Long-term follow-up of an attenuated presentation of NAXE-related disease, a potentially actionable neurometabolic disease: a case report.

Background: Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy (PEBEL-1) is an autosomal recessive disorder whereby a fluctuating clinical course is exacerbated by febrile illnesses. Pathogenic NAD(P)HX epimerase (NAXE) gene mutations underpin this disorder. This mutation damages the metabolite repair system involved in regenerating crucial redox carriers. Longer survival has rarely been reported in this potentially actionable entity. Objectives: This case study aims to report a milder phenotype of a patient with NAXE gene mutation and his longitudinal follow-up of more than 20 years. Case report: A 24-year-old man first became symptomatic in infancy with frequent initial neurological decompensations in the setting of infections with subsequent clinical improvement followed by stability with residual cerebellar dysfunction. Clinical features noted over the years include chronic ataxia, nystagmus, ptosis, mild spasticity of lower limbs, and neuropsychiatric symptoms. Cerebellar and spinal cord atrophy were noted in cranial and spinal MR imaging. Biallelic homozygous variants in the NAXE gene (c.733 A>C) were identified on whole exome sequencing. Symptom management included the initiation of a mitochondrial cocktail with carnitine, coenzyme Q, and thiamine. Subsequently, niacin (Vitamin B3), which is involved in the cellular biosynthesis of NAD+, was added, given its potentially beneficial therapeutic impact. Conclusion: A missense homozygous variant in the NAXE gene is described in this patient with a milder clinical phenotype of the disease. Supplementation with niacin in addition to a mitochondrial cocktail presents a potential supportive therapeutic option to reduce disease progression.

De novo mutation of NAXE (APOAIBP)-related early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1: A case report.

BACKGROUND: Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is a rare autosomal recessive severe neurometabolic disease. The aim of this study was to investigate the clinical characteristics and genetic pathogenicity of PEBEL1 caused by rare NAXE (or APOA1BP)-related defects. CASE SUMMARY: The patient was a girl aged 2 years and 10 mo. She was hospitalized due to walking disorder for > 40 d. The clinical manifestations were ataxia, motor function regression, hypotonia, and eyelid ptosis. Within 1 mo of hospitalization, she developed sigh breathing, respiratory failure, cerebellar edema and brain hernia, and finally she died. Changes were found in cranial imaging, including cerebellar edema accompanied by symmetrical myelopathy. Through whole exome sequencing, we detected NAXE compound heterozygous variation (NM 144772.3) c.733A>C (p. Lys245Gln, dbSNP: rs770023429) and novel variation c.370G>T (p.Gly124Cys) in the germline gene. The clinical features and core phenotypes of this case were consistent with 18 previously reported cases of PEBEL1. CONCLUSION: This is the first case of NAXE-related PEBEL1 with severe clinical phenotype in Mainland China. The p.Gly124Cys mutation discovered in this case has enriched the pathogenic variation spectrum of NAXE.

Identification of a novel homozygous mutation in NAXE gene associated with early-onset progressive encephalopathy by whole-exome sequencing: in silico protein structure characterization, molecular docking, and dynamic simulation.

Progressive encephalopathy with brain edema and/or leukoencephalopathy, PEBEL1, is a severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration associated with a febrile illness. PEBEL1 is a lethal encephalopathy caused by NAXE gene mutations. Here we report a 6-month-old boy with mitochondrial encephalomyopathy from a consanguineous family. Molecular analysis was performed using whole-exome sequencing followed by segregation analysis. In addition, in silico prediction tools and molecular dynamic approaches were used to predict the structural effect of the mutation. Furthermore, molecular docking of the substrate NADP in both wild-type and mutated NAXE protein was carried out. Molecular analysis revealed the presence of the novel homozygous mutation c.641 T > A (p. Ile214Asn) in the NAXE gene, located at the NAD (P)H hydrate epimerase domain. In addition, bioinformatics analyses and molecular dynamics revealed that p. Ile214Asn mutation could affect the structure, stability, and compactness of the NAXE protein. Moreover, the result of the molecular docking showed that the p. Ile214Asn mutation leads to conformational changes in the catalytic cavity, thus modifying interaction with the substrate and restricting its access. We also compared the phenotype of our patient with those of previously reported cases with PEBEL syndrome. All bioinformatics findings provide evidence that the NAXE variant Asn214 disrupts NAXE protein functionality leading to an insufficient NAD (P)HX repair system and the development of clinical features of PEBEL1 syndrome in our patient. To our knowledge, our case is the 21st case of PEBEL1 patient worldwide and the first case in North Africa.