Corinne De Laet

Postinfectious immune-mediated encephalitis after pediatric herpes simplex encephalitis

We report a 3-year-old patient who presented a secondary acute neurological deterioration clinically characterized by a partial Kluver-Bucy syndrome, 1 month after the onset of herpes simplex encephalitis. This episode is unlikely due to continuation or resumption of cerebral viral replication but might be related to an immune-inflammatory process. In children, postinfectious immune-mediated encephalitis occurring after HSE are usually clinically characterized by choreoathetoid movements. This type of movement disorder was, however, not observed in this patient. On the basis of this case and a review of the literature, we hypothesize the existence of a spectrum of secondary immune-mediated process triggered by herpes simplex virus cerebral infection ranging from asymptomatic cases with diffuse white matter involvement to secondary acute neurological deteriorations with or without extrapyramidal features.

Neuropsychological outcome of NTBC-treated patients with tyrosinaemia type 1

Corinne De Laet, Vanessa Terrones Munoz, Jaak Jaeken, Baudouin FranAois, Dietbrandt Carton, Etienne M Sokal, Bernard Dan, Philippe J Goyens 1 Nutrition and Metabolism Unit, H pital Universitaire des Enfants Reine Fabiola, Universit Libre de Bruxelles (ULB), Brussels, Belgium. 2 Centre for Metabolic Diseases, University Hospital Gasthuisberg, Leuven, Belgium. 3 Pinocchio Centre for Inborn Metabolic Diseases, Esperance Hospital, Li ge, Belgium. 4 Centre for Metabolic Diseases, Ghent University Hospital, Ghent, Belgium. 5 Paediatric Department, St Luc Clinics, Brussels, Belgium. Correspondence to: corinne.delaet@huderf.be

Heterogeneity of follow-up procedures in French and Belgian patients with treated hereditary tyrosinemia type 1: results of a questionnaire and proposed guidelines.

The 1991 introduction of 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC) as a treatment for hereditary tyrosinemia type 1 (HT-1), a disorder of tyrosine catabolism, has radically modified the natural history of this disorder. Despite the dramatic improvements in survival, outcomes and quality of life seen with NTBC treatment, HT-1 remains a chronic disorder with several long-term complications, including, a persistent (albeit low) risk of hepatocellular carcinoma and suboptimal neuropsychological outcomes. There remain unsolved key-questions concerning the long-term outcomes of patients with HT-1, which closely depend on the quality of follow-up in these patients. In the absence of published guidelines, we investigated the follow-up methods used for French and Belgian patients with HT-1. A simple questionnaire providing a rapid overview of follow-up procedures was sent to the 19 physicians in charge of HT-1 patients treated with NTBC and low-tyrosine diet in France and Belgium. Several areas of heterogeneity (especially liver imaging, slit lamp examination, neuropsychological evaluation and maximal plasma tyrosine level accepted) were observed. In an attempt to improve long-term management and outcome of patients with HT-1, we proposed follow-up recommendations.

Evidence of a wide spectrum of cardiac involvement due to ACAD9 mutations: report on nine patients

Acyl-CoA dehydrogenase 9 (ACAD9) is a mitochondrial protein involved in oxidative phosphorylation complex I biogenesis. This protein also exhibits acyl-CoA dehydrogenase (ACAD) activity. ACAD9-mutated patients have been reported to suffer from primarily heart, muscle, liver, and nervous system disorders. ACAD9 mutation is suspected in cases of elevated lactic acid levels combined with complex I deficiency, and confirmed by ACAD9 gene analysis. At least 18 ACAD9-mutated patients have previously been reported, usually displaying severe cardiac involvement. We retrospectively studied nine additional patients from three unrelated families with a wide spectrum of cardiac involvement between the families as well as the patients from the same families. All patients exhibited elevated lactate levels. Deleterious ACAD9 mutations were identified in all patients except one for whom it was not possible to recover DNA. To our knowledge, this is one of the first reports on isolated mild ventricular hypertrophy due to ACAD9 mutation in a family with moderate symptoms during adolescence. This report also confirms that dilated cardiomyopathy may occur in conjunction with ACAD9 mutation and that some patients may respond clinically to riboflavin treatment. Of note, several patients suffered from patent ductus arteriosus (PDA), with one exhibiting a complex congenital heart defect. It is yet unknown whether these cardiac manifestations were related to ACAD9 mutation. In conclusion, this disorder should be suspected in the presence of lactic acidosis, complex I deficiency, and any cardiac involvement, even mild.

Cutaneous porphyria in a neonate with tyrosinaemia type 1

Abstract A term infant born to consanguineous parents presented at birth with hypoglycaemia, thrombocytopenia, coagulopathy and hyperbilirubinaemia associated with polycythaemia due to delayed cord clamping. Despite phototherapy and correction of polycythaemia by partial exchange transfusion, coagulopathy, hypoglycaemia and conjugated hyperbilirubinaemia persisted, suggesting hepatic failure. Metabolic work-up led to the diagnosis of tyrosinaemia type 1 on day 4. Two – (2-nitro-4-trifluoromethylbenzoyl) – 1,3 cyclohexanedione (NTBC) treatment, started on day 5, resulted in progressive clinical improvement and unambiguous biochemical response. Severe skin purpuric lesions occurred in areas exposed to phototherapy. These resolved slowly after its discontinuation. Urine analysis sampled just before and 6 days after starting NTBC treatment showed high levels of type 1 coproporphyrin isomers. Such findings do not seem directly related to tyrosinaemia type 1 where succinylacetone inhibits δ-aminolevulinic acid (δ-ALA) dehydratase and where the accumulation of δ-ALA results in neurotoxicity without photosensitivity. Conclusion We describe a cutaneous form of porphyria in a neonate presenting with severe liver failure due to tyrosinaemia