TY  - JOUR
AB  - Pyridoxine-dependent epilepsy due to recessive ALDH7A1 mutations is characterized byintractable epilepsy that is often unresponsive to antiseizure medications. Irrespective ofpyridoxine (vitamin B6) supplementation and lysine reduction therapy, patients present severeresidual neurocognitive deficits. We evaluated upstream inhibition of 2-aminoadipicsemialdehyde synthase as a novel therapeutic strategy to reduce the accumulating metabolites (α-aminoadipic semialdehyde , Δ1-piperideine-6-carboxylate, pipecolic acid, 6-oxo-pipecolic acid,and 2S,6S-/2s,6R-oxopropylpiperidine-2-carboylic acid) considered neurotoxic.We utilized an existing mouse knockout model of hyperlysinemia (Aass-knockout) andgenerated a PDE model, a Aldh7a1 single knockout model via CRISPR/Cas (clustered regularlyinterspaced short palindromic repeats and CRISPR-associated protein) and generated the double-knockout Aass/Aldh7a1 mice. Next-Generation metabolomics screening was performed tomeasure all known biomarkers in brain, liver, and plasma of wildtype and mutant mice.Metabolomics confirmed the known metabolite markers for Aldh7a1-knockout and Aassknockout mice in all samples. The potentially neurotoxic metabolites (Δ1-piperideine-6-carboxylate, pipecolic acid, 6-oxo-pipecolic acid, and 2S,6S-/2s,6R-oxopropylpiperidine-2-carboylic acid) significantly decreased in double knock-out Aass/Aldh7a1 mice brain and livertissues compared to Aldh7a1-knockout mice. Plasma analysis revealed a significant reduction ofknown biomarkers, suggesting a reliable monitoring option in human patients.We demonstrate the first mammalian evidence that AASS inhibition is a viable strategy to rescueabnormal brain metabolism associated with pyridoxine-dependent epilepsy. This may target theintellectual disability and neurologic deficits caused by persistent lysine catabolic-relatedneurotoxicity despite adequate vitamin B6 supplementation.
AU  - Karnebeek, C.D.v.*
AU  - Gailus-Durner, V.
AU  - Engelke, U.F.H.*
AU  - Seisenberger, C.
AU  - Marschall, S.
AU  - Dragano, N.R.V.
AU  - da Silva Buttkus, P.
AU  - Leuchtenberger, S.
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Wevers, R.A.*
AU  - Coughlin, C.R.*
AU  - Lefeber, D.J.*
C1  - 75805
C2  - 58050
TI  - New treatment for PDE-ALDH7A1: First proof-of-principle of upstream enzyme inhibition in the mouse.
JO  - Brain Commun.
PY  - 2025
SN  - 2632-1297
ER  - 

TY  - JOUR
AB  - First small sample studies indicate that disturbances of spinal morphology may impair craniospinal flow of cerebrospinal fluid and result in neurodegeneration. The aim of this study was to evaluate the association of cervical spinal canal width and scoliosis with grey matter, white matter, ventricular and white matter hyperintensity volumes of the brain in a large study sample. Four hundred participants underwent whole-body 3 T magnetic resonance imaging. Grey matter, white matter and ventricular volumes were quantified using a warp-based automated brain volumetric approach. Spinal canal diameters were measured manually at the cervical vertebrae 2/3 level. Scoliosis was evaluated using manual measurements of the Cobb angle. Linear binomial regression analyses of measures of brain volumes and spine anatomy were performed while adjusting for age, sex, hypertension, cholesterol levels, body mass index, smoking and alcohol consumption. Three hundred eighty-three participants were included [57% male; age: 56.3 (±9.2) years]. After adjustment, smaller spinal canal width at the cervical vertebrae 2/3 level was associated with lower grey matter (P = 0.034), lower white matter (P = 0.012) and higher ventricular (P = 0.006, inverse association) volume. Participants with scoliosis had lower grey matter (P = 0.005), lower white matter (P = 0.011) and larger brain ventricular (P = 0.003) volumes than participants without scoliosis. However, these associations were attenuated after adjustment. Spinal canal width at the cervical vertebrae 2/3 level and scoliosis were not associated with white matter hyperintensity volume before and after adjustment (P > 0.864). In our study, cohort smaller spinal canal width at the cervical vertebrae 2/3 level and scoliosis were associated with lower grey and white matter volumes and larger ventricle size. These characteristics of the spine might constitute independent risk factors for neurodegeneration.
AU  - Grosu, S.*
AU  - Nikolova, T.*
AU  - Lorbeer, R.*
AU  - Stoecklein, V.M.*
AU  - Rospleszcz, S.
AU  - Fink, N.R.*
AU  - Schlett, C.L.*
AU  - Storz, C.*
AU  - Beller, E.*
AU  - Keeser, D.*
AU  - Heier, M.
AU  - Kiefer, L.S.*
AU  - Maurer, E.*
AU  - Walter, S.S.*
AU  - Ertl-Wagner, B.B.*
AU  - Ricke, J.*
AU  - Bamberg, F.*
AU  - Peters, A.
AU  - Stoecklein, S.*
C1  - 72174
C2  - 56464
CY  - Great Clarendon St, Oxford Ox2 6dp, England
TI  - The spine-brain axis: Is spinal anatomy associated with brain volume?
JO  - Brain Commun.
VL  - 6
IS  - 5
PB  - Oxford Univ Press
PY  - 2024
SN  - 2632-1297
ER  - 

