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The study’s purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH). Genetic results, parental phase, ethnic origin, and gender data were collected from subjects suspected to have classic NKH. Mutations were compared with those in the existing literature and to the population frequency from the Exome Aggregation Consortium (ExAC) database. In 578 families, genetic analyses identified 410 unique mutations, including 246 novel mutations. 80% of subjects had mutations in GLDC. Missense mutations were noted in 52% of all GLDC alleles, most private. Missense mutations were 1.5 times as likely to be pathogenic in the carboxy terminal of GLDC than in the amino-terminal part. Intragenic copy-number variations (CNVs) in GLDC were noted in 140 subjects, with biallelic CNVs present in 39 subjects. The position and frequency of the breakpoint for CNVs correlated with intron size and presence of Alu elements. Missense mutations, most often recurring, were the most common type of disease-causing mutation in AMT. Sequencing and CNV analysis identified biallelic pathogenic mutations in 98% of subjects. Based on genotype, 15% of subjects had an attenuated phenotype. The frequency of NKH is estimated at 1:76,000. The 484 unique mutations now known in classic NKH provide a valuable overview for the development of genotype-based therapies.

A patient with late-onset exercise intolerance had haploinsufficiency of SLC25A32, which encodes the human mitochondrial flavin adenine dinucleotide transporter. The patient's symptoms were highly responsive to oral supplementation with riboflavin. To the Editor: Multiple acyl–coenzyme A dehydrogenation deficiency is an inborn error of metabolism with frequent muscle involvement. This deficiency is due to defects in the electron-transfer flavoprotein genes ETFA and ETFB 1 or in the electron-transfer flavoprotein ubiquinone oxidoreductase gene ETFDH . 2 In patients with this deficiency, all the mitochondrial flavoprotein dehydrogenases are defective with a specific biochemical phenotype for multiple acyl–coenzyme A dehydrogenation deficiency. Yet, in a few patients who have a deficiency that is similar to multiple acyl–coenzyme A dehydrogenation deficiency, no mutations are identified in ETFA, ETFB, or ETFDH . 3 We report on a 14-year-old girl who . . .

The management of sporadic late-onset cerebellar ataxias represents a very heterogeneous group of patients and remains a challenge for neurologist in clinical practice. We aimed at describing the different causes of sporadic late-onset cerebellar ataxias that were diagnosed following standardized, exhaustive investigations and the population characteristics according to the aetiologies as well as at evaluating the relevance of these investigations. All patients consecutively referred to our centre due to sporadic, progressive cerebellar ataxia occurring after 40 years of age were included in the prospective, observational study. 80 patients were included over a 2 year period. A diagnosis was established for 52 patients (65%) corresponding to 18 distinct causes, the most frequent being cerebellar variant of multiple system atrophy ( n  = 29). The second most frequent cause was inherited diseases (including spinocerebellar ataxias, late-onset Friedreich’s disease, SLC20A2 mutations, FXTAS, MELAS, and other mitochondrial diseases) ( n  = 9), followed by immune-mediated or other acquired causes. The group of patient without diagnosis showed a slower worsening of ataxia ( p  < 0.05) than patients with multiple system atrophy. Patients with later age at onset experienced faster progression of ataxia ( p  = 0.001) and more frequently parkinsonism ( p  < 0.05) than patients with earlier onset. Brain MRI, DaT scan, genetic analysis and to some extent muscle biopsy, thoracic-abdominal-pelvic tomodensitometry, and cerebrospinal fluid analysis were the most relevant investigations to explore sporadic late-onset cerebellar ataxia. Sporadic late-onset cerebellar ataxias should be exhaustively investigated to identify the underlying causes that are numerous, including inherited causes, but dominated by multiple system atrophy.

