The basis for the discordant expression of this de novo mutation in the twins was investigated by studying their X inactivation status. Analysis of the inactive X specific methylation at the androgen receptor gene showed unbalanced inactivation in the twins' fibroblasts and in opposite directions. While the maternally derived X chromosome was preferentially active in the asymptomatic twin, the paternal X chromosome was active in the other, affected twin and was found in her hemizygotic nephew. These data suggest that the paternal X chromosome carries the de novo a-galactosidase A mutation and that uneven X inactivation is the underlying mechanism for disease expression in this novel female MZ twin pair. This is the first documented case of female twins discordant for Fabry disease.

To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.

Although growing evidence indicates that bioenergetic metabolism plays an important role in the progression of tumorigenesis, little information is available on the contribution of reprogramming of energy metabolism in cancer initiation. By applying a quantitative proteomic approach and targeted metabolomics, we find that specific metabolic modifications precede primary skin tumor formation. Using a multistage model of ultraviolet B (UVB) radiation-induced skin cancer, we show that glycolysis, tricarboxylic acid (TCA) cycle, and fatty acid β-oxidation are decreased at a very early stage of photocarcinogenesis, while the distal part of the electron transport chain (ETC) is upregulated. Reductive glutamine metabolism and the activity of dihydroorotate dehydrogenase (DHODH) are both necessary for maintaining high ETC. Mice with decreased DHODH activity or impaired ETC failed to develop pre-malignant and malignant lesions. DHODH activity represents a major link between DNA repair efficiency and bioenergetic patterning during skin carcinogenesis.

Dual-energy X-ray absorptiometry (DEXA) of the spine has shown that phenylketonuric children develop osteopenia [1, 4,5]. While the exact reasons for low bone mineral density remain unclear, many explanations have been proposed: the diet being too restrictive [5], poor dietary compliance [2] or a direct effect of the disease [4]. In order to determine the role of the control of phenylalanine (Phe) blood levels in the pathogenesis of osteopenia, we performed a retrospective study of Phe levels from birth up to the present date in 13 children (5 females, 7 males) with classical phenylketonuria, diagnosed in the neonatal period by the French neonatal screening programme. Amino acid supplementation was started upon diagnosis and regularly adapted, based on the serum Phe levels.We compared the Phe values with the spine bone mineral density (BMD). DEXA was performed at the age of 12 years (range 5-21 years) using a Hologic QDR 4500A instrument. Spine BMD were interpreted according to French references values [3] and expressed as Z-score for gender and age. Patients were divided according to their spine BMD results into two groups: patients with osteopenia (Z-score <)1; n=8) and controls (Z-score ‡)1; n=5). Spine Z-scores were -2.39±0.88 (range -3.60 to -1.40) and 0.28±0.83 (range -0.70 to 1.40) for osteopenic patients and controls, respectively. All the Phe levels recorded in the patients' medical notes since the 1st month following birth up to the date the DEXA was done were used for the statistical analysis. The non-parametric MannWhitney test was used to compare continuous data between the two groups.We found that the age when DEXA was performed and the estimators of Phe levels position were similar between osteopenic patients and controls (Table 1). Nevertheless, although the difference was not significant, both the 3rd and 10th percentiles of Phe levels are lower and the percentage of Phe levels <2 mg/dl was higher in osteopenic patients. For the analysis of Phe level variations, we used the mean of cumulative variations which was defined as the sum of the differences between two successive Phe levels divided by the number of the differences studying per patient: i.e. Mean of cumulative variations = (S Phe X -Phe X+1)/(n-1); where Phe X, Phe X+1 are successive Phe levels, n, the number of the successive Phe levels studying per patient. Despite the small size of the population, osteopenic patients had a higher mean of cumulative variations (3.1±0.4 mg/dl) than controls (2.5±0.3 mg/dL, P=0.006). Linear regression analysis revealed a significant negative correlation of BMD spine (Z-score) with mean of cumulative variations (r=)0.61, P=0.025). These results suggest that the variations of serum Phe levels may contribute to osteopenia in phenylketonuric children. References 1. Allen JR, Humphries IRJ, Waters DL, Roberts DCK, Lipson AH, Howman-Giles RG, Gaskin KJ (1994) Decreased bone mineral density in children with phenyketonuria. Am J Clin Nutr 59: 419-422 2. Al-Qadreh A, Schulpis KH, Athanasopoulou H, Mengreli C, Ska...

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Urea cycle disorders (UCD) are rare diseases that usually affect neonates or young children. During decompensations, hyperammonemia is neurotoxic, leading to severe symptoms and even coma and death if not treated rapidly. The aim was to describe a cohort of patients with adult onset of UCDs in a multicentric, retrospective and descriptive study of French adult patients with a diagnosis after 16 years of age of UCDs due to a deficiency in one of the 6 enzymes (arginase, ASL, ASS, CPS1, NAGS, OTC) or the two transporters (ORNT1 or citrin). Seventy‐one patients were included (68% female, 32% male). The diagnosis was made in the context of (a) a metabolic decompensation (42%), (b) family history (55%), or (c) chronic symptoms (3%). The median age at diagnosis was 33 years (range 16‐86). Eighty‐nine percent of patients were diagnosed with OTC deficiency, 7% CPS1 deficiency, 3% HHH syndrome and 1% argininosuccinic aciduria. For those diagnosed during decompensations (including 23 OTC cases, mostly female), 89% required an admission in intensive care units. Seven deaths were attributed to UCD—6 decompensations and 1 epilepsy secondary to inaugural decompensation. This is the largest cohort of UCDs diagnosed in adulthood, which confirms the triad of neurological, gastrointestinal and psychiatric symptoms during hyperammonemic decompensations. We stress that females with OTC deficiency can be symptomatic. With 10% of deaths in this cohort, UCDs in adults remain a life‐threatening condition. Physicians working in adult care must be aware of late‐onset presentations given the implications for patients and their families.

This study demonstrates that a lentiviral vector including therapeutic and G156A MGMT genes followed by BG/BCNU exposure can lead to a full metabolic correction of deficient cells. This vector might form the basis of new EPP mouse gene therapy protocols without a preconditioning regimen followed by in vivo selection of corrected hematopoietic stem cells.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.controller of cell growth. However, glutaminolysis did not play any role in Notch1-induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1-driven leukemia progression.Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1-driven leukemia.