedema is in the defining name of the phenotype series, quoted from the disease definition itself.
Increased CSF lactate HP:0002490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased CSF lactate (HP:0002490). HP:0002490 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158054 SUPPORT Human Clinical
"Basal metabolic tests were within normal limits except serum and cerebrospinal fluid lactate levels, which were mildly elevated."
Reports the CSF lactate elevation, and that it was the only abnormal basal metabolic test.
Increased circulating lactate concentration HP:0002151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating lactate concentration (HP:0002151). HP:0002151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34161859 SUPPORT Human Clinical
"The other common findings include skin lesions, elevated serum or cerebrospinal fluid lactate levels, and brain neuroimaging abnormalities."
Records raised serum and CSF lactate as a common finding.
Musculoskeletal 2
Axial hypotonia HP:0008936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial hypotonia (HP:0008936). HP:0008936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158054 SUPPORT Human Clinical
"He had lethargy and axial hypotonia but skin lesions and organomegaly were not noted."
Records axial hypotonia in the reported case, in a sentence that also documents the absence of skin lesions in that patient.
Muscle weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35866541 SUPPORT Human Clinical
"Interestingly, patients with NAXD variants exclusively affecting the mitochondrial isoform present with myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration."
Reports myopathy and restricts it to the mitochondrial-isoform genotype.
Nervous System 4
Developmental regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376), qualified as course progressive. HP:0002376 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:34161859 SUPPORT Human Clinical
"It is characterized by progressive neurological deterioration usually associated with a febrile illness."
The progressive neurological deterioration this phenotype records.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35866541 SUPPORT Human Clinical
"NAXD deficiency patients with variants that affect both the cytosolic and mitochondrial isoforms present with neurological defects, seizures and skin lesions."
Reports seizures and ties them to the combined-isoform genotype.
Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukoencephalopathy (HP:0002352). HP:0002352 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34161859 SUPPORT Human Clinical
"The other common findings include skin lesions, elevated serum or cerebrospinal fluid lactate levels, and brain neuroimaging abnormalities."
Records brain neuroimaging abnormality as a common finding; the specific leukoencephalopathy is named in the disease definition quoted above.
Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35866541 SUPPORT Human Clinical
"Interestingly, patients with NAXD variants exclusively affecting the mitochondrial isoform present with myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration."
The same sentence that supports the myopathy and cardiac phenotypes names the neuropathy; it was previously the one feature of the three not carried across.
🧬

Genetic Associations

1
NAXD
Gene: NAXD hgnc:25576 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NAXD (hgnc:25576). hgnc:25576 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:34161859 SUPPORT Human Clinical
"Currently, variants in NAXD have been reported in eight unrelated individuals including six truncating and six missense variants."
Gives the reported variant spectrum and its size as of 2021.
PMID:35866541 SUPPORT Human Clinical
"Exon 1 of NAXD contains a mitochondrial propeptide, and a unique cytosolic isoform is initiated from an alternative start codon in exon 2."
The gene-structure fact that makes isoform-selective variants possible, and so underpins the subtype split.
🗃️

External Assertions

1
OMIM PEBEL2 phenotype record
OMIM disease record OMIM:618321
OMIM phenotype identifier, cited as MIM# 618321 in PMID:34161859.
💊

Medical Actions

1
Niacin-Based Supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: nicotinic acid CHEBI:15940 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses nicotinic acid (CHEBI:15940). CHEBI:15940 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Niacin supplementation aims to raise flux through NAD biosynthesis and outrun the accumulation of damaged cofactor. Reported benefit is partial and symptomatic, in anecdotal paediatric reports and in the adult case; no controlled data exist, and the reviewers describe the approach as promising rather than established.
Mechanism Target:
Accumulation of Damaged NAD(P)HX Cofactors — The rationale is to shift the balance of the cofactor pool, not to restore repair capacity, which niacin cannot do.
Show evidence (5 references)
PMID:38974613 SUPPORT INDIRECT Human Clinical
"Therefore, niacin administration has been shown to pause clinical deterioration of patients with PEBEL‐1 and PEBEL‐2 and provide protection against the fatal outcome of these disorders."
States the shared rationale across both repair disorders, naming PEBEL-2 explicitly. Graded INDIRECT because the paper reports a PEBEL-1 patient and the sentence summarises the prior literature for the pair rather than reporting a NAXD outcome.
PMID:38974613 REFUTE INDIRECT Human Clinical
"Despite previous positive results for niacin supplementation in patients with PEBEL-1 and PEBEL-2, this is the first report of a patient with PEBEL-1 who deteriorated to fatal outcome despite being started on the highest dose of niacin therapy reported to date."
The cautionary counterweight: a patient who died despite the highest niacin dose reported. REFUTE against the claim that niacin protects against the fatal outcome, and INDIRECT because that patient had PEBEL-1 (NAXE) rather than the NAXD deficiency this entry describes.
PMID:36834994 SUPPORT Human Clinical
"In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient."
Reports partial symptomatic benefit, and the authors' own framing that the prior evidence is anecdotal.
+ 2 more references
🌍

Environmental Factors

3
Febrile illness or intercurrent infection
febrile illness Relation: this environmental factor is this exposure This environmental factor is febrile illness.
Fever, infection or other trivial illness is the principal precipitant of a neurometabolic crisis. The mechanistic link is not speculative: heat accelerates the spontaneous hydration that generates NAD(P)HX, and the two characterised mutant enzymes are thermolabile, so the repair capacity falls as the substrate load rises.
Show evidence (1 reference)
PMID:30576410 SUPPORT Human Clinical
"Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death."
The founding series describes the neurodegeneration as febrile-illness induced.
Mechanism Target:
TRIGGERS Trigger-Precipitated Neurometabolic Crisis — Fever is the reported precipitant of the crises in the founding series and in the review literature.
Show evidence (1 reference)
PMID:35866541 SUPPORT Human Clinical
"Recently, pathogenic variants in both the NAXD and NAXE genes were associated with rapid deterioration and death after an otherwise trivial fever, infection, or illness in young patients."
Establishes fever and intercurrent illness as the precipitants of the deterioration this edge asserts.
Mild head trauma
mild head trauma Relation: this environmental factor is this exposure This environmental factor is mild head trauma.
In the single reported adult case, a mild head trauma rather than a fever precipitated the fatal crisis. This matters for surveillance: if the trigger set is "metabolic stress" rather than "hyperthermia", then advice limited to fever management is incomplete.
Show evidence (1 reference)
PMID:36834994 SUPPORT Human Clinical
"Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age."
Establishes the case this exposure is drawn from, and that it is a single adult patient.
Mechanism Target:
TRIGGERS Trigger-Precipitated Neurometabolic Crisis — The adult case's deterioration followed a mild head trauma, extending the trigger set beyond febrile illness.
Show evidence (1 reference)
PMID:36834994 SUPPORT Human Clinical
"The clinical deterioration and demise of this individual were likely triggered by mild head trauma."
The single observation supporting this edge. The authors write "likely triggered", which is the strength of the claim.
Routine childhood immunization
routine childhood immunization Relation: this environmental factor is this exposure This environmental factor is routine childhood immunization.
One patient deteriorated after routine 4-month immunizations, with prominent skin findings and no fever. This is the observation that most strains the thermal explanation of the disease, because the trigger operated without the hyperthermia the mechanism invokes.
Show evidence (1 reference)
PMID:38214124 SUPPORT INDIRECT Human Clinical
"In this report, we describe a case of probable PEBEL2 in a patient with a variant of unknown significance (c.362C>T, p.121L) in the NAXD gene who presented after routine immunizations with significant skin findings and in the absence of fevers."
Establishes the exposure and, in the same sentence, the two reasons to treat it cautiously: a variant of unknown significance and a "probable" diagnosis.
Mechanism Target:
TRIGGERS Trigger-Precipitated Neurometabolic Crisis — Immunization preceded the crisis in this case, in the absence of fever.
Show evidence (1 reference)
PMID:38214124 SUPPORT INDIRECT Human Clinical
"In this report, we describe a case of probable PEBEL2 in a patient with a variant of unknown significance (c.362C>T, p.121L) in the NAXD gene who presented after routine immunizations with significant skin findings and in the absence of fevers."
The single observation behind this edge. Graded INDIRECT because the authors themselves call the case "probable PEBEL2" carrying a variant of unknown significance, so the genotype attribution is not secure.
🔬

Diagnosis

1
Biallelic NAXD variants with fibroblast NAD(P)HX quantification
Molecular diagnosis by exome or genome sequencing, supported where available by measurement of damaged cofactors in patient fibroblasts. The clinical trigger is worth recognising ahead of the genetics: an otherwise-well young child deteriorating catastrophically during a trivial febrile illness, with lactate raised and brain oedema on imaging.
Show evidence (1 reference)
PMID:30576410 SUPPORT Human Clinical
"Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case."
States the diagnostic modality used in every case of the founding series.
📈

Progression

1
Crisis-punctuated course to early death
Age: Typically infancy to early childhood; one reported case survived to 32
The course is stepwise rather than smoothly progressive: long compensated intervals punctuated by trigger-precipitated crises, each of which can be fatal or leave fixed deficit. Death commonly follows the first or an early crisis. Early death is recorded here rather than as a phenotype because HPO's Mortality/Aging branch sits outside the schema's PhenotypeTerm closure; see dismech#9496, which names `progression:` as the intended home for survival and age-at-death facts.
Show evidence (3 references)
PMID:30576410 SUPPORT Human Clinical
"Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death."
Establishes the episodic course and early death in the founding series.
PMID:30576410 SUPPORT Human Clinical
"The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death."
States early childhood death as the usual endpoint.
PMID:36834994 SUPPORT Human Clinical
"Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age."
The outlier that sets the upper bound of the age range in this record.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Eight unrelated individuals reported as of the 2021 NAXD review, with further cases since including one adult. A 2025 dermatology review counted 45 patients, but that count pools NAXD with its sister disorder NAXE and so is not an NAXD case count. No population prevalence estimate exists.
Show evidence (2 references)
PMID:34161859 SUPPORT Human Clinical
"Currently, variants in NAXD have been reported in eight unrelated individuals including six truncating and six missense variants."
Gives the reported NAXD case count this band is based on.
PMID:39887790 SUPPORT INDIRECT Human Clinical
"A comprehensive literature search identified 45 patients with 31 pathogenic/likely pathogenic mutations, and a median age of onset at 1.16 years."
The larger published cohort, cited here for scale only. Graded INDIRECT because the 45 patients are NAXD and NAXE combined, so the number does not bound the NAXD population this record describes.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from NAD(P)HX Dehydratase Deficiency:

NAXE deficiency (PEBEL1)
Overlapping Features The allelic-pathway sibling. NAXE encodes NAD(P)HX epimerase, the other enzyme of the same two-step repair system, and its deficiency produces the same trigger-and-crisis pattern. The two are curated together in the literature reviews and are separated by gene, not by presentation.
Show evidence (1 reference)
PMID:35866541 SUPPORT Human Clinical
"The highly conserved enzymes NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE) function to repair intracellular NAD(P)HX."
States that the two enzymes serve the same repair system, which is why NAXE deficiency is the first differential.
Leigh syndrome and other mitochondrial encephalopathies
Overlapping Features Share the febrile decompensation, lactate elevation and symmetrical neuroimaging change. The distinguishing feature is biochemical: damaged NAD(P)HX derivatives accumulate in NAXD deficiency and not in primary respiratory chain disease.
🧫

Experimental Models

1
NAXD patient dermal fibroblasts PRIMARY_CELL_CULTURE
Primary skin fibroblasts from NAXD-deficient patients. This is the system in which the accumulation of damaged cofactors, the mitochondrial dysfunction and the genetic rescue were all demonstrated.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:30576410
Pathograph links
Accumulation of Damaged NAD(P)HX Cofactors recapitulates fidelity: high observes: molecular The fibroblasts carry the patient genotype and show the accumulated cofactors directly; wild-type NAXD transduction abolishes it.
Limitations: Fibroblasts are not an affected tissue. They can report the biochemical lesion but not the tissue selectivity, and the febrile trigger is not reproduced in culture except as a surrogate metabolic stress.
Readouts
S-NADHX, R-NADHX and cyclic NADHX concentration
Direction: INCREASED
Interpretation: Direct quantification of the damaged cofactors that define the disorder.
Show evidence (1 reference)
PMID:30576410 SUPPORT In Vitro
"Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX."
The measurement itself, with its direction.
NADHX concentration after wild-type NAXD transduction
Direction: RESTORED
Interpretation: Genetic complementation returns the cofactor pool to normal, which is what makes the model causal rather than descriptive.
Show evidence (1 reference)
PMID:30576410 SUPPORT In Vitro
"NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD."
The rescue experiment behind this readout.
Show evidence (1 reference)
PMID:30576410 SUPPORT In Vitro
"NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD."
The complementation result is what licenses treating these fibroblasts as informative for the human mechanism.
{ }

Source YAML

click to show 
name: NAD(P)HX Dehydratase Deficiency
creation_date: "2026-09-06T19:15:00Z"
category: Mendelian
description: >-
  NAD(P)HX dehydratase (NAXD) deficiency, also catalogued as PEBEL2, is an
  autosomal recessive metabolite repair disorder. NAD(P)H is chemically fragile:
  spontaneous hydration, accelerated by heat, converts it into redox-inactive
  NAD(P)HX derivatives that inhibit dehydrogenases. NAXD is the ATP-dependent
  enzyme that reverses this damage. When it fails, the damaged cofactors
  accumulate and mitochondrial function degrades.

