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

Table_1_Biallelic pathogenic variants in POLR3D alter tRNA transcription and cause a hypomyelinating leukodystrophy: A case report.xlsx

RNA polymerase III-related leukodystrophy (POLR3-related leukodystrophy) is a rare, genetically determined hypomyelinating disease arising from biallelic pathogenic variants in genes encoding subunits of RNA polymerase III (Pol III). Here, we describe the first reported case of POLR3-related leukodystrophy caused by biallelic pathogenic variants in POLR3D, encoding the RPC4 subunit of Pol III. The individual, a female, demonstrated delays in walking and expressive and receptive language as a child and later cognitively plateaued. Additional neurological features included cerebellar signs (e.g., dysarthria, ataxia, and intention tremor) and dysphagia, while non-neurological features included hypodontia, hypogonadotropic hypogonadism, and dysmorphic facial features. Her MRI was notable for diffuse hypomyelination with myelin preservation of early myelinating structures, characteristic of POLR3-related leukodystrophy. Exome sequencing revealed the biallelic variants in POLR3D, a missense variant (c.541C > T, p.P181S) and an intronic splice site variant (c.656-6G > A, p.?). Functional studies of the patient’s fibroblasts demonstrated significantly decreased RNA-level expression of POLR3D, along with reduced expression of other Pol III subunit genes. Notably, Pol III transcription was also shown to be aberrant, with a significant decrease in 7SK RNA and several distinct tRNA genes analyzed. Affinity purification coupled to mass spectrometry of the POLR3D p.P181S variant showed normal assembly of Pol III subunits yet altered interaction of Pol III with the PAQosome chaperone complex, indicating the missense variant is likely to alter complex maturation. This work identifies biallelic pathogenic variants in POLR3D as a novel genetic cause of POLR3-related leukodystrophy, expanding the molecular spectrum associated with this disease, and proposes altered tRNA homeostasis as a factor in the underlying biology of this hypomyelinating disorder.</p