Hematopoietic stem cell transplantation is becoming an increasingly important approach to treatment of different malignant and non-malignant disorders. There is thus growing demand for diagnostic assays permitting the surveillance of donor/recipient chimerism posttransplant. Current techniques are heterogeneous, rendering uniform evaluation and comparison of diagnostic results between centers difficult. Leading laboratories from 10 European countries have therefore performed a collaborative study supported by a European grant, the EuroChimerism Concerted Action, with the aim to develop a standardized diagnostic methodology for the detection and monitoring of chimerism in patients undergoing allogeneic stem cell transplantation. Following extensive analysis of a large set of microsatellite/short tandem repeat (STR) loci, the EuroChimerism (EUC) panel comprising 13 STR markers was established with the aim to optimally meet the specific requirements of quantitative chimerism analysis. Based on highly stringent selection criteria, the EUC panel provides multiple informative markers in any transplant setting. The standardized STR-PCR tests permit detection of donor- or recipient-derived cells at a sensitivity ranging between 0.8 and 1.6%. Moreover, the EUC assay facilitates accurate and reproducible quantification of donor and recipient hematopoietic cells. Wide use of the European-harmonized protocol for chimerism analysis presented will provide a basis for optimal diagnostic support and timely treatment decisions.

Background. Multiple acyl-coA dehydrogenase deficiency (MADD) is a rare, inherited, autosomal-recessive disorder leading to the accumulation of acylcarnitine of all chain lengths. Acute decompensation with cardiac, respiratory or hepatic failure and metabolic abnormalities may be life-threatening. Case Presentation. A 29-year-old woman presented with severe lactic acidosis associated with intense myalgia and muscle weakness. The clinical examination revealed symmetric upper and lower limb motor impairment (rated at 2 or 3 out of 5 on the Medical Research Council scale) and clear amyotrophy. Laboratory tests had revealed severe rhabdomyolysis, with a serum creatine phosphokinase level of 8,700 IU/L and asymptomatic hypoglycemia in the absence of ketosis. Electromyography revealed myotonic bursts in all four limbs. The absence of myositis-specific autoantibodies ruled out a diagnosis of autoimmune myositis. Finally, Acylcarnitine profile and gas chromatography–mass spectrometry analysis of organic acids led to the diagnosis of MADD. A treatment based on the intravenous infusion of glucose solutes, administration of riboflavin, and supplementation with coenzyme Q10 and carnitine was effective. Lipid consumption was strictly prohibited in the early stages of treatment. The clinical and biochemical parameters rapidly improved and we noticed a complete disappearance of the motor deficit, without sequelae. Conclusion. A diagnosis of MADD must be considered whenever acute or chronic muscle involvement is associated with metabolic disorders. Acute heart, respiratory or hepatic failure and metabolic abnormalities caused by MADD may be life-threatening, and will require intensive care.

Background Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency affects ketone body and isoleucine catabolism. Neurological impairment may occur secondary to ketoacidotic episodes. However, we observed neuromotor abnormalities without ketoacidotic events in two T2-deficient families. We hypothesized that the neurological signs were related to the genetic defect and may occur independently of ketoacidotic episodes. We therefore conducted a retrospective review on a French T2-deficient patient series searching for neuromotor impairment. Methods In total, 26 cases were retrospectively analysed for clinical, biological and neuroimaging data. Results Neurological findings were observed for 6/26 (23%) patients. Among these, two had never experienced ketoacidotic episodes, though they developed extrapyramidal signs with putamen involvement. Two of the other four patients developed neurological abnormalities before the first ketoacidotic crisis, with putamen involvement in one case. The third patient developed extrapyramidal symptoms more than 10 years after the initial decompensation with globus pallidus involvement. The last patient developed extrapyramidal signs immediately after a severe ketoacidotic crisis with putaminal lesions. Conclusions Most T2-deficient patients achieved normal neurodevelopment. However, on account of the role of T2 in isoleucine catabolism, these patients are potentially exposed to accumulation of toxic isoleucine-derived metabolites, which may contribute to neurological impairment. Our findings confirm previous observations that neurological symptoms in T2 deficiency may occur unrelated to ketoacidosis. The role of protein restriction as a preventive measure against neurological symptoms could not be established in this study and deserves further evaluation. Long-term follow-up data on children diagnosed by newborn screening may clarify the pathogenesis of this neurometabolic association.

