Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up.

Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are mainly described during acute crises, and many reports do not mention them because hypoglycemia and hyperlactatemia are more frequently in the forefront. Herein, the liver manifestations of 18 patients affected with fructose-1,6-bisphosphatase deficiency are described and the corresponding literature is reviewed. Interestingly, all 18 patients had liver abnormalities either during follow-up (hepatomegaly [n = 8/18], elevation of transaminases [n = 6/15], bright liver [n = 7/11]) or during acute crises (hepatomegaly [n = 10/17], elevation of transaminases [n = 13/16], acute liver failure [n = 6/14], bright liver [n = 4/14]). Initial reports described cases of liver steatosis, when liver biopsy was necessary to confirm the diagnosis by an enzymatic study. There is no clear pathophysiological basis for this fatty liver disease but we postulate that endoplasmic reticulum stress and de novo lipogenesis activation could be key factors, as observed in FBP1 knockout mice. Liver steatosis may expose patients to severe long-term liver complications. As hypoglycemia becomes less frequent with age, most adult patients are no longer monitored by hepatologist. Signs of fructose-1,6-bisphosphatase deficiency may be subtle and can be missed in childhood. We suggest that fructose-1,6-bisphosphatase deficiency should be considered as an etiology of hepatic steatosis, and a liver monitoring protocol should be set up for these patients, during lifelong follow-up.

[New Inborn Errors of Metabolism added in the French program of neonatal screening]. / Les nouvelles maladies héréditaires du métabolisme du programme français de dépistage néonatal.

Inborn Errors of Metabolism (IEM) are rare and heterogenous disorders. For most IEMs, clinical signs are non-specific or belated. Late diagnosis is frequent, leading to death or severe sequelae. Some IEM induce intermediate metabolites circulating in the blood. They may be detected by tandem mass spectrometry. This method allows the simultaneous detection of many IEM in different metabolic pathways. In France, newborn screening (NBS) program for IEM, limited to phenylketonuria for decades, has been recently extended to medium chain acyl-CoA dehydrogenase deficiency. Rationale, methodology and organization of this new NBS program are described. Seven other IEM (maple syrup urine disease, homocystinuria, tyrosinemia type I, glutaric aciduria type I, isovaleric acidemia, long chain hydroxy-acyl-CoA dehydrogenase deficiency, carnitine uptake disorder) should be screened in the next program extension. Efforts are needed to fully understand the predictive value of each abnormal testing at birth, decrease the false positive rate, and develop the adequate management strategies.

TITLE: Les nouvelles maladies héréditaires du métabolisme du programme français de dépistage néonatal. ABSTRACT: Les maladies héréditaires du métabolisme (MHM) sont un groupe de maladies rares et cliniquement hétérogènes. Le retard diagnostique est fréquent, conduisant souvent au décès du patient ou à de graves séquelles. Certaines MHM entraînent l'accumulation de métabolites intermédiaires circulant dans le sang, qui sont détectables par une méthode commune utilisant la spectrométrie de masse en tandem. Cette méthode permet la reconnaissance simultanée de plusieurs de ces maladies affectant différentes voies métaboliques. En France, le programme de dépistage néonatal (DNN) des MHM, longtemps limité à la phénylcétonurie, a récemment été étendu au déficit en déshydrogénase des acyl-CoA à chaîne moyenne (MCADD). Le rationnel, la méthode et l'organisation de ce nouveau DNN sont décrits dans cet article. Sept nouvelles MHM (leucinose, homocystinurie, tyrosinémie de type I, acidurie glutarique de type I, acidurie isovalérique, déficit en déshydrogénase des hydroxy-acyl-CoA à chaîne longue, déficit du transporteur de la carnitine) devraient être dépistées, grâce à une prochaine extension du programme de DNN. Des efforts sont nécessaires pour mieux comprendre et prévoir la signification de chaque test anormal à la naissance, diminuer les taux de faux positifs, et développer les stratégies de prise en charge adéquates.

Biallelic loss-of-function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth.

The family of Tre2-Bub2-Cdc16 (TBC)-domain containing GTPase activating proteins (RABGAPs) is not only known as key regulatorof RAB GTPase activity but also has GAP-independent functions. Rab GTPases are implicated in membrane trafficking pathways, such as vesicular trafficking. We report biallelic loss-of-function variants in TBC1D2B, encoding a member of the TBC/RABGAP family with yet unknown function, as the underlying cause of cognitive impairment, seizures, and/or gingival overgrowth in three individuals from unrelated families. TBC1D2B messenger RNA amount was drastically reduced, and the protein was absent in fibroblasts of two patients. In immunofluorescence analysis, ectopically expressed TBC1D2B colocalized with vesicles positive for RAB5, a small GTPase orchestrating early endocytic vesicle trafficking. In two independent TBC1D2B CRISPR/Cas9 knockout HeLa cell lines that serve as cellular model of TBC1D2B deficiency, epidermal growth factor internalization was significantly reduced compared with the parental HeLa cell line suggesting a role of TBC1D2B in early endocytosis. Serum deprivation of TBC1D2B-deficient HeLa cell lines caused a decrease in cell viability and an increase in apoptosis. Our data reveal that loss of TBC1D2B causes a neurodevelopmental disorder with gingival overgrowth, possibly by deficits in vesicle trafficking and/or cell survival.