Niacin therapy improves outcome and normalizes metabolic abnormalities in an NAXD-deficient patient

Manor, Joshua; Calame, Daniel G.; Gijavanekar, Charul; Tran, Alyssa A.; Fatih, Jawid M.; Lalani, Seema R.; Mizerik, Elizabeth; Parnes, Mered; Mehta, Vidya; Adesina, Adekunle; Lupski, James R.; Scaglia, Fernando; Elsea, Sarah H.

doi:10.1093/brain/awac065

Cited by 8 publications

(33 citation statements)

References 10 publications

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“…Now, it is exciting to see potential treatments being tested in patients and providing a degree of protection against severe clinical outcomes. The outcomes reported so far for the two treated NAXD deficiency patients 13,14 and two treated NAXE deficiency cases 15,20 support the use of niacin‐based therapies for stabilising the clinical progression and furnish some evidence that these disorders may be treatable. However, more specific targeted therapies could be of even greater benefit, particularly if applied early in the clinical course, and so a systematic approach to identification of novel therapies is of utmost priority.…”

Section: Current Therapeutic Approaches For Naxd Deficiencymentioning

confidence: 74%

“…A patient with NAXE deficiency was treated with Coenzyme Q10 and niacin (40–80 mg/d) and showed improved clinical outcomes after treatment including dramatic improvements in severe spasticity, and continuous motor and cognitive improvement 20 . Another patient with NAXE deficiency received vitamin B complex (thiamine 60 mg, riboflavin 3 mg, nicotinamide 30 mg and pyridoxine 3 mg per day) and coenzyme Q10, and this patient showed progressive neurological improvement, recovery of muscle power and at the time of the report, remained alive 15 …”

Section: Current Therapeutic Approaches For Naxd Deficiencymentioning

confidence: 98%

“… 20 Another patient with NAXE deficiency received vitamin B complex (thiamine 60 mg, riboflavin 3 mg, nicotinamide 30 mg and pyridoxine 3 mg per day) and coenzyme Q10, and this patient showed progressive neurological improvement, recovery of muscle power and at the time of the report, remained alive. 15 …”

Section: Current Therapeutic Approaches For Naxd D...mentioning

confidence: 99%

“…Many fundamental questions remain regarding the biology of NAXD and NAXE deficiency and a better understanding of their consequences will be essential for the development of more efficient and targeted therapies. Despite the early success of the preliminary niacin‐based n‐of‐1 interventions for NAXD and NAXE deficiency cases, 13 , 14 , 15 , 20 the precise pathways critically impacted during crises and disease progression remain to be identified. It would therefore be of great interest to probe the molecular and cellular consequences of both NAXD and NAXE deficiency in appropriate disease models.…”

Section: The Future Of Targeted Therapeutic Approaches For ...mentioning

confidence: 99%

“…Children with NAXE deficiency have an almost identical, nearly always fatal neurodegenerative course (OMIM # 617186, PEBEL1), also generally triggered after mild fever, respiratory or urinary tract infection or other illnesses including gastroenteritis or tonsilitis. 15 , 16 , 17 , 18 , 19 , 20 , 21 NAXD and NAXE are critical metabolite repair enzymes, and physical or heat stress can damage the central metabolite NAD(P)H to form a toxic compound NAD(P)HX, and it is likely that the fever or illness‐induced stress in children triggers a rapid accumulation of NAD(P)HX which cannot be effectively cleared due to a lack of NAXD (or NAXE) enzymes. Additionally, because the brain is one of the most energy‐demanding organs in the body, failure of key metabolite repair enzymes involved in energy production will have devastating consequences on brain function.…”

Section: Introductionmentioning

confidence: 99%

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Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency

