Researchers have strengthened the case for early treatment with high-dose niacin, concluding that NAXD deficiency should now be considered a treatable disease.
Children with a rare genetic disorder that can cause rapid and fatal deterioration after relatively minor illnesses may have a new treatment option, with researchers reporting encouraging outcomes from early treatment with high-dose vitamin B3.
The study, led by the Murdoch Children’s Research Institute (MCRI) and Luxembourg Centre for Systems Biomedicine, identified nine previously unreported cases of NAXD deficiency, substantially broadening the known clinical spectrum of the disease.
The findings suggest the disorder may present not only with the neurological deterioration typically associated with NAXD deficiency, but also with severe cardiac complications and, in one case, neurological deterioration occurring before birth.
NAXD deficiency, also known as progressive early-onset encephalopathy with brain oedema and/or leukoencephalopathy-2 (PEBEL2), is caused by pathogenic variants in both copies of the NAXD gene.
This gene encodes an enzyme involved in repairing damaged forms of NADH and NADPH, metabolic cofactors that are essential for cellular energy production. Under conditions of physiological stress, including fever and infection, these cofactors can become chemically altered and interfere with normal cellular metabolism.
NAXD normally helps restore these damaged molecules to their functional forms. When the enzyme is deficient, the resulting accumulation of damaged cofactors can disrupt energy-producing pathways, with tissues such as the brain and heart appearing particularly vulnerable.
The condition was first identified in 2019 and is exceptionally rare. Many affected children are initially well before experiencing rapid neurological deterioration following a febrile illness, infection or, in some reported cases, injury.
The nine children with pathogenic NAXD variants were referred to MCRI for further investigation. Four had the more familiar neurological presentation, developing features such as seizures and developmental delay following an illness.
However, four others had significant cardiac involvement, and one pregnancy was complicated by severe neurological deterioration in utero and resulted in stillbirth.
Four patients were provided high-dose niacin, in the hopes that replenishing the cellular NAD pool would support energy metabolism despite their impaired NAXD activity.
All four survived subsequent periods of illness or infection that might otherwise have triggered severe deterioration or death.
Two of the children developed their disease following covid-19 infection, highlighting the potential importance of infection as a trigger and the need for careful prevention and management of illness in affected children.
The findings build on previous reports of NAXD deficiency patients treated with niacin. Across the cases reported to date, nine children with PEBEL2 have received niacin, with all but one alive at the time of reporting.
While the treatment evidence remains limited and the optimal dose, duration, long-term effectiveness, and safety of niacin have yet to be established, Dr Nicole Van Bergen, senior research fellow at MCRI, said the findings could change the outlook for children living with NAXD deficiency by highlighting the importance of early recognition and intervention.
“This disorder is often devastating, with children deteriorating rapidly after even mild illness,” she said. “Common infections and minor injuries can end up in life-threatening complications.
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“But seeing children survive illnesses after treatment with high-dose vitamin B3 offers new hope for affected children and their families. While further research into the long-term use of vitamin B3 is needed, the condition should now be considered as a treatable disease.
“Our team is also testing medicines that are proven to increase cellular energy levels to see if they can also safely and effectively treat NAXD. This approach could provide a lower-cost alternative to developing a new drug from scratch.”
One child who began niacin relatively late in the course of disease after deterioration triggered by a head injury subsequently died, while a patient with the related disorder PEBEL1 did not respond to escalating doses, suggesting that treatment may not be universally effective.
Previous animal studies have similarly suggested that the benefits of niacin may diminish over time and that excessive supplementation could potentially lead to further accumulation of damaged NADHX metabolites.
Nevertheless, the researchers argued that the overall evidence now supports considering PEBEL2 a treatable mitochondrial disease, particularly when treatment is initiated early.
Along with the treatment findings, the researchers also noted that the location and nature of the genetic variant may influence how the disease presents.
Variants affecting the mitochondrial targeting sequence of the NAXD protein were associated with cardiac and muscular disease, while other variants were linked to the more typical neurological presentation.
Laboratory studies provided further evidence of the biological consequences of the different variants, including altered protein stability, enzyme activity, and accumulation of damaged NAD(P)HX metabolites.
The researchers suggested that these findings could help clinicians recognise NAXD deficiency in children whose presentation does not fit the previously recognised pattern, explaining that NAXD deficiency should be considered in a broader range of diagnostic investigations.
“There is significant value in NAXD being considered for inclusion in other gene panels (e.g., cardiac, fetal anomalies, adult-onset epilepsy) to facilitate more rapid diagnosis and potentially preventing a fatal disease outcome,” the authors concluded.
The newly identified cardiac cases may be particularly important for diagnosis, given that NAXD deficiency has historically been associated primarily with neurological disease.