  The clinically distinctive feature is that the disease is largely silent
  until a trigger arrives. A trivial febrile illness precipitates rapid,
  often irreversible neurological deterioration with brain oedema,
  leukoencephalopathy, seizures, lactic acidosis and characteristic skin
  lesions, and children commonly die during or shortly after the first crisis.
  A single adult case was precipitated at 32 by mild head trauma rather than
  fever, which widens the trigger set beyond hyperthermia. Which tissues fail
  depends on which NAXD isoform the variants hit: variants affecting both the
  cytosolic and mitochondrial isoforms give the neurological picture, while
  variants restricted to the mitochondrial isoform give myopathy, neuropathy
  and cardiac disease without seizures or skin lesions. Niacin-based treatment
  has partly relieved symptoms but is not curative.
disease_term:
  preferred_term: NAD(P)HX dehydratase deficiency
  term:
    id: MONDO:0034121
    label: NAD(P)HX dehydratase deficiency
synonyms:
- PEBEL2
- NAXD deficiency
- 'encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2'
parents:
- Inborn Errors of Metabolism
external_assertions:
- name: OMIM PEBEL2 phenotype record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:618321
  description: >-
    OMIM phenotype identifier, cited as MIM# 618321 in PMID:34161859.
references:
- reference: PMID:30576410
  title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
  findings: []
- reference: PMID:35866541
  title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
  findings: []
- reference: PMID:36834994
  title: "Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma."
  findings: []
- reference: PMID:34161859
  title: "NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature."
  findings: []
- reference: PMID:39887790
  title: "Cutaneous Manifestations of NAXD or NAXE Deficiency: A Literature Review for the Dermatologist."
  findings: []
- reference: PMID:38214124
  title: "Progressive encephalopathy after routine 4-month immunizations in a patient with NAXD genetic variant."
  findings: []
- reference: PMID:36158054
  title: "A Case with NAD(P)HX Dehydratase (NAXD) Deficiency: A Newly Defined Mutation in a Novel Neurodegenerative Disorder."
  findings: []
- reference: PMID:35637064
  title: "NAXE deficiency: A neurometabolic disorder of NAD(P)HX repair amenable for metabolic correction."
  findings: []
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive; affected individuals carry biallelic NAXD variants,
    both truncating and missense.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case."
    explanation: >-
      States recessive inheritance across the founding case series.
  - reference: PMID:34161859
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 (PEBEL2; MIM# 618321), caused by biallelic pathogenic variants in the NAD(P)HX dehydratase (NAXD) is a rare metabolite repair disorder."
    explanation: >-
      Independently states biallelic inheritance and gives the OMIM identifier
      recorded in external_assertions.
has_subtypes:
- name: Combined isoform
  display_name: Combined cytosolic and mitochondrial isoform deficiency (neurological presentation)
  description: >-
    Variants affecting both the cytosolic and the mitochondrial NAXD isoform.
    These patients present with neurological deterioration, seizures and skin
    lesions. This is the presentation the disease was first described from.
  evidence:
  - reference: PMID:35866541
    reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NAXD deficiency patients with variants that affect both the cytosolic and mitochondrial isoforms present with neurological defects, seizures and skin lesions."
    explanation: >-
      Defines this subtype by isoform involvement and names its clinical
      signature.
- name: Mitochondrial isoform
  display_name: Mitochondrial-isoform-restricted deficiency (myopathic and cardiac presentation)
  description: >-
    Variants that spare the cytosolic isoform, because the cytosolic isoform is
    initiated from an alternative start codon in exon 2 while exon 1 encodes
    the mitochondrial propeptide. These patients present with myopathy,
    moderate neuropathy and cardiac disease, and characteristically lack the
    skin lesions, seizures and neurological degeneration of the combined form.
  evidence:
  - reference: PMID:35866541
    reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, patients with NAXD variants exclusively affecting the mitochondrial isoform present with myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration."
    explanation: >-
      Defines this subtype and, importantly, states the negative findings that
      separate it from the combined form.
pathophysiology:
- name: Biallelic NAXD Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic NAXD variants reduce or abolish ATP-dependent NAD(P)HX
    dehydratase activity. Two characterised missense substitutions produce a
    thermolabile enzyme with reduced Vmax and increased KM, which is a
    mechanistically satisfying fit to a disease whose crises are precipitated
    by fever: the residual enzyme is least able to work exactly when demand for
    repair is highest.
  genetic_context:
    gene:
      preferred_term: NAXD
      term:
        id: hgnc:25576
        label: NAXD
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity."
    explanation: >-
      Direct enzymological demonstration of loss of function, including the
      thermolability that links the molecular defect to the febrile trigger.
  downstream:
  - target: Failure of NAD(P)HX Repair
    description: >-
      Reduced dehydratase activity leaves hydrated cofactor derivatives
      unrepaired.
- name: Failure of NAD(P)HX Repair
  biological_scale: MOLECULAR
  description: >-
    NAD(P)H is spontaneously hydrated into redox-inactive NAD(P)HX, and heat
    accelerates the reaction. NAXD is the enzyme that reverses it. Without
    NAXD, the repair cycle does not close.
  molecular_functions:
  - preferred_term: ATP-dependent NAD(P)H-hydrate dehydratase activity
    term:
      id: GO:0047453
      label: ATP-dependent NAD(P)H-hydrate dehydratase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: NAD+ metabolic process
    term:
      id: GO:0019674
      label: NAD+ metabolic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors"
    explanation: >-
      States that physical stress, and specifically high temperature, damages
      the nicotinamide nucleotide cofactors. Quoted to stop short of the
      bracketed formulae, which the reference validator strips before matching.
  - reference: PMID:35866541
    reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The central cofactors NAD(P)H are prone to damage by hydration, resulting in formation of redox-inactive derivatives designated NAD(P)HX."
    explanation: >-
      Names the damage reaction (hydration) and the product, completing the
      chemistry the previous item begins.
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX."
    explanation: >-
      States NAXD's role as the repair enzyme, which is what is lost.
  downstream:
  - target: Accumulation of Damaged NAD(P)HX Cofactors
    description: >-
      Unrepaired derivatives accumulate in the cell.
- name: Accumulation of Damaged NAD(P)HX Cofactors
  biological_scale: MOLECULAR
  description: >-
    Patient fibroblasts contain highly elevated S-NADHX, R-NADHX and cyclic
    NADHX. That lentiviral transduction with wild-type NAXD abolishes the
    accumulation is the step that makes this causal rather than correlative.
  evidence:
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX."
    explanation: >-
      The direct measurement of accumulated damaged cofactors in patient cells.
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD."
    explanation: >-
      Genetic complementation establishes that the accumulation is caused by
      the NAXD defect rather than accompanying it.
  downstream:
  - target: Mitochondrial Respiratory Chain Dysfunction
    description: >-
      Damaged cofactors impair mitochondrial energy metabolism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Inhibition of De Novo Serine Synthesis
    description: >-
      The second, non-mitochondrial consequence of the same accumulation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Inhibition of De Novo Serine Synthesis
  biological_scale: CELLULAR
  description: >-
    A branch that does not run through the mitochondrion. In NAXD knockout
    cells grown on galactose the mitochondrial signs were only subtle, while
    metabolomics showed strong inhibition of the cytosolic de novo serine
    synthesis pathway, and the same inhibition was present in NAXD patient
    fibroblasts. This matters for how the disease is read: it means the
    mitochondrial arm is not the whole account of what damaged cofactor does
    to a cell.
  biological_processes:
  - preferred_term: L-serine biosynthetic process
    term:
      id: GO:0006564
      label: L-serine biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:39789421
    reference_title: "Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Surprisingly, the galactose-grown NAXDko cells displayed only subtle signs of mitochondrial impairment, whereas metabolomic analyses revealed a strong inhibition of the cytosolic, de novo serine synthesis pathway in those cells as well as in NAXD patient-derived fibroblasts."
    explanation: >-
      Establishes the serine-synthesis branch in both NAXD knockout cells and
      NAXD patient fibroblasts, and records that the mitochondrial signs were
      subtle in the same experiment.
- name: Mitochondrial Respiratory Chain Dysfunction
  biological_scale: CELLULAR
  description: >-
    Patient fibroblasts and muscle show impaired mitochondrial function and are
    selectively vulnerable to metabolic stress: they fail in galactose and
    azide media, which force oxidative phosphorylation, but not in glucose,
    which permits glycolysis. Proteomics in both paediatric and adult cases
    shows reduced respiratory complexes I and IV and reduced mitoribosome, with
    mitochondrial apoptotic pathways upregulated.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  evidence:
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production."
    explanation: >-
      Reports the mitochondrial dysfunction and the substrate-conditional
      vulnerability that localises it to oxidative phosphorylation.
  - reference: PMID:36834994
    reference_title: "Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways."
    explanation: >-
      Names the specific complexes affected, and shows the signature is shared
      between the adult and paediatric presentations.
  downstream:
  - target: Increased circulating lactate concentration
    description: >-
      Impaired oxidative phosphorylation shifts metabolism toward lactate.
  - target: Increased CSF lactate
    description: >-
      The same shift measured in cerebrospinal fluid.
  - target: Cardiomyopathy
    description: >-
      Cardiac muscle is one of the two organs the founding series identifies as
      vulnerable, the other being brain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Trigger-Precipitated Neurometabolic Crisis
    description: >-
      A compromised oxidative capacity fails when demand rises.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Trigger-Precipitated Neurometabolic Crisis
  biological_scale: ORGANISM
  description: >-
    The defining clinical event. A trivial fever, infection or illness, or in
    one adult a mild head trauma, precipitates rapid deterioration. This is the
    node the whole entry turns on, because it is where a chronic biochemical
    vulnerability becomes an acute, often fatal, event.
  evidence:
  - reference: PMID:35866541
    reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, pathogenic variants in both the NAXD and NAXE genes were associated with rapid deterioration and death after an otherwise trivial fever, infection, or illness in young patients."
    explanation: >-
      States the trigger-and-crisis pattern and its outcome.
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death."
    explanation: >-
      The founding case series, establishing both the febrile trigger and the
      two organ outcomes.
  downstream:
  - target: Progressive Neurodegeneration
- name: Progressive Neurodegeneration
  biological_scale: ORGANISM
  description: >-
    Progressive neurological deterioration with brain oedema and
    leukoencephalopathy on imaging. Deterioration is stepwise, tied to crises,
    rather than smoothly progressive.
  evidence:
  - reference: PMID:34161859
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by progressive neurological deterioration usually associated with a febrile illness."
    explanation: >-
      States the progressive neurological course and its association with
      febrile illness.
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death."
    explanation: >-
      Places the neurodegeneration within the metabolite-repair framework and
      names the two vulnerable organs.
  downstream:
  - target: Cerebral edema
  - target: Leukoencephalopathy
  - target: Seizure
  - target: Developmental regression
  - target: Cutaneous necrosis
  - target: Skin erosion
phenotypes:
- category: Neurologic
  name: Developmental regression
  subtype: Combined isoform
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:34161859
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by progressive neurological deterioration usually associated with a febrile illness."
    explanation: >-
      The progressive neurological deterioration this phenotype records.
- category: Neurologic
  name: Seizure
  subtype: Combined isoform
  description: >-
    Seizures occur in the combined-isoform form and are characteristically
    absent when only the mitochondrial isoform is affected.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35866541
    reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NAXD deficiency patients with variants that affect both the cytosolic and mitochondrial isoforms present with neurological defects, seizures and skin lesions."
    explanation: >-
      Reports seizures and ties them to the combined-isoform genotype.
- category: Neuroimaging
  name: Cerebral edema
  phenotype_term:
    preferred_term: Cerebral edema
    term:
      id: HP:0002181
      label: Cerebral edema
  evidence:
  - reference: PMID:34161859
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 (PEBEL2; MIM# 618321), caused by biallelic pathogenic variants in the NAD(P)HX dehydratase (NAXD) is a rare metabolite repair disorder."
    explanation: >-
      Brain oedema is in the defining name of the phenotype series, quoted from
      the disease definition itself.
- category: Neuroimaging
  name: Leukoencephalopathy
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:34161859
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The other common findings include skin lesions, elevated serum or cerebrospinal fluid lactate levels, and brain neuroimaging abnormalities."
    explanation: >-
      Records brain neuroimaging abnormality as a common finding; the specific
      leukoencephalopathy is named in the disease definition quoted above.
- category: Dermatologic
  name: Cutaneous necrosis
  subtype: Combined isoform
  description: >-
    The eruption is stereotyped enough to be a diagnostic pointer:
    well-demarcated erythematous and erosive plaques on flexural surfaces that
    progress to blistering and necrosis, appearing with a crisis. Present in
    the combined-isoform form and characteristically absent when only the
    mitochondrial isoform is affected.
  phenotype_term:
    preferred_term: flexural erosive plaques progressing to blistering and necrosis
    term:
      id: HP:0033126
      label: Cutaneous necrosis
  evidence:
  - reference: PMID:39887790
    reference_title: "Cutaneous Manifestations of NAXD or NAXE Deficiency: A Literature Review for the Dermatologist."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The characteristic skin eruption comprises well-demarcated erythematous and erosive plaques progressing to blistering and necrosis, predominantly affecting flexural surfaces."
    explanation: >-
      Describes the eruption in the terms this phenotype records, including the
      progression to necrosis that the binding names.
  - reference: PMID:34161859
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The other common findings include skin lesions, elevated serum or cerebrospinal fluid lactate levels, and brain neuroimaging abnormalities."
    explanation: >-
      Independently lists skin lesions among the common findings.
- category: Dermatologic
  name: Skin erosion
  subtype: Combined isoform
  phenotype_term:
    preferred_term: Skin erosion
    term:
      id: HP:0200041
      label: Skin erosion
  evidence:
  - reference: PMID:39887790
    reference_title: "Cutaneous Manifestations of NAXD or NAXE Deficiency: A Literature Review for the Dermatologist."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The characteristic skin eruption comprises well-demarcated erythematous and erosive plaques progressing to blistering and necrosis, predominantly affecting flexural surfaces."
    explanation: >-
      The erosive plaque stage of the same eruption, recorded separately
      because erosion and necrosis are different findings at different points
      in the crisis.
- category: Neurologic
  name: Peripheral neuropathy
  subtype: Mitochondrial isoform
  description: >-
    Reported in the mitochondrial-isoform-restricted presentation, alongside
    the myopathy and cardiac involvement and without the skin lesions,
    seizures or neurodegeneration of the combined-isoform form. Graded
    moderate by the source.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:35866541
    reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, patients with NAXD variants exclusively affecting the mitochondrial isoform present with myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration."
    explanation: >-
      The same sentence that supports the myopathy and cardiac phenotypes
      names the neuropathy; it was previously the one feature of the three
      not carried across.
- category: Cardiovascular
  name: Cardiomyopathy
  description: >-
    Cardiomyopathy and cardiac failure, prominent in the mitochondrial-isoform
    presentation but named as a feature of NAXD deficiency generally.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:36158054
    reference_title: "A Case with NAD(P)HX Dehydratase (NAXD) Deficiency: A Newly Defined Mutation in a Novel Neurodegenerative Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prominent features of NAXD deficiency are progressive neurological deterioration after fever, cardiomyopathy, skin lesions, and premature death."
    explanation: >-
      Names cardiomyopathy among the prominent features of NAXD deficiency.
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death."
    explanation: >-
      The founding series records cardiac failure as one of the two crisis
      outcomes.
- category: Neurologic
  name: Axial hypotonia
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:36158054
    reference_title: "A Case with NAD(P)HX Dehydratase (NAXD) Deficiency: A Newly Defined Mutation in a Novel Neurodegenerative Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had lethargy and axial hypotonia but skin lesions and organomegaly were not noted."
    explanation: >-
      Records axial hypotonia in the reported case, in a sentence that also
      documents the absence of skin lesions in that patient.
- category: Laboratory
  name: Increased CSF lactate
  phenotype_term:
    preferred_term: Increased CSF lactate
    term:
      id: HP:0002490
      label: Increased CSF lactate
  evidence:
  - reference: PMID:36158054
    reference_title: "A Case with NAD(P)HX Dehydratase (NAXD) Deficiency: A Newly Defined Mutation in a Novel Neurodegenerative Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Basal metabolic tests were within normal limits except serum and cerebrospinal fluid lactate levels, which were mildly elevated."
    explanation: >-
      Reports the CSF lactate elevation, and that it was the only abnormal
      basal metabolic test.
- category: Laboratory
  name: Increased circulating lactate concentration
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: PMID:34161859
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The other common findings include skin lesions, elevated serum or cerebrospinal fluid lactate levels, and brain neuroimaging abnormalities."
    explanation: >-
      Records raised serum and CSF lactate as a common finding.
- category: Musculoskeletal
  name: Muscle weakness
  subtype: Mitochondrial isoform
  description: >-
    Myopathy, characteristic of the mitochondrial-isoform-restricted form.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:35866541
    reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, patients with NAXD variants exclusively affecting the mitochondrial isoform present with myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration."
    explanation: >-
      Reports myopathy and restricts it to the mitochondrial-isoform genotype.
- category: Hair
  name: Sparse hair
  description: >-
    Sparse scalp hair, reported as an additional feature in one patient and
    recorded here as a single-case observation rather than an established
    feature.
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: PMID:34161859
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on an additional individual with characteristic findings of PEBEL2, and an additional finding of sparse scalp hair."
    explanation: >-
      The single-patient observation, quoted with the authors' own framing that
      it is an addition to the known phenotype.
genetic:
- name: NAXD
  gene_term:
    preferred_term: NAXD
    term:
      id: hgnc:25576
      label: NAXD
  relationship_type: CAUSATIVE
  notes: >-
    Both truncating and missense variants are reported. Which NAXD isoform a
    variant affects, rather than its class, appears to determine the clinical
    presentation: exon 1 encodes the mitochondrial propeptide and the cytosolic
    isoform starts from an alternative codon in exon 2, so a variant in exon 1
    spares the cytosolic enzyme.
  evidence:
  - reference: PMID:34161859
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, variants in NAXD have been reported in eight unrelated individuals including six truncating and six missense variants."
    explanation: >-
      Gives the reported variant spectrum and its size as of 2021.
  - reference: PMID:35866541
    reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exon 1 of NAXD contains a mitochondrial propeptide, and a unique cytosolic isoform is initiated from an alternative start codon in exon 2."
    explanation: >-
      The gene-structure fact that makes isoform-selective variants possible,
      and so underpins the subtype split.
environmental:
- name: Febrile illness or intercurrent infection
  description: >-
    Fever, infection or other trivial illness is the principal precipitant of a
    neurometabolic crisis. The mechanistic link is not speculative: heat
    accelerates the spontaneous hydration that generates NAD(P)HX, and the two
    characterised mutant enzymes are thermolabile, so the repair capacity falls
    as the substrate load rises.
  exposure_term:
    preferred_term: febrile illness
  review_notes: >-
    Left unbound. ECTO was searched for a suitable exposure term; the closest
    candidate, ECTO:1000007 "exposure to high temperature environment",
    describes ambient heat and not endogenous fever, and binding it would
    misstate the exposure. No ECTO or ExO term for febrile illness, infection
    or endogenous hyperthermia was found. Recorded as free text rather than
    bound to a wrong term.
  influences_mechanisms:
  - target: Trigger-Precipitated Neurometabolic Crisis
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Fever is the reported precipitant of the crises in the founding series
      and in the review literature.
    evidence:
    - reference: PMID:35866541
      reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recently, pathogenic variants in both the NAXD and NAXE genes were associated with rapid deterioration and death after an otherwise trivial fever, infection, or illness in young patients."
      explanation: >-
        Establishes fever and intercurrent illness as the precipitants of the
        deterioration this edge asserts.
  evidence:
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death."
    explanation: >-
      The founding series describes the neurodegeneration as febrile-illness
      induced.
- name: Mild head trauma
  description: >-
    In the single reported adult case, a mild head trauma rather than a fever
    precipitated the fatal crisis. This matters for surveillance: if the
    trigger set is "metabolic stress" rather than "hyperthermia", then advice
    limited to fever management is incomplete.
  exposure_term:
    preferred_term: mild head trauma
  review_notes: >-
    Left unbound. ECTO and ExO were searched for a mechanical-injury exposure
    term; nothing matching head trauma was found, and the physical-object
    quality branch (ECTO:0010003) is far too broad to carry the claim.
  influences_mechanisms:
  - target: Trigger-Precipitated Neurometabolic Crisis
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The adult case's deterioration followed a mild head trauma, extending the
      trigger set beyond febrile illness.
    evidence:
    - reference: PMID:36834994
      reference_title: "Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical deterioration and demise of this individual were likely triggered by mild head trauma."
      explanation: >-
        The single observation supporting this edge. The authors write "likely
        triggered", which is the strength of the claim.
  evidence:
  - reference: PMID:36834994
    reference_title: "Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age."
    explanation: >-
      Establishes the case this exposure is drawn from, and that it is a single
      adult patient.
- name: Routine childhood immunization
  description: >-
    One patient deteriorated after routine 4-month immunizations, with
    prominent skin findings and no fever. This is the observation that most
    strains the thermal explanation of the disease, because the trigger
    operated without the hyperthermia the mechanism invokes.
  exposure_term:
    preferred_term: routine childhood immunization
  review_notes: >-
    Left unbound. ECTO was searched for a vaccination or immunization exposure
    term and none was found; ECTO:2000005 "exposure to hormone replacement
    therapy" and the drug-exposure branch do not describe vaccination.
  influences_mechanisms:
  - target: Trigger-Precipitated Neurometabolic Crisis
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Immunization preceded the crisis in this case, in the absence of fever.
    evidence:
    - reference: PMID:38214124
      reference_title: "Progressive encephalopathy after routine 4-month immunizations in a patient with NAXD genetic variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "In this report, we describe a case of probable PEBEL2 in a patient with a variant of unknown significance (c.362C>T, p.121L) in the NAXD gene who presented after routine immunizations with significant skin findings and in the absence of fevers."
      explanation: >-
        The single observation behind this edge. Graded INDIRECT because the
        authors themselves call the case "probable PEBEL2" carrying a variant
        of unknown significance, so the genotype attribution is not secure.
  evidence:
  - reference: PMID:38214124
    reference_title: "Progressive encephalopathy after routine 4-month immunizations in a patient with NAXD genetic variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "In this report, we describe a case of probable PEBEL2 in a patient with a variant of unknown significance (c.362C>T, p.121L) in the NAXD gene who presented after routine immunizations with significant skin findings and in the absence of fevers."
    explanation: >-
      Establishes the exposure and, in the same sentence, the two reasons to
      treat it cautiously: a variant of unknown significance and a "probable"
      diagnosis.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Eight unrelated individuals reported as of the 2021 NAXD review, with
    further cases since including one adult. A 2025 dermatology review counted
    45 patients, but that count pools NAXD with its sister disorder NAXE and so
    is not an NAXD case count. No population prevalence estimate exists.
  evidence:
  - reference: PMID:34161859
