Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndrome.

BACKGROUND: Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can 'open' chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones. METHODS: Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n = 4) versus controls (n = 4). FINDINGS: Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. A 12-year-old boy with KS, suffering from recurrent episodes of cognitive decline, exhibited improved cognitive function and neuropsychological assessment performance after 12 months on the ketogenic diet, with concomitant improvement in transcriptomic ribosomal protein dysregulation. INTERPRETATION: Our data reveals that lysine methyltransferase deficiency is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders. FUNDING: This study was supported by the Dale NHMRC Investigator Grant (APP1193648) (R.D), Petre Foundation (R.D), and The Sydney Children's Hospital Foundation/Kids Research Early and Mid-Career Researcher Grant (E.T).

A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome.

Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/ßGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/ßGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/ßGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.

A short nutritional intervention in a cohort of hematological inpatients improves energy and protein intake and stabilizes nutritional status.

INTRODUCTION: Oncohematological diseases are associated with an important prevalence of malnutrition. AIM: Our aim is to determine if early recognition and treatment of malnourished hematological inpatients can improve their oral intake, nutritional status and reduce the length of hospital stay. METHODS: Prospective 2-year study conducted in a cohort of hematology inpatients. Malnutrition Screening Tool (MST) was carried out on the first day of admission. Patients with a positive screening were recruited to have a complete nutritional evaluation and intervention, following usual clinical practice. Nutritional evaluation was repeated after one week. RESULTS: Six hundred and seventeen hematological patients were screened (37.8% with positive screening). After one week, median diet intake increased from 80% to 90% (p < 0.001), and an increase of 407.36 Kcal (SD 679.37) and 17.58 g of protein (SD 31.97) was also achieved. More patients reached their energy and protein requirements (41.6 vs.% 63.3%, p = 0.009) and nutritional parameters remained stable. A trend to a lower stay (3.5 to 4.5 days less) was detected in the groups of patients who covered their needs. CONCLUSIONS: The implementation of early malnutrition screening and short nutritional interventions improved energy and protein intake, increasing the percentage of patients who meet their requirements and avoiding deterioration of nutritional status.

[The use of food supplements - beverages and concentrated food products in tablets made from plants in sanatory and health resort rehabilitation of patients with chronic pathology]. / Ispol'zovanie biologicheski aktivnykh dobavok k pishche - napitkov i tabletirovannykh kontsentrirovannykh pishchevykh produktov iz rastitel'nogo syr'ia pri sanatorno-kurortnoi reabilitatsii bol'nykh s khronicheskoi patologiei.

The effectiveness of a recovery complex optimization in conditions of the sanatorium-resort rehabilitation of patients with chronic pathology by provision of the dietotherapy ration balance on nutrients, the use of natural (of the plant raw material cryopowders in the form of teas and tableted forms) and the "Centrum" synthetic vitamin-mineral complexes, probiotics was substantiated and demonstrated.

[Evaluation of patient diet in sanatoria and health resorts]. / Otsenka ratsionov pitaniia bol'nykh v sanatorno-kurortnykh usloviiakh.

By the example of nutrition of patients from sanatorium "Kristall" (the Black Sea coast) an evaluation of patients nutrition in sanatoria and health resorts is made. It is determined, that the standard patients diets (Table N 15, 5, 10) do not differ from the reference ones regarding their calorie content, main food components and energy value. Though insufficient content of vitamins, unsaturated fatty acids and linoleic/linolein acids imbalance is marked.