TY  - JOUR
AB  - Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.
AU  - Manzoni, E.*
AU  - Carli, S.*
AU  - Gaignard, P.*
AU  - Schlieben, L.D.
AU  - Hirano, M.*
AU  - Ronchi, D.*
AU  - Gonzales, E.*
AU  - Shimura, M.*
AU  - Murayama, K.*
AU  - Okazaki, Y.*
AU  - Barić, I.*
AU  - Petkovic Ramadža, D.*
AU  - Karall, D.*
AU  - Mayr, J.*
AU  - Martinelli, D.*
AU  - La Morgia, C.*
AU  - Primiano, G.*
AU  - Santer, R.*
AU  - Servidei, S.*
AU  - Bris, C.*
AU  - Cano, A.*
AU  - Furlan, F.*
AU  - Gasperini, S.*
AU  - Laborde, N.*
AU  - Lamperti, C.*
AU  - Lenz, D.*
AU  - Mancuso, M.*
AU  - Montano, V.*
AU  - Menni, F.*
AU  - Musumeci, O.*
AU  - Nesbitt, V.*
AU  - Procopio, E.*
AU  - Rouzier, C.*
AU  - Staufner, C.*
AU  - Taanman, J.W.*
AU  - Tal, G.*
AU  - Ticci, C.*
AU  - Cordelli, D.M.*
AU  - Carelli, V.*
AU  - Procaccio, V.*
AU  - Prokisch, H.
AU  - Garone, C.*
C1  - 70697
C2  - 55817
CY  - Great Clarendon St, Oxford Ox2 6dp, England
TI  - Deoxyguanosine kinase deficiency: Natural history and liver transplant outcome.
JO  - Brain Commun.
VL  - 6
IS  - 3
PB  - Oxford Univ Press
PY  - 2024
SN  - 2632-1297
ER  - 

TY  - JOUR
AU  - Oexle, K.
C1  - 72730
C2  - 56717
CY  - Great Clarendon St, Oxford Ox2 6dp, England
TI  - Are there two disjunct episignatures for KMT2B-related disease?
JO  - Brain Commun.
VL  - 6
IS  - 6
PB  - Oxford Univ Press
PY  - 2024
SN  - 2632-1297
ER  - 

TY  - JOUR
AB  - Metabolomics in the Alzheimer's Disease Neuroimaging Initiative cohort provides a powerful tool for mapping biochemical changes in Alzheimer's disease, and a unique opportunity to learn about the association between circulating blood metabolites and brain amyloid-β deposition in Alzheimer's disease. We examined 140 serum metabolites and their associations with brain amyloid-β deposition, cognition and conversion from mild cognitive impairment to Alzheimer's disease in the Alzheimer's Disease Neuroimaging Initiative. Processed [18F] Florbetapir PET images were used to perform a voxel-wise statistical analysis of the effect of metabolite levels on amyloid-β accumulation across the whole brain. We performed a multivariable regression analysis using age, sex, body mass index, apolipoprotein E ε4 status and study phase as covariates. We identified nine metabolites as significantly associated with amyloid-β deposition after multiple comparison correction. Higher levels of one acylcarnitine (C3; propionylcarnitine) and one biogenic amine (kynurenine) were associated with decreased amyloid-β accumulation and higher memory scores. However, higher levels of seven phosphatidylcholines (lysoPC a C18:2, PC aa C42:0, PC ae C42:3, PC ae C44:3, PC ae C44:4, PC ae C44:5 and PC ae C44:6) were associated with increased brain amyloid-β deposition. In addition, higher levels of PC ae C44:4 were significantly associated with lower memory and executive function scores and conversion from mild cognitive impairment to Alzheimer's disease dementia. Our findings suggest that dysregulation of peripheral phosphatidylcholine metabolism is associated with earlier pathological changes noted in Alzheimer's disease as measured by brain amyloid-β deposition as well as later clinical features including changes in memory and executive functioning. Perturbations in phosphatidylcholine metabolism may point to issues with membrane restructuring leading to the accumulation of amyloid-β in the brain. Additional studies are needed to explore whether these metabolites play a causal role in the pathogenesis of Alzheimer's disease or if they are biomarkers for systemic changes during preclinical phases of the disease.
AU  - Nho, K.*
AU  - Kueider-Paisley, A.*
AU  - Arnold, M.
AU  - MahmoudianDehkordi, S.*
AU  - Risacher, S.L.*
AU  - Louie, G.*
AU  - Blach, C.*
AU  - Baillie, R.*
AU  - Han, X.*
AU  - Kastenmüller, G.
AU  - Doraiswamy, P.M.*
AU  - Kaddurah-Daouk, R.*
AU  - Saykin, A.J.*
C1  - 62902
C2  - 51160
TI  - Serum metabolites associated with brain amyloid beta deposition, cognition and dementia progression.
JO  - Brain Commun.
VL  - 3
IS  - 3
PY  - 2021
SN  - 2632-1297
ER  -