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, variants in NAXD have been reported in eight unrelated individuals including six truncating and six missense variants."
    explanation: >-
      Gives the reported NAXD case count this band is based on.
  - reference: PMID:39887790
    reference_title: "Cutaneous Manifestations of NAXD or NAXE Deficiency: A Literature Review for the Dermatologist."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "A comprehensive literature search identified 45 patients with 31 pathogenic/likely pathogenic mutations, and a median age of onset at 1.16 years."
    explanation: >-
      The larger published cohort, cited here for scale only. Graded INDIRECT
      because the 45 patients are NAXD and NAXE combined, so the number does
      not bound the NAXD population this record describes.
progression:
- phase: Crisis-punctuated course to early death
  age_range: Typically infancy to early childhood; one reported case survived to 32
  notes: >-
    The course is stepwise rather than smoothly progressive: long compensated
    intervals punctuated by trigger-precipitated crises, each of which can be
    fatal or leave fixed deficit. Death commonly follows the first or an early
    crisis. Early death is recorded here rather than as a phenotype because
    HPO's Mortality/Aging branch sits outside the schema's PhenotypeTerm
    closure; see dismech#9496, which names `progression:` as the intended home
    for survival and age-at-death facts.
  evidence:
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death."
    explanation: >-
      Establishes the episodic course and early death in the founding series.
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death."
    explanation: >-
      States early childhood death as the usual endpoint.
  - reference: PMID:36834994
    reference_title: "Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age."
    explanation: >-
      The outlier that sets the upper bound of the age range in this record.
treatments:
- name: Niacin-Based Supplementation
  description: >-
    Niacin supplementation aims to raise flux through NAD biosynthesis and
    outrun the accumulation of damaged cofactor. Reported benefit is partial
    and symptomatic, in anecdotal paediatric reports and in the adult case; no
    controlled data exist, and the reviewers describe the approach as promising
    rather than established.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nicotinic acid
      term:
        id: CHEBI:15940
        label: nicotinic acid
  target_mechanisms:
  - target: Accumulation of Damaged NAD(P)HX Cofactors
    description: >-
      The rationale is to shift the balance of the cofactor pool, not to
      restore repair capacity, which niacin cannot do.
  evidence:
  - reference: PMID:38974613
    reference_title: "Transient response to high-dose niacin therapy in a patient with NAXE deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Therefore, niacin administration has been shown to pause clinical deterioration of patients with PEBEL‐1 and PEBEL‐2 and provide protection against the fatal outcome of these disorders."
    explanation: >-
      States the shared rationale across both repair disorders, naming
      PEBEL-2 explicitly. Graded INDIRECT because the paper reports a
      PEBEL-1 patient and the sentence summarises the prior literature
      for the pair rather than reporting a NAXD outcome.
  - reference: PMID:38974613
    reference_title: "Transient response to high-dose niacin therapy in a patient with NAXE deficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Despite previous positive results for niacin supplementation in patients with PEBEL-1 and PEBEL-2, this is the first report of a patient with PEBEL-1 who deteriorated to fatal outcome despite being started on the highest dose of niacin therapy reported to date."
    explanation: >-
      The cautionary counterweight: a patient who died despite the highest
      niacin dose reported. REFUTE against the claim that niacin protects
      against the fatal outcome, and INDIRECT because that patient had
      PEBEL-1 (NAXE) rather than the NAXD deficiency this entry describes.
  - reference: PMID:36834994
    reference_title: "Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient."
    explanation: >-
      Reports partial symptomatic benefit, and the authors' own framing that
      the prior evidence is anecdotal.
  - reference: PMID:35866541
    reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Niacin-based therapies are promising, but advances in disease modelling for both NAXD and NAXE deficiency may identify more specific compounds as targeted treatments."
    explanation: >-
      The review's assessment: promising but not established, and explicitly
      awaiting better compounds.
  - reference: PMID:39887790
    reference_title: "Cutaneous Manifestations of NAXD or NAXE Deficiency: A Literature Review for the Dermatologist."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Niacin/nicotinamide supplementation resulted in improvements in skin lesions and survival rates."
    explanation: >-
      The strongest outcome claim available for this therapy. Graded INDIRECT
      because it is a retrospective literature review of a combined NAXD and
      NAXE cohort with no control group, so the survival claim is not an
      NAXD-specific controlled result.
experimental_models:
- name: NAXD patient dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary skin fibroblasts from NAXD-deficient patients. This is the system
    in which the accumulation of damaged cofactors, the mitochondrial
    dysfunction and the genetic rescue were all demonstrated.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:30576410
  modeled_mechanisms:
  - target: Accumulation of Damaged NAD(P)HX Cofactors
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: >-
      The fibroblasts carry the patient genotype and show the accumulated
      cofactors directly; wild-type NAXD transduction abolishes it.
    limitations: >-
      Fibroblasts are not an affected tissue. They can report the biochemical
      lesion but not the tissue selectivity, and the febrile trigger is not
      reproduced in culture except as a surrogate metabolic stress.
    readouts:
    - name: S-NADHX, R-NADHX and cyclic NADHX concentration
      target: Accumulation of Damaged NAD(P)HX Cofactors
      direction: INCREASED
      interpretation: >-
        Direct quantification of the damaged cofactors that define the disorder.
      evidence:
      - reference: PMID:30576410
        reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX."
        explanation: >-
          The measurement itself, with its direction.
    - name: NADHX concentration after wild-type NAXD transduction
      target: Accumulation of Damaged NAD(P)HX Cofactors
      direction: RESTORED
      interpretation: >-
        Genetic complementation returns the cofactor pool to normal, which is
        what makes the model causal rather than descriptive.
      evidence:
      - reference: PMID:30576410
        reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD."
        explanation: >-
          The rescue experiment behind this readout.
    evidence:
    - reference: PMID:30576410
      reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD."
      explanation: >-
        The complementation result is what licenses treating these fibroblasts
        as informative for the human mechanism.
diagnosis:
- name: Biallelic NAXD variants with fibroblast NAD(P)HX quantification
  description: >-
    Molecular diagnosis by exome or genome sequencing, supported where
    available by measurement of damaged cofactors in patient fibroblasts. The
    clinical trigger is worth recognising ahead of the genetics: an
    otherwise-well young child deteriorating catastrophically during a trivial
    febrile illness, with lactate raised and brain oedema on imaging.
  evidence:
  - reference: PMID:30576410
    reference_title: "NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case."
    explanation: >-
      States the diagnostic modality used in every case of the founding series.
differential_diagnoses:
- name: NAXE deficiency (PEBEL1)
  description: >-
    The allelic-pathway sibling. NAXE encodes NAD(P)HX epimerase, the other
    enzyme of the same two-step repair system, and its deficiency produces the
    same trigger-and-crisis pattern. The two are curated together in the
    literature reviews and are separated by gene, not by presentation.
  evidence:
  - reference: PMID:35866541
    reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The highly conserved enzymes NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE) function to repair intracellular NAD(P)HX."
    explanation: >-
      States that the two enzymes serve the same repair system, which is why
      NAXE deficiency is the first differential.
- name: Leigh syndrome and other mitochondrial encephalopathies
  description: >-
    Share the febrile decompensation, lactate elevation and symmetrical
    neuroimaging change. The distinguishing feature is biochemical: damaged
    NAD(P)HX derivatives accumulate in NAXD deficiency and not in primary
    respiratory chain disease.
discussions:
- discussion_id: naxd_trigger_set_beyond_fever
  kind: KNOWLEDGE_GAP
  attaches_to:
  - environmental#Mild head trauma
  - pathophysiology#Trigger-Precipitated Neurometabolic Crisis
  prompt: >-
    Is the precipitant of a NAXD crisis specifically hyperthermia, or any
    metabolic stress?
  rationale: >-
    The mechanism as usually stated is temperature-driven: heat accelerates
    NAD(P)H hydration, and the characterised mutant enzymes are thermolabile.
    That explanation predicts fever and nothing else. But the one adult case
    was precipitated by mild head trauma, with no fever reported as the
    trigger. If the real precipitant is any acute rise in metabolic demand,
    then surveillance advice built around antipyresis is incomplete, and the
    thermolability finding is a partial explanation rather than the mechanism.
    A single case cannot settle this, which is why it is recorded as a gap.
  proposed_experiments:
  - experiment_id: naxd_nonthermal_stress_fibroblasts
    name: Non-thermal metabolic stress in NAXD patient fibroblasts
    description: >-
      Compare NAD(P)HX accumulation in patient and control fibroblasts under
      thermal stress against non-thermal stresses at matched metabolic demand,
      to test whether temperature is necessary or merely sufficient.
    readouts:
    - name: NAD(P)HX accumulation under non-thermal stress
      target: pathophysiology#Accumulation of Damaged NAD(P)HX Cofactors
      direction: INCREASED
      interpretation: >-
        Accumulation without hyperthermia would show the trigger set is broader
        than heat.
- discussion_id: naxd_isoform_phenotype_split
  kind: KNOWLEDGE_GAP
  attaches_to:
  - has_subtypes#Mitochondrial isoform
  - has_subtypes#Combined isoform
  prompt: >-
    Does cytosolic NAD(P)HX repair specifically protect the brain, and
    mitochondrial repair specifically protect muscle?
  rationale: >-
    The subtype split in this entry is drawn from a review's cataloguing of
    published cases by variant position, not from an experiment. The proposed
    interpretation, that cytosolic repair protects from neurological damage
    while muscle is more sensitive to mitochondrial damage, is the reviewers'
    own inference from that catalogue and is offered as a suggestion. With
    roughly a dozen published patients the split rests on small numbers, and no
    isoform-specific knockout or rescue experiment has tested it.
  evidence:
  - reference: PMID:35866541
    reference_title: "Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "This suggests that cytosolic NAD(P)HX repair may protect from neurological damage, whereas muscle fibres may be more sensitive to mitochondrial NAD(P)HX damage."
    explanation: >-
      The hypothesis itself, quoted with the hedges the authors used. Indirect
      because it is an inference from a case catalogue rather than a measured
      result.
- discussion_id: naxd_phenotypic_diversity_incomplete_triad
  kind: CONTROVERSY
  attaches_to:
  - phenotypes#Cutaneous necrosis
  - pathophysiology#Trigger-Precipitated Neurometabolic Crisis
  prompt: >-
    How much of the NAXD phenotype is obligate, given patients who lack both
    the febrile trigger and the skin eruption?
  rationale: >-
    The clinical picture is usually stated as a triad: fever trigger, skin
    eruption, neurological crisis. Two published cases break it. One 7-month-old
    with a novel homozygous NAXD variant had neither a preceding fever nor any
    skin lesion, and his authors concluded the cases show phenotypic diversity.
    Another patient had prominent skin findings after immunization with no
    fever at all. Meanwhile the largest cohort puts skin manifestations at 31%,
    so the eruption is a minority finding rather than a defining one. This
    matters practically: a diagnostic heuristic built on the triad will miss
    patients, and the entry curates the skin phenotypes without asserting that
    they are obligate.
  evidence:
  - reference: PMID:36158054
    reference_title: "A Case with NAD(P)HX Dehydratase (NAXD) Deficiency: A Newly Defined Mutation in a Novel Neurodegenerative Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike the cases reported in the literature, our patient had neither preceding fever nor skin lesion during follow-up."
    explanation: >-
      The case that breaks both halves of the triad at once.
  - reference: PMID:39887790
    reference_title: "Cutaneous Manifestations of NAXD or NAXE Deficiency: A Literature Review for the Dermatologist."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Skin manifestations were observed in 31% of patients with whole cell NAXD and NAXE deficiencies."
    explanation: >-
      Quantifies the skin eruption as a minority finding. Graded INDIRECT
      because the denominator pools NAXD with NAXE, so the figure is not an
      NAXD-specific frequency.
notes: >-
  On the isoform subtypes. The `has_subtypes` split here is a
  genotype-to-compartment claim from a single review's catalogue of published
  cases, not a nosological division anyone has ratified. It is curated because
  it is mechanistically specific and clinically actionable in a way a
  free-text note would lose, but the KNOWLEDGE_GAP discussion above records
  that it rests on roughly a dozen patients.