Bergen

Walvekar

Patraskaki

et al. 2022

J of Inher Metab Disea

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The central cofactors NAD(P)H are prone to damage by hydration, resulting in formation of redox-inactive derivatives designated NAD(P)HX. The highly conserved enzymes NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE) function to repair intracellular NAD(P)HX. 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. As more patients are identified, distinct clinical features are emerging depending on the location of the pathogenic variant. In this review, we carefully catalogued the clinical features of all published NAXD deficiency patients and found distinct patterns in clinical presentations depending on which subcellular compartment is affected by the enzymatic deficiency. Exon 1 of NAXD contains a mitochondrial propeptide, and a unique cytosolic isoform is initiated from an alternative start codon in exon 2. NAXD deficiency patients with variants that affect both the cytosolic and mitochondrial isoforms present with neurological defects, seizures and skin lesions. 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. 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.A deeper understanding of the clinical phenotype may facilitate rapid identification of new cases and allow earlier therapeutic intervention. Niacin-based therapies are promising, but advances in disease modelling for both NAXD and NAXE deficiency may identify more specific compounds as targeted treatments. In this review, we found distinct patterns in the clinical presentations of NAXD deficiency patients based on the location of the pathogenic variant, Nicole J. Van Bergen and Adhish S. Walvekar contributed equally to this work and should be considered joint first authors. Carole L. Linster and John Christodoulou contributed equally to this work and should be considered joint last authors.

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Section: Current Therapeutic Approaches For Naxd Deficiencymentioning

confidence: 74%

Section: Current Therapeutic Approaches For Naxd Deficiencymentioning

confidence: 98%

Section: Current Therapeutic Approaches For Naxd D...mentioning

confidence: 99%

Section: The Future Of Targeted Therapeutic Approaches For ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency

Bergen

Walvekar

Patraskaki

et al. 2022

J of Inher Metab Disea

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Progressive encephalopathy after routine 4‐month immunizations in a patient with NAXD genetic variant

Cepress,

Grund,

Leng

et al. 2024

American J of Med Genetics Pt A

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Metabolic pathways are known to generate byproducts—some of which have no clear metabolic function and some of which are toxic. Nicotinamide adenine dinucleotide phosphate hydrate (NAD(P)HX) is a toxic metabolite that is produced by stressors such as a fever, infection, or physical stress. Nicotinamide adenine dinucleotide phosphate hydrate dehydratase (NAXD) and nicotinamide adenine dinucleotide phosphate hydrate epimerase (NAXE) are part of the nicotinamide repair system that function to break down this toxic metabolite. Deficiency of NAXD and NAXE interrupts the critical intracellular repair of NAD(P)HX and allows for its accumulation. Clinically, deficiency of NAXE manifests as progressive, early onset encephalopathy with brain edema and/or leukoencephalopathy (PEBEL) 1, while deficiency of NAXD manifests as PEBEL2. 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.

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Transient response to high‐dose niacin therapy in a patient with NAXE deficiency

Al‐Amrani,

Al‐Thihli,

Al‐Ajmi

et al. 2024

JIMD Reports

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BackgroundNAXE‐encephalopathy or early‐onset progressive encephalopathy with brain edema and/or leukoencephalopathy‐1 (PEBEL‐1) and NAXD‐encephalopathy (PEBEL‐2) have been described recently as mitochondrial disorders causing psychomotor regression, hypotonia, ataxia, quadriparesis, ophthalmoparesis, respiratory insufficiency, encephalopathy, and seizures with the onset being usually within the first three years of life. It usually leads to rapid disease progression and death in early childhood. Anecdotal reports suggest that niacin, through its role in nicotinamide adenine dinucleotinde (NAD) de novo synthesis, corrects biochemical derangement, and slows down disease progression. Reports so far have supported this observation.MethodsWe describe a patient with a confirmed PEBEL‐1 diagnosis and report his clinical response to niacin therapy. Moreover, we systematically searched the literature for PEBEL‐1 and PEBEL‐2 patients treated with niacin and details about response to treatment and clinical data were reviewed. Furthermore, we are describing off‐label use of a COX2 inhibitor to treat niacin‐related urticaria in NAXE‐encephalopathy.ResultsSo far, seven patients with PEBEL‐1 and PEBEL‐2 treated with niacin were reported, and all patients showed a good response for therapy or stabilization of symptoms. We report a patient exhibiting PEBEL‐1 with an unfavorable outcome despite showing initial stabilization and receiving the highest dose of niacin reported to date. Niacin therapy failed to halt disease progression or attain stabilization of the disease in this patient.ConclusionDespite 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.

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Niacin therapy improves outcome and normalizes metabolic abnormalities in an NAXD-deficient patient

Cited by 8 publications

References 10 publications

Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency

Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency

Progressive encephalopathy after routine 4‐month immunizations in a patient with NAXD genetic variant

Transient response to high‐dose niacin therapy in a patient with NAXE deficiency

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