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

BackgroundEarly-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.ObjectivesThis 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 reportA 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.ConclusionA 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

Methylmalonic aciduria as a biochemical marker for mitochondrial DNA depletion syndrome in patients with developmental delay and movement disorders: a case series

BackgroundMitochondrial DNA (mtDNA) depletion syndromes (MDDS) are genetically and clinically variable disorders resulting from a reduction in mtDNA content in the cells, tissues, and organ systems, leading to symptoms related to energy deficits. Deficiency of the mitochondrial succinyl-CoA ligase/synthetase enzyme secondary to pathogenic variations in the SUCLG1 and SUCLA2 genes is a subtype of MDDS that presents with neurological manifestations and a specific biochemical profile.MethodsThis cross-sectional series describes five patients with MDDS secondary to pathogenic variations in the SUCLG1 and SUCLA2 genes from two tertiary care centers in Canada and India. Clinical data concerning the course, investigations, and outcome were gathered through chart reviews.ResultsAll subjects presented in early infancy with neurological manifestations, including movement disorder, psychomotor regression, developmental delay, hearing loss, behavioral issues, or a combination thereof. Elevated methylmalonic acid metabolites, an abnormal acylcarnitine profile, and lactic acidemia were noted in the biochemical profile of each patient (n = 5/5, 100%). Molecular genetic testing disclosed the presence of pathogenic homozygous mutations in four subjects and compound heterozygosity in one subject.ConclusionMDDS associated with SUCLG1 and SUCLA2 genes can be detected biochemically by the presence of methylmalonic aciduria besides the elevation of lactate, C3, C4DC, and C5-OH acylcarnitine. Conducting metabolic workups including MMA and acylcarnitine profiles in patients with heterogeneity of clinical symptoms associated with the presence of this biochemical marker may potentially reduce the time to diagnosis and management

Data_Sheet_1_Long-term follow-up of an attenuated presentation of NAXE-related disease, a potentially actionable neurometabolic disease: a case report.docx

BackgroundEarly-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.ObjectivesThis 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 reportA 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.ConclusionA 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.</p

Data_Sheet_2_Long-term follow-up of an attenuated presentation of NAXE-related disease, a potentially actionable neurometabolic disease: a case report.PDF

BackgroundEarly-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.ObjectivesThis 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 reportA 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.ConclusionA 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.</p