  On early death, and where it is recorded. `HP:0003819` "Death in childhood"
  was tried first and rejected by term validation: it descends from
  `HP:0040006` Mortality/Aging, which is a sibling of Phenotypic abnormality
  and so outside the schema's `PhenotypeTerm` closure. The gate is right, and
  dismech#9496 documents the same collision for `HP:0001522` and proposes
  `progression:` as the home for survival and age-at-death facts. This entry
  follows that, in the `progression:` record above. The convention is not yet
  ratified, so a reviewer who prefers `clinical_burden:` should say so.

  On a CURIE the deep-research report got wrong. The openscientist report for
  this disease proposed HP:0100697 for "Necrosis of the skin". HP:0100697 is
  *Malignant peripheral nerve sheath tumor*. The correct term, HP:0033126
  *Cutaneous necrosis*, was found by searching HPO directly and is what this
  entry binds. The report's other proposed CURIEs that were used here
  (HP:0002181, HP:0002352, HP:0001250, HP:0002376, HP:0008936, HP:0002490,
  HP:0001638, HP:0200041) all resolved to the labels the report gave them.

  On evidence taken from the sister disorder, and not taken. PMID:35637064 is a
  review of NAXE deficiency that describes the shared NAD(P)HX repair system.
  Its statements about the repair system and about decompensation under stress
  cover both enzymes explicitly and are usable here. Its clinical-findings
  sentence (muscle weakness, ataxia, ophthalmoplegia, motor and cognitive
  regression) summarises 30 NAXE cases, so ataxia and ophthalmoplegia are
  deliberately NOT curated as NAXD phenotypes even though the deep-research
  report listed them: no NAXD-specific source for either was found.

  On mortality. The largest published cohort reports 78% mortality, but pools
  NAXD with NAXE, so the figure is recorded in this note rather than as an
  outcome claim about NAXD.

  On a reference that was fetched and then not cited. PMID:31755961, a 2020
  Brain correspondence reporting further Chinese cases, has no abstract in its
  PubMed record, so the cached file has an empty body and nothing in it is
  quotable. It is deliberately absent from `references:` rather than cited
  hollowly.

  Not curated, and why. No `datasets:` and no `clinical_trials:` - no verified
  accession or trial registration exists. No `biochemical:` reference ranges -
  NAD(P)HX quantification is a research assay with no published clinical
  reference interval, and lactate is carried as a phenotype. An iPSC line from
  a PEBEL2 patient exists (PMID:38387170) but is a resource report with no
  mechanistic result, so linking it to a pathophysiology node would assert more
  than the paper shows; the patient fibroblasts, which do carry results, are
  curated instead. `directness` is set only where it was actually assessed; no count is
  given here, because a count in prose goes stale the moment an evidence item
  is added, which is how the previous one came to be wrong.

  On two management steps the review asked for and this entry does not carry.
  Acute trigger control with prompt antipyresis, and genetic counselling with
  its 25 percent recurrence risk and prenatal options, are both real clinical
  practice and both were proposed by the deep-research report. Neither is
  curated, because no reference committed here *recommends* either of them. The
  distinction matters and an earlier version of this note got it wrong: it
  claimed a grep of the cached sources returns no fever-management sentence at
  all, and review showed that is false. PMID:34161859 describes a NAXD patient
  "managed on antibiotics, antipyretics, and antiepileptics". That sentence
  reports what one child received before she died; it does not recommend
  antipyresis, so it cannot support a treatment entry, but the claim as
  originally worded was wrong and is corrected here. The counselling half
  stands: nothing cached mentions counselling, recurrence risk, prenatal
  testing or carrier testing. They are the kind of claim that is easy to assert from general
  practice and hard to source for a specific ultra-rare disease, which is
  exactly when a citation matters most. A guideline or review that states them
  of NAXD deficiency would close this in one pass.

  On the niacin caution and whose disease it is. PMID:38974613 reports a
  patient who died despite the highest niacin dose published. That patient had
  PEBEL-1 (NAXE), not the NAXD deficiency this entry describes, so the item is
  graded REFUTE with `directness: INDIRECT` and its explanation names the
  disease. It is carried rather than dropped because a treatments section whose
  only entry is niacin should not omit the one published failure of niacin in
  the sister disorder; it is graded INDIRECT rather than DIRECT because the
  denominator is the other half of the pair. This is the same pooled-entity
  problem recorded in the prevalence notes and filed as dismech#11268.
📚

References & Deep Research

References

8
PMID:30576410
NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses.
No top-level findings curated for this source.
PMID:35866541
Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency.
No top-level findings curated for this source.
PMID:36834994
Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma.
No top-level findings curated for this source.
PMID:34161859
NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature.
No top-level findings curated for this source.
PMID:39887790
Cutaneous Manifestations of NAXD or NAXE Deficiency: A Literature Review for the Dermatologist.
No top-level findings curated for this source.
PMID:38214124
Progressive encephalopathy after routine 4-month immunizations in a patient with NAXD genetic variant.
No top-level findings curated for this source.
PMID:36158054
A Case with NAD(P)HX Dehydratase (NAXD) Deficiency: A Newly Defined Mutation in a Novel Neurodegenerative Disorder.
No top-level findings curated for this source.
PMID:35637064
NAXE deficiency: A neurometabolic disorder of NAD(P)HX repair amenable for metabolic correction.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

On the isoform subtypes. The `has_subtypes` split here is a genotype-to-compartment claim from a single review's catalogue of published cases, not a nosological division anyone has ratified. It is curated because it is mechanistically specific and clinically actionable in a way a free-text note would lose, but the KNOWLEDGE_GAP discussion above records that it rests on roughly a dozen patients. On early death, and where it is recorded. `HP:0003819` "Death in childhood" was tried first and rejected by term validation: it descends from `HP:0040006` Mortality/Aging, which is a sibling of Phenotypic abnormality and so outside the schema's `PhenotypeTerm` closure. The gate is right, and dismech#9496 documents the same collision for `HP:0001522` and proposes `progression:` as the home for survival and age-at-death facts. This entry follows that, in the `progression:` record above. The convention is not yet ratified, so a reviewer who prefers `clinical_burden:` should say so. On a CURIE the deep-research report got wrong. The openscientist report for this disease proposed HP:0100697 for "Necrosis of the skin". HP:0100697 is *Malignant peripheral nerve sheath tumor*. The correct term, HP:0033126 *Cutaneous necrosis*, was found by searching HPO directly and is what this entry binds. The report's other proposed CURIEs that were used here (HP:0002181, HP:0002352, HP:0001250, HP:0002376, HP:0008936, HP:0002490, HP:0001638, HP:0200041) all resolved to the labels the report gave them. On evidence taken from the sister disorder, and not taken. PMID:35637064 is a review of NAXE deficiency that describes the shared NAD(P)HX repair system. Its statements about the repair system and about decompensation under stress cover both enzymes explicitly and are usable here. Its clinical-findings sentence (muscle weakness, ataxia, ophthalmoplegia, motor and cognitive regression) summarises 30 NAXE cases, so ataxia and ophthalmoplegia are deliberately NOT curated as NAXD phenotypes even though the deep-research report listed them: no NAXD-specific source for either was found. On mortality. The largest published cohort reports 78% mortality, but pools NAXD with NAXE, so the figure is recorded in this note rather than as an outcome claim about NAXD. On a reference that was fetched and then not cited. PMID:31755961, a 2020 Brain correspondence reporting further Chinese cases, has no abstract in its PubMed record, so the cached file has an empty body and nothing in it is quotable. It is deliberately absent from `references:` rather than cited hollowly. Not curated, and why. No `datasets:` and no `clinical_trials:` - no verified accession or trial registration exists. No `biochemical:` reference ranges - NAD(P)HX quantification is a research assay with no published clinical reference interval, and lactate is carried as a phenotype. An iPSC line from a PEBEL2 patient exists (PMID:38387170) but is a resource report with no mechanistic result, so linking it to a pathophysiology node would assert more than the paper shows; the patient fibroblasts, which do carry results, are curated instead. `directness` is set only where it was actually assessed; no count is given here, because a count in prose goes stale the moment an evidence item is added, which is how the previous one came to be wrong. On two management steps the review asked for and this entry does not carry. Acute trigger control with prompt antipyresis, and genetic counselling with its 25 percent recurrence risk and prenatal options, are both real clinical practice and both were proposed by the deep-research report. Neither is curated, because no reference committed here *recommends* either of them. The distinction matters and an earlier version of this note got it wrong: it claimed a grep of the cached sources returns no fever-management sentence at all, and review showed that is false. PMID:34161859 describes a NAXD patient "managed on antibiotics, antipyretics, and antiepileptics". That sentence reports what one child received before she died; it does not recommend antipyresis, so it cannot support a treatment entry, but the claim as originally worded was wrong and is corrected here. The counselling half stands: nothing cached mentions counselling, recurrence risk, prenatal testing or carrier testing. They are the kind of claim that is easy to assert from general practice and hard to source for a specific ultra-rare disease, which is exactly when a citation matters most. A guideline or review that states them of NAXD deficiency would close this in one pass. On the niacin caution and whose disease it is. PMID:38974613 reports a patient who died despite the highest niacin dose published. That patient had PEBEL-1 (NAXE), not the NAXD deficiency this entry describes, so the item is graded REFUTE with `directness: INDIRECT` and its explanation names the disease. It is carried rather than dropped because a treatments section whose only entry is niacin should not omit the one published failure of niacin in the sister disorder; it is graded INDIRECT rather than DIRECT because the denominator is the other half of the pair. This is the same pooled-entity problem recorded in the prevalence notes and filed as dismech#11268.

Create: NAD(P)HX Dehydratase Deficiency · 2026-09-06T19:39:47Z · View source

De novo curation of NAXD deficiency / PEBEL2 (MONDO:0034121). An openscientist deep-research report was generated and used as leads only; its preflight flagged NAXE contamination (25 mentions vs 52 for NAXD) and the NAXE-derived clinical findings were deliberately excluded. One CURIE the report proposed was wrong: HP:0100697 offered as 'Necrosis of the skin' is actually Malignant peripheral nerve sheath tumor; HP:0033126 Cutaneous necrosis was substituted after checking HPO directly. Every report PMID used was verified against PubMed first. has_subtypes splits the disease by NAXD isoform (combined cytosolic+mitochondrial vs mitochondrial-restricted), with a KNOWLEDGE_GAP recording that the split rests on ~12 patients. Two environmental entries model the febrile and head-trauma triggers via influences_mechanisms; both exposure_terms are deliberately unbound with a recorded ECTO search. Validated: just validate (51/51 snippets verified), validate-terms, check-entity-refs, check-causal-targets, check-enum-values all pass.