Le déficit multiple en acyl-coenzyme A déshydrogénase (DMAD), aussi appelé acidurie glutarique de type 2, est un trouble de l’oxydation des acides gras [1]. Bien qu’il soit habituellement diagnostiqué en période néonatale, certaines de ses formes se distinguent par un début plus tardif et peuvent parfois se révéler à l’âge adulte [1–3]. Nous rapportons le cas d’une patiente prise en charge en médecine intensive et réanimation pour un déficit moteur des quatre membres associé à une rhabdomyolyse, une acidose lactique sévère et une hypoglycémie hypocétosique. L’objectif de ce cas clinique est d’illustrer la démarche diagnostique ainsi que la prise en charge thérapeutique d’une décompensation aiguë de DMAD.

c- fos gene is expressed constitutively in a number of tissues as well as in certain tumor cells and is inducible, in general rapidly and transiently, in virtually all other cell types by a variety of stimuli. Its protein product, c-Fos, is a short-lived transcription factor that heterodimerizes with various protein partners within the AP-1 transcription complex via leucine zipper/leucine zipper interactions for binding to specific DNA sequences. It is mostly, if not exclusively, degraded by the proteasome. To localize the determinant(s) responsible for its instability, we have conducted a genetic analysis in which the half-lives of c-Fos mutants and chimeras made with the stable EGFP reporter protein were compared under two experimental conditions taken as example of continous and inducible expression. Those were constitutive expression in asynchronously growing Balb/C 3T3 mouse embryo fibroblasts and transient induction in the same cells undergoing the G0/G1 phase transition upon stimulation by serum. Our work shows that c-Fos is degraded faster in synchronous- than in asynchronous cells. This difference in turnover is primarily accounted for by several mechanisms. First, in asynchronous cells, a unique C-terminal destabilizer is active whereas, in serum-stimulated cells two destabilizers located at both extremities of the protein are functional. Second, heterodimerization and/or binding to DNA accelerates protein degradation only during the G0/G1 phase transition. Adding another level of complexity to turnover control, phosphorylation at serines 362 and 374, which are c-Fos phosphorylation sites largely modified during the G0/G1 phase transition, stabilizes c-Fos much more efficiently in asynchronous than in serum-stimulated cells. In both cases, the reduced degradation rate is due to inhibition of the activity of the C-terminal destabilizer. However, in serum-stimulated cells, this effect is partially masked by the activation of the N-terminal destabilizer and basic domain/leucine zipper-dependent mechanisms. Taken together, our data show that multiple degradation mechanisms, differing according to the conditions of expression, may operate on c-Fos to ensure a proper level and/or timing of expression. Moreover, they also indicate that the half-life of c-Fos during the G0/G1 phase transition is determined by a delicate balance between opposing stabilizing and destabilizing mechanisms operating at the same time.

c-Fos proto-oncoprotein is rapidly and transiently expressed in cells undergoing the G(0)-to-S phase transition in response to stimulation for growth by serum. Under these conditions, the rapid decay of the protein occurring after induction is accounted for by efficient recognition and degradation by the proteasome. PEST motifs are sequences rich in Pro, Glu, Asp, Ser and Thr which have been proposed to constitute protein instability determinants. c-Fos contains three such motifs, one of which comprises the C-terminal 20 amino acids and has already been proposed to be the major determinant of c-Fos instability. Using site-directed mutagenesis and an expression system reproducing c-fos gene transient expression in transfected cells, we have analysed the turnover of c-Fos mutants deleted of the various PEST sequences in synchronized mouse embryo fibroblasts. Our data showed no role for the two internal PEST motifs in c-Fos instability. However, deletion of the C-terminal PEST region led to only a twofold stabilization of the protein. Taken together, these data indicate that c-Fos instability during the G0-to-S phase transition is governed by a major non-PEST destabilizer and a C-terminal degradation-accelerating element. Further dissection of c-Fos C-terminal region showed that the degradation-accelerating effect is not contributed by the whole PEST sequence but by a short PTL tripeptide which cannot be considered as a PEST motif and which can act in the absence of any PEST environment. Interestingly, the PTL motif is conserved in other members of the fos multigene family. Nevertheless, its contribution to protein instability is restricted to c-Fos suggesting that the mechanisms whereby the various Fos proteins are broken down are, at least partially, different. MAP kinases-mediated phosphorylation of two serines close to PTL, which are both phosphorylated all over the G(0)-to-S phase transition, have been proposed by others to stabilize c-Fos protein significantly. We, however, showed that the PTL motif does not exert its effect by counteracting a stabilizing effect of these phosphorylations under our experimental conditions.