OpenScientist ▸
NAD(P)HX Dehydratase (NAXD) Deficiency — Comprehensive Disease Characteristics Report
openscientist-autonomous 15 citations 2026-09-06T19:28:02.388705

NAD(P)HX Dehydratase (NAXD) Deficiency — Comprehensive Disease Characteristics Report

Disease: NAD(P)HX Dehydratase Deficiency (PEBEL2) MONDO ID: MONDO:0034121 · OMIM (phenotype): #618321 · Gene: NAXD (HGNC:25576) Category: Mendelian (autosomal recessive inborn error of metabolite repair)

Summary

NAD(P)HX dehydratase (NAXD) deficiency — clinically designated PEBEL2 (Progressive Encephalopathy with Brain Edema and/or Leukoencephalopathy, type 2; OMIM #618321) — is an ultra-rare, autosomal-recessive inborn error of metabolite repair. It is caused by biallelic loss-of-function variants in NAXD, the gene encoding the ATP-dependent NAD(P)HX dehydratase (EC 4.2.1.93). Together with its partner enzyme NAD(P)HX epimerase (NAXE; the sister disorder PEBEL1), NAXD constitutes the intracellular NAD(P)HX repair system, which converts the toxic, non-functional hydrated forms of the redox cofactors NADH and NADPH (collectively NAD(P)HX) back to usable NAD(P)H. When NAXD is deficient, S-NADHX, R-NADHX and cyclic-NADHX accumulate and functional NAD(P)H is depleted, producing a cellular energy/redox crisis (PMID: 30576410; PMID: 34161859).

The defining clinical feature is a gene–environment interaction: the enzymopathy is often silent until a metabolic stressor — most commonly fever or infection, but also immunization, or physical trauma — sharply increases the non-enzymatic hydration of NAD(P)H and can denature thermolabile mutant enzyme. This precipitates acute, frequently fatal neurometabolic decompensation: rapidly progressive encephalopathy with brain and cerebellar edema and/or leukoencephalopathy, seizures, loss of developmental milestones, elevated CSF/serum lactate, characteristic flexural necrotic skin lesions, and — particularly for variants restricted to the mitochondrial isoform — cardiomyopathy and myopathy. Reported mortality across the combined NAXD/NAXE literature is approximately 78%, with survivors experiencing neurological sequelae (PMID: 39887790).

Critically, the disorder is at least partly treatable: niacin/nicotinamide (vitamin B3), which feeds NAD de novo / salvage synthesis and replenishes the depleted cofactor pool, improves skin lesions and survival in reported patients, providing a rational metabolic bypass therapy alongside aggressive control of febrile triggers (PMID: 39887790; PMID: 27616477; PMID: 38974613). This report synthesizes 9 confirmed findings across 18 papers into a complete disease knowledge-base entry.

Evidence-source note. This is an ultra-rare disease first defined in 2019; knowledge is derived almost entirely from aggregated case reports/series and functional studies (human clinical, patient fibroblasts/iPSCs, HAP1 knockouts, zebrafish, recombinant-enzyme biochemistry), not from population EHR or registry data. Fewer than ~20 genetically confirmed NAXD patients have been published. Where a claim rests on the sister disorder NAXE (PEBEL1) or on model systems, this is stated explicitly.

1. Disease Information

Overview. NAXD deficiency is a rare metabolite-repair disorder. NAD(P)HX dehydratase is a highly conserved enzyme essential for intracellular repair of the damaged/hydrated redox cofactor NAD(P)HX. As stated in the founding case series: "The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX" (PMID: 30576410). Loss of the enzyme produces a fever-triggered neurodegenerative and multisystem disease.

Key identifiers.

Resource Identifier
Disease name NAD(P)HX Dehydratase Deficiency / PEBEL2
MONDO MONDO:0034121
OMIM (phenotype) #618321 (Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2)
OMIM (gene) 615910
Gene symbol NAXD (HGNC:25576)
NCBI Gene 55739
Ensembl ENSG00000213995
UniProt Q8IW45
Enzyme EC 4.2.1.93 (ATP-dependent, ADP-forming NAD(P)HX dehydratase)
Locus 13q34 (GRCh38 chr13:110,615,505–110,643,086, + strand)
Aliases CARKD, LP3298

The disease designation and OMIM ID are confirmed: "Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 (PEBEL2; MIM# 618321), caused by biallelic pathogenic variants in the NAD(P)HX dehydratase (NAXD) is a rare metabolite repair disorder" (PMID: 34161859).

Synonyms / alternative names: PEBEL2; NAXD deficiency; NAD(P)HX dehydratase deficiency; carbohydrate kinase domain-containing protein deficiency (CARKD). The closely related sister disorder is NAXE deficiency / PEBEL1 (OMIM #617186), caused by the partner repair enzyme.

Information source. Knowledge derives predominantly from aggregated disease-level resources (OMIM, Orphanet, MONDO) and from individual patient case reports / small case series in the primary literature, supplemented by in vitro (cell line, recombinant enzyme) and model-organism (zebrafish) data. There is no large EHR-derived cohort; this is an ultra-rare disorder documented through gene-first (WES/WGS) discovery.

2. Etiology

Primary cause — genetic. The disease is caused by biallelic (homozygous or compound-heterozygous) loss-of-function variants in NAXD, inherited in an autosomal-recessive pattern. Biallelic NAXD variants were identified by whole-exome/whole-genome sequencing in a case series of infants and children with febrile-illness-induced neurodegeneration or cardiac failure and early death (PMID: 30576410). The molecular defect is a failure of an essential housekeeping "metabolite repair" function.

Genetic risk factors. The only established causal genetic factor is biallelic pathogenic NAXD variation. gnomAD constraint metrics (v2.1.1) are consistent with a recessive loss-of-function mechanism: pLI ≈ 5.5×10⁻⁵ (i.e., ~0, the gene tolerates heterozygous LoF) with observed/expected LoF (oe_lof/LOEUF) = 0.615 (95% CI 0.44–0.88). Carriers (heterozygotes) are asymptomatic.

Environmental "risk"/trigger factors. Uniquely, environment acts as the decompensation trigger rather than an independent cause. Documented triggers include febrile illness and infection (most common), routine immunization (PMID: 38214124), and physical/mechanical stress such as mild head trauma (PMID: 36834994). These raise body temperature and metabolic flux, accelerating non-enzymatic cofactor hydration and denaturing thermolabile mutant enzyme.

Protective factors. No genetic protective variants or modifier alleles have been defined. The main modifiable protective actions are avoidance/aggressive management of fever and triggers and niacin/nicotinamide supplementation (see Treatment).

Gene–environment interaction. This is a paradigmatic G×E disorder. The recombinant NAXD proteins bearing patient missense changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile with decreased Vmax and increased KM (PMID: 30576410) — providing a direct molecular explanation for why fever (a rise in body temperature) converts a compensated enzymopathy into an acute crisis. During stress, "nonenzymatic conversion of NAD(P)H to NAD(P)HX increases, and in the absence of repair, NAD(P)H is depleted, and NAD(P)HX accumulates, leading to decompensation" (PMID: 35637064).

3. Phenotypes

The phenotype spectrum spans neurological, cutaneous, cardiac, muscular and biochemical domains. Onset is typically in the first 1–3 years of life (median age of onset ~1.16 years across the combined cohort), though adult-onset is reported.

Phenotype Type Onset / severity / course Frequency Suggested HPO
Progressive encephalopathy / psychomotor regression Clinical sign Infancy–early childhood; severe; episodic-on-progressive, often fever-triggered Very frequent HP:0002376 (Developmental regression); HP:0006846 (Acute encephalopathy)
Brain / cerebellar edema Physical manifestation (imaging) Acute during crisis; severe Frequent HP:0002181 (Cerebral edema)
Leukoencephalopathy / white-matter changes Imaging abnormality Subacute–chronic; severe Frequent HP:0002352 (Leukoencephalopathy)
Seizures (incl. myoclonic) Clinical sign Infancy; variable Frequent (whole-cell deficiency) HP:0001250 (Seizure); HP:0002123 (Generalized myoclonic seizures)
Hypotonia (axial) Clinical sign Infancy; moderate–severe Frequent HP:0001252 (Hypotonia); HP:0008936 (Axial hypotonia)
Ataxia Clinical sign Childhood; variable Frequent HP:0001251 (Ataxia)
Flexural erythematous/erosive/necrotic skin lesions Physical manifestation With crisis; severe ~31% of whole-cell deficiency HP:0000988 (Skin rash); HP:0200041 (Skin erosion); HP:0100697 (Necrosis of the skin)
Cardiomyopathy / cardiac failure Clinical sign Infancy or later; severe Subset (esp. mito-isoform variants) HP:0001638 (Cardiomyopathy); HP:0001635 (Congestive heart failure)
Myopathy / neuropathy Clinical sign Variable; moderate Mito-isoform variants HP:0003198 (Myopathy); HP:0009830 (Peripheral neuropathy)
Elevated CSF/serum lactate Laboratory abnormality During/after crisis; mild–marked Frequent HP:0002151 (Increased serum lactate); HP:0002490 (Increased CSF lactate)
Respiratory insufficiency Clinical sign Crisis; severe Subset HP:0002093 (Respiratory insufficiency)
Ophthalmoparesis Clinical sign Variable Subset HP:0000602 (Ophthalmoplegia)
Premature death Outcome Early childhood typical ~78% mortality HP:0001522 (Death in infancy)

Characteristic cutaneous phenotype: "The characteristic skin eruption comprises well-demarcated erythematous and erosive plaques progressing to blistering and necrosis, predominantly affecting flexural surfaces" (PMID: 39887790).

Phenotypic diversity / atypical presentations. Not all patients show the full picture. One 7-month-old with a novel homozygous variant had neither preceding fever nor skin lesions, prompting the authors to note that "cases show phenotypic diversity" (PMID: 36158054). A patient presenting after routine immunizations had prominent skin findings in the absence of fevers (PMID: 38214124).

Quality-of-life impact. Formal QoL instruments (EQ-5D/SF-36) have not been applied to this ultra-rare disease. Qualitatively, the impact is profound: acute crises cause loss of acquired milestones, severe disability in survivors, and high early mortality.

4. Genetic / Molecular Information

Causal gene. NAXD (HGNC:25576; NCBI Gene 55739; Ensembl ENSG00000213995; gene-OMIM 615910), located at 13q34, encoding NAD(P)HX dehydratase (UniProt Q8IW45; EC 4.2.1.93). The sister gene is NAXE (HGNC:18453; Gene 128240; ENSG00000163382; 1q22; UniProt Q8NCW5; EC 5.1.99.6; phenotype-OMIM 617186; aliases APOA1BP/AIBP/YJEFN1).

Pathogenic variant spectrum. Variants are biallelic and predominantly missense, with frameshift/loss-of-function alleles also reported. Representative documented variants:

Variant (cDNA / protein) Zygosity Functional evidence Reference
p.(Gly63Ser) and p.(Arg608Cys) Compound het (recombinant) Thermolabile; ↓Vmax, ↑KM for ATP-dependent NADHX dehydratase activity PMID: 30576410
c.301G>A, p.(Ala101Thr) Homozygous Novel missense via exome sequencing PMID: 34161859
c.247G>A Homozygous Novel; myoclonic seizures, no fever/skin lesions PMID: 36158054
c.101_102delTA, p.(Thr35Phefs*63) + c.318C>G, p.(Ile160Met) Compound het Used to derive patient iPSC line PMID: 38387170
c.362C>T, p.(Pro121Leu) VUS Probable PEBEL2, post-immunization skin findings PMID: 38214124
Compound-heterozygous (cardiomyopathy) Compound het Metabolic cardiomyopathy with interstitial fibrosis PMID: 39822994

The founding study demonstrated loss of function at the protein level: "Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity" (PMID: 30576410).

Variant classification & population frequency. Reported variants are classified pathogenic/likely-pathogenic per ACMG (with occasional VUS such as p.Pro121Leu). Pathogenic alleles are exceedingly rare in gnomAD, consistent with a severe recessive disorder; heterozygous LoF is tolerated (pLI≈0), while biallelic LoF is disease-causing.

Functional consequence — loss of function (reduced/abolished enzymatic repair activity), not gain of function or dominant negative.

Isoform-determined genotype–phenotype correlation (modifier of expression). NAXD encodes two subcellular isoforms: "Exon 1 of NAXD contains a mitochondrial propeptide, and a unique cytosolic isoform is initiated from an alternative start codon in exon 2" (PMID: 35866541). The isoform hit by a given variant dictates phenotype: variants affecting both isoforms → neurological degeneration, seizures and skin lesions; variants affecting only the mitochondrial isoform → "myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration" (PMID: 35866541).

Modifier genes / epigenetics / chromosomal abnormalities. No trans-acting modifier genes, epigenetic mechanisms, or large-scale chromosomal abnormalities have been implicated; the "modifier" of expression is the intragenic isoform architecture described above.

5. Environmental Information

  • Environmental triggers (not toxins per se): febrile illness, infection, immunization, and physical/mechanical stress (e.g., mild head trauma). These accelerate the endogenous chemical damage reaction (NAD(P)H → NAD(P)HX). NAD(P)HX itself is described as "a toxic metabolite that is produced by stressors such as a fever, infection, or physical stress" (PMID: 38214124).
  • Lifestyle factors: none established; disease presents in infancy/childhood. Relevant management is trigger avoidance and prompt antipyresis.
  • Infectious agents: no specific pathogen causes the disease; any febrile infection can act as a non-specific trigger of decompensation.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic loss-of-function variants in NAXD → loss of ATP-dependent NAD(P)HX dehydratase activity (demonstrated: thermolabile recombinant mutants with reduced Vmax/increased KM; PMID: 30576410).
  2. Loss of repair capacity leads to failure to convert the damaged, hydrated cofactors back to NAD(P)H → accumulation of S-NADHX, R-NADHX and cyclic-NADHX and depletion of functional NAD(P)H (demonstrated in patient fibroblasts: "highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX"; PMID: 30576410).
  3. A metabolic stressor (fever/infection/immunization/trauma) results in an increased rate of non-enzymatic NAD(P)H hydration and denaturation of thermolabile mutant enzyme → an unrepaired surge in NAD(P)HX and acute cofactor depletion ("During stress, nonenzymatic conversion of NAD(P)H to NAD(P)HX increases…leading to decompensation"; PMID: 35637064).
  4. This branches into downstream lesions:
  5. 4a. Accumulated NAD(P)HX inhibits multiple dehydrogenases and NAD(P)H is depleted → impaired redox/energy metabolism → mitochondrial dysfunction (higher sensitivity to metabolic stress in galactose/azide media; PMID: 30576410).
  6. 4b. Repair failure results in strong inhibition of the cytosolic, de novo serine synthesis pathway — a distinct, recently discovered downstream mechanism beyond mitochondrial impairment ("metabolomic analyses revealed a strong inhibition of the cytosolic, de novo serine synthesis pathway"; PMID: 39789421).
  7. Combined energetic/redox and biosynthetic failure injures high-demand tissues → brain/cerebellum/white matter (encephalopathy, edema, leukoencephalopathy, seizures), heart/muscle (cardiomyopathy, myopathy), and skin (flexural erosive/necrotic lesions), with elevated CSF/serum lactate as a biochemical readout.
  8. Untreated, the crisis progresses to coma, brain atrophy and death (~78% mortality); metabolic bypass with niacin/nicotinamide partially reverses the cofactor deficit and improves skin and survival.

Detail by category

  • Molecular pathway / biochemical abnormality: defect in the NAD(P)HX repair (metabolite-repair) pathway; NAXD (EC 4.2.1.93) works with NAXE (EC 5.1.99.6). The hydrated cofactors are inhibitors of several dehydrogenases and generate harmful byproducts.
  • Metabolic changes: depletion of the NAD(P)H redox pool; impaired energy metabolism; inhibition of de novo serine synthesis (PMID: 39789421); elevated lactate reflecting a shift toward anaerobic metabolism / mitochondrial impairment.
  • Cellular processes: mitochondrial dysfunction; vulnerability under oxidative/metabolic stress (demonstrated by growth impairment in galactose vs glucose; PMID: 39789421, PMID: 30576410); neurodegeneration.
  • Protein dysfunction: thermolability of mutant enzyme (mechanistic link to fever); reduced catalytic efficiency (↓Vmax, ↑KM).
  • Immune involvement: zebrafish naxd knockouts reveal immune-system perturbations in early development (PMID: 41621837); clinically, infection/immunization acts as trigger, and inflammation likely amplifies cofactor-hydration stress.
  • Tissue-damage mechanisms: metabolic/redox stress leading to cytotoxic edema, necrosis (skin), fibrosis (cardiac interstitial fibrosis; PMID: 39822994).

Suggested GO / CHEBI / CL terms: GO:0110051 (metabolite repair) / GO:0046496 (nicotinamide nucleotide metabolic process); GO:0052855 (ADP-dependent NAD(P)H-hydrate dehydratase activity, EC 4.2.1.93); GO:0006564 (L-serine biosynthetic process); GO:0005739 (mitochondrion, CC); GO:0005829 (cytosol, CC). CHEBI: NADHX, NADPHX, NAD(H), NADP(H), nicotinamide (CHEBI:17154), niacin (CHEBI:15940). CL: neuron (CL:0000540), cardiomyocyte (CL:0000746), keratinocyte (CL:0000312).

7. Anatomical Structures Affected

  • Organ level (primary): brain and cerebellum (UBERON:0000955 brain; UBERON:0002037 cerebellum), cerebral white matter (UBERON:0002316), spinal cord (UBERON:0002240; myelopathy reported in the NAXE sister disorder). Skin (UBERON:0002097), predominantly flexural surfaces. Heart (UBERON:0000948) and skeletal muscle (UBERON:0001134) in cardiac/myopathic presentations.
  • Body systems: central and peripheral nervous system, integumentary system, cardiovascular system, musculoskeletal system; respiratory insufficiency during crisis.
  • Tissue/cell level: neurons and glia (white-matter/leukoencephalopathy → oligodendrocyte-supported myelin); cardiomyocytes (with interstitial fibrosis); keratinocytes/epidermis (necrotic skin lesions).
  • Subcellular level: mitochondrion (GO:0005739) and cytosol (GO:0005829) — the two compartments corresponding to the mitochondrial and cytosolic NAXD isoforms; this compartmentalization directly maps to phenotype (Section 4).
  • Lateralization: central lesions are typically bilateral/symmetric (edema, leukoencephalopathy); skin lesions are bilateral and flexural.

8. Temporal Development

  • Onset: typically congenital-to-early-childhood, most within the first 1–3 years; median age of onset ~1.16 years in the combined NAXD/NAXE cohort (PMID: 39887790). Adult onset is possible: a 32-year-old presented after mild head trauma (PMID: 36834994).
  • Onset pattern: characteristically (sub)acute decompensation superimposed on a previously well or mildly affected child, precipitated by a trigger.
  • Progression: episodic-on-progressive — stepwise deterioration with each febrile/stress event, often rapidly progressive to coma and death without intervention. Between crises, patients may be relatively stable.
  • Disease course / duration: frequently fatal in early childhood; survivors have chronic, lifelong neurological sequelae.
  • Remission: no spontaneous cure; treatment-induced stabilization/improvement is reported with niacin/nicotinamide and trigger control.
  • Critical periods / window of opportunity: the peri-febrile window is both the period of maximal vulnerability and the key intervention window — prompt antipyresis, supportive care and NAD-precursor supplementation.

9. Inheritance and Population

  • Inheritance: autosomal recessive (biallelic NAXD variants). Both parents are asymptomatic carriers.
  • Penetrance/expressivity: appears high penetrance in the biallelic state but variable expressivity — modulated by which isoform is affected (Section 4) and by exposure to triggers; some homozygotes present atypically without fever or skin lesions (PMID: 36158054).
  • Epidemiology: ultra-rare; only case reports and small series (tens of patients worldwide across NAXD and NAXE). No reliable prevalence/incidence estimate exists; Orphanet lists it among ultra-rare metabolic disorders. A literature review compiled 45 NAXD/NAXE patients with 31 pathogenic/likely-pathogenic mutations (PMID: 39887790).
  • Founder effects / consanguinity: homozygous variants in reported patients suggest a role for consanguinity in some families; no defined founder allele has been reported.
  • Carrier frequency: not formally established; consistent with rarity, gnomAD shows very low pathogenic-allele frequencies.
  • Population demographics / geography: cases reported across diverse populations (Europe, Middle East, Asia including China; a Chinese cardiomyopathy case is noted as "one of the few" in China; PMID: 39822994). No strong sex bias is established (both sexes affected). Age distribution skews to infancy/early childhood.

10. Diagnostics

Laboratory tests / biomarkers. - Elevated CSF and/or serum lactate is a key, reproducible biochemical clue (mild-to-marked; present in the NAXE sister disorder in all affected individuals: "Lactate was elevated in cerebrospinal fluid of all affected individuals"; PMID: 27616477). Basal metabolic tests may otherwise be near-normal (PMID: 36158054). - Definitive biomarker: markedly elevated damaged cofactors S-NADHX, R-NADHX and cyclic-NADHX in patient fibroblasts (research/specialized assay), abrogated by wild-type NAXD rescue (PMID: 30576410). - LOINC: lactate CSF (LOINC 2519-7), lactate plasma/serum (LOINC 2524-7 / 32693-4).

Imaging. Brain MRI showing cerebral/cerebellar edema, leukoencephalopathy, and (in progression) global brain atrophy is central to recognizing the acute encephalopathy.

Cardiac work-up. Echocardiography/cardiac MRI and endomyocardial evaluation may reveal metabolic cardiomyopathy with interstitial fibrosis in the absence of coronary disease or hypertension (PMID: 39822994).

Genetic testing (diagnostic gold standard). Diagnosis is molecular. Whole-exome or whole-genome sequencing identifies biallelic NAXD variants (the discovery and most subsequent diagnoses used WES/WGS; PMID: 30576410; PMID: 34161859). Targeted single-gene/panel testing (mitochondrial/leukodystrophy/metabolic-encephalopathy panels including NAXD and NAXE) is appropriate when the phenotype is suggestive. Segregation confirms biallelic status. Functional confirmation (fibroblast NAD(P)HX measurement or recombinant enzyme assay) can resolve VUS.

Clinical criteria / differential diagnosis. No formal consensus criteria exist; diagnosis rests on the triad of fever-triggered neuroregression + suggestive MRI (edema/leukoencephalopathy) + elevated lactate, confirmed genetically. Because it can be mistaken for a primary mitochondrial disease (patients have been treated with a "mitochondrial cocktail"; PMID: 36158054), key differentials include Leigh syndrome and other mitochondrial encephalopathies, other leukodystrophies, biotin-thiamine-responsive basal ganglia disease, and — with skin involvement — nutritional/genetic niacin-deficiency states (pellagra-like). The sister disorder NAXE deficiency (PEBEL1) is the closest differential and is distinguished by gene.

Screening. Not part of routine newborn screening. Cascade carrier testing of relatives and prenatal/preimplantation genetic testing are available once the familial variants are known.

11. Outcome / Prognosis

  • Mortality: high — "The mortality rate was 78%, with survivors experiencing varying degrees of neurological sequelae" (PMID: 39887790). In the NAXE sister disorder, the course was rapidly progressive to coma, global brain atrophy and death.
  • Morbidity/disability: survivors typically have significant neurological disability (developmental regression, spasticity, epilepsy, motor impairment).
  • Prognostic factors: which isoform is affected (mitochondrial-only vs whole-cell) shapes organ involvement and course; frequency/severity of triggering events; and early institution of niacin/nicotinamide and trigger control, which improve skin lesions and survival. Niacin response, however, is not universal: one PEBEL1 patient deteriorated to a fatal outcome despite the highest reported niacin dose (PMID: 38974613).
  • Complications: status epilepticus, respiratory failure, cardiac failure, secondary infections, and sequelae of brain injury.

12. Treatment

There is no curative therapy; management is metabolic bypass + aggressive trigger control + supportive care.

Pharmacotherapy / metabolic bypass. - Niacin / nicotinamide (vitamin B3) — the principal disease-modifying agent. By feeding NAD de novo/salvage synthesis it replenishes the depleted NAD(P) pool: "Niacin/nicotinamide supplementation resulted in improvements in skin lesions and survival rates" (PMID: 39887790). The rationale is explicit in the NAXE literature: "NAD or nicotinic acid (vitamin B3) supplementation might have therapeutic implications for this fatal disorder" (PMID: 27616477). A systematic review of 7 PEBEL1/PEBEL2 patients found most improved or stabilized on niacin, though one deteriorated fatally (PMID: 38974613). NCIT: niacin (NCIT:C574), nicotinamide (NCIT:C577). - Adverse-event management: niacin-related urticaria has been managed off-label with a COX-2 inhibitor (PMID: 38974613).

Acute supportive care. Prompt antipyresis and treatment of the precipitating infection, intensive supportive/neurocritical care during crises, seizure management, and cardiac support as needed. Empirical mitochondrial "cocktail" has been used but is not specifically corrective (PMID: 36158054).

Advanced / experimental therapeutics. No approved gene, cell, or RNA therapy exists. Wild-type NAXD lentiviral rescue corrects the biochemical defect in patient fibroblasts (proof of concept for gene replacement; PMID: 30576410). NAD-precursor strategies (nicotinamide riboside, nicotinic acid) are of mechanistic interest.

Personalized approach. Genotype (isoform affected) and trigger history should guide monitoring (e.g., cardiac surveillance for mitochondrial-isoform variants) and preventive planning.

13. Prevention

  • Primary prevention: for at-risk families, genetic counseling, carrier testing, and reproductive options (prenatal/PGT) prevent recurrence. There is no population-level primary prevention (not vaccine-preventable; disease is genetic).
  • Secondary prevention (trigger mitigation): in known-affected individuals, prompt and aggressive control of fever/infection, vigilance around immunizations and physical stress, and prophylactic niacin/nicotinamide aim to prevent decompensation. Caution and close monitoring are warranted around immunization given a reported post-vaccination decompensation (PMID: 38214124).
  • Tertiary prevention: rehabilitation, epilepsy management, cardiac and respiratory support to limit complications in survivors.
  • Counseling: autosomal-recessive recurrence risk is 25% per pregnancy for carrier couples; cascade testing of relatives is recommended.
  • Screening: cascade carrier screening; prenatal diagnosis where familial variants are known. Not currently in newborn-screening panels.

14. Other Species / Natural Disease

  • Evolutionary conservation: the NAD(P)HX repair system is ancient and highly conserved. NAXD/NAXE orthologs function in plants (Arabidopsis thaliana, Zea mays), E. coli, and vertebrates: "Arabidopsis thaliana and Zea mays NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE), two enzymes that are involved in repair of chemically damaged NAD(P)H cofactors" (PMID: 36710015).
  • Orthologs / taxonomy (NCBI Taxon): human NAXD (Gene 55739); zebrafish naxd (used for CRISPR models; Danio rerio, taxon 7955); plant orthologs in A. thaliana (taxon 3702) and Z. mays (taxon 4577); bacterial yjeF-family in E. coli.
  • Natural disease in other species: no spontaneously occurring NAXD-deficiency disease has been catalogued in companion animals/wildlife (no OMIA entry noted); relevance to date is via engineered models.
  • Zoonotic potential: not applicable (genetic, non-transmissible).

15. Model Organisms

Model Type Key features / recapitulation Reference
Zebrafish naxd (and naxe) CRISPR/Cas9 knockouts Vertebrate, in vivo Both accumulate NADHX; naxd line shows distinctive features and immune-system perturbations in early development PMID: 41621837
Human HAP1 NAXD knockout Cellular, in vitro Growth impairment specifically in galactose vs glucose; metabolomics reveals de novo serine synthesis inhibition; models the metabolic lesion PMID: 39789421
Patient fibroblasts Primary human cells Elevated S-/R-/cyclic-NADHX; corrected by WT NAXD rescue; mitochondrial-stress sensitivity PMID: 30576410
Patient iPSC line BCHNDi001-A iPSC Derived from PEBEL2 fibroblasts (c.101_102delTA; c.318C>G); enables differentiation into affected lineages PMID: 38387170
Recombinant NAXD/NAXE (E. coli; plant systems) In vitro enzymology Purified enzymes for kinetic/thermostability assays (demonstrated thermolability of mutants) PMID: 30576410; PMID: 36710015

Zebrafish CRISPR evidence: "we generated zebrafish lines deficient in naxe or naxd using CRISPR/Cas9 technology. While both models accumulated NADHX, only naxd…" (PMID: 41621837). iPSC evidence: "we generated an induced pluripotent stem cell (iPSC) line from the dermal fibroblasts (HDFs) of a PEBEL2 patient who carried biallelic mutations, c.101_102delTA(p.Thr35Phefs63) and c.318C > G (p.Ile160Met) in NAXD"* (PMID: 38387170).

Model applications & limitations: these systems recapitulate the core NADHX accumulation and metabolic lesion and enable therapeutic testing; limitations include incomplete recapitulation of the full human multisystem/fever-triggered clinical phenotype and species-specific differences. Resources: ZFIN (zebrafish), Cellosaurus (HAP1, iPSC lines).

Mechanistic Model / Interpretation

 Biallelic LoF NAXD (recessive; gnomAD pLI≈0)
│  loss of ATP-dependent NAD(P)HX dehydratase (EC 4.2.1.93)
▼
 Failure of NAD(P)HX repair
   ├── ↑ S-NADHX / R-NADHX / cyclic-NADHX  (toxic, inhibit dehydrogenases)
   └── ↓ functional NAD(P)H  (redox/energy pool depleted)
│
   [ TRIGGER: fever / infection / immunization / trauma ]
│  ↑ non-enzymatic NAD(P)H→NAD(P)HX  +  denatures thermolabile mutant enzyme
▼
 Acute unrepaired NAD(P)HX surge  →  metabolic decompensation
├──► Mitochondrial dysfunction  ─┐
└──► ↓ de novo serine synthesis ─┤ combined energetic/biosynthetic failure
                                  ▼
Injury to high-demand tissues:
• Brain/cerebellum/white matter → encephalopathy, edema, leukoencephalopathy, seizures, ↑lactate
• Heart/muscle → cardiomyopathy (interstitial fibrosis), myopathy   [esp. mito-isoform variants]
• Skin (flexural) → erosive/necrotic plaques   [whole-cell deficiency]
▼
~78% mortality  ── niacin/nicotinamide (↑NAD synthesis) + trigger control → improved skin & survival

Upstream vs downstream: the NAXD mutation and cofactor-repair failure are upstream; mitochondrial dysfunction and serine-synthesis inhibition are parallel downstream effectors; tissue injury and clinical crisis are terminal. The fever/thermolability node is the key modifiable amplifier converting a compensated enzymopathy into acute disease, and the niacin bypass is the key therapeutic lever.

Evidence Base

PMID Title (abbrev.) Contribution
30576410 NAXD deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses Founding disease description; recessive WES/WGS diagnosis; elevated S-/R-/cyclic-NADHX; thermolabile mutant enzyme (↓Vmax, ↑KM); mitochondrial-stress sensitivity; WT rescue
34161859 NAXD deficiency due to a novel biallelic missense variant + review Disease name/OMIM #618321; recessive basis; novel c.301G>A p.(Ala101Thr)
35866541 Clinical/biochemical distinctions for NAXD or NAXE deficiency Isoform architecture (mito propeptide exon 1 vs cytosolic exon 2) → genotype–phenotype correlation
39789421 Failure to repair NAD(P)H blocks de novo serine synthesis HAP1 KO galactose sensitivity; serine-synthesis inhibition mechanism
39887790 Cutaneous manifestations of NAXD/NAXE deficiency 45-patient review; ~78% mortality; flexural necrotic skin phenotype; niacin improves skin/survival
35637064 NAXE deficiency amenable for metabolic correction Stress-triggered decompensation mechanism (NAD(P)H depletion)
27616477 NAXE mutations cause a lethal neurometabolic disorder Sister disorder (PEBEL1): febrile-triggered ataxia/edema/skin; elevated CSF lactate; niacin rationale
41621837 Zebrafish models of NADHX repair deficiency naxd/naxe CRISPR models; NADHX accumulation; immune perturbation
38387170 iPSC line BCHNDi001-A from PEBEL2 patient Patient-derived iPSC with defined biallelic variants
39822994 Metabolic cardiomyopathy from compound-het NAXD Cardiac phenotype with interstitial fibrosis
36834994 Severe NAXD syndrome in adulthood after mild head trauma Adult onset; non-febrile physical-stress trigger
36158054 A case with NAXD deficiency (novel c.247G>A) Phenotypic diversity; atypical case without fever/skin lesions; mild lactate elevation
38214124 Progressive encephalopathy after 4-month immunizations Immunization as trigger; skin findings without fever; VUS c.362C>T
38974613 Transient response to high-dose niacin (NAXE) Niacin efficacy but not universal (one fatal outcome despite highest dose)
36710015 Systems for plant protein expression Evolutionary conservation of NAXD/NAXE (Arabidopsis, maize)

Evidence source types: human clinical (case reports/series, literature reviews), in vitro (patient fibroblasts, HAP1 KO, recombinant enzyme, iPSC), model organism (zebrafish), and computational/genomic constraint (gnomAD).

Limitations and Knowledge Gaps

  • Ultra-rare, no cohort epidemiology. Prevalence/incidence, carrier frequency, sex ratio, and penetrance estimates are unavailable; all clinical data come from small series prone to ascertainment/publication bias toward severe cases (mortality may be overestimated).
  • Treatment evidence is anecdotal. Niacin/nicotinamide benefit is based on case reports and one small systematic review; there are no randomized trials, optimal dosing is undefined, and at least one patient deteriorated despite maximal therapy (PMID: 38974613).
  • Mechanistic gaps. The relative contributions of mitochondrial dysfunction versus serine-synthesis inhibition to specific organ phenotypes are not resolved; why skin and cerebellum are especially vulnerable is unexplained; the immune-perturbation finding is model-derived and needs human validation.
  • Genotype–phenotype nuance. The isoform rule explains broad patterns but individual variability (atypical fever-negative cases) indicates unidentified modifiers.
  • No natural animal disease / limited long-term outcome data.

Proposed Follow-up Experiments / Actions

  1. Establish an international patient registry to define natural history, prevalence, penetrance, sex ratio, and standardized outcomes; harmonize trigger and treatment data.
  2. Prospective, dose-finding evaluation of NAD precursors (niacin, nicotinamide, nicotinamide riboside) with biochemical endpoints (NADHX/NAD(P)H, lactate) — ideally a basket trial spanning PEBEL1/PEBEL2.
  3. iPSC-derived organoid modeling (neuronal, cardiac, keratinocyte) from BCHNDi001-A and new lines to test whether serine supplementation and NAD precursors rescue tissue-specific phenotypes (PMID: 38387170; PMID: 39789421).
  4. Thermal-stress assays across the variant panel to build a genotype→thermolability→clinical-severity map, informing prognosis and trigger-avoidance counseling (PMID: 30576410).
  5. Gene-replacement proof-of-concept in vivo (zebrafish naxd and/or AAV-NAXD in mammalian models), building on fibroblast lentiviral rescue.
  6. Dissect the immune-perturbation phenotype from zebrafish in human systems to test whether inflammation independently amplifies decompensation (PMID: 41621837).
  7. Develop a clinical NAD(P)HX/serine metabolite biomarker assay for rapid diagnosis and treatment monitoring, and evaluate inclusion of NAXD/NAXE in mitochondrial/leukodystrophy gene panels and consideration for newborn screening pilots.

Report compiled from 9 confirmed findings across 18 reviewed papers. All quoted material is verbatim from the cited PubMed abstracts.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 15
Resolved 15
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 15
On topic 14
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 44
Resolved 42
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 14
Terms named correctly 10
Terms named as a different term 1
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0034121 (2 mentions) - the report calls it "MONDO"; MONDO calls it NAD(P)HX dehydratase deficiency

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0005739 (2 mentions) - the report calls it "mitochondrion, CC", "mitochondrion", "Subcellular level: mitochondrion"; GO calls it mitochondrion
  • GO:0005829 (2 mentions) - the report calls it "cytosol, CC", "cytosol"; GO calls it cytosol
  • UBERON:0002097 (1 mention) - the report calls it "Skin"; UBERON calls it skin of body, and lists "skin" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0005739 - called "mitochondrion, CC", "mitochondrion", "Subcellular level: mitochondrion"
  • GO:0005829 - called "cytosol, CC", "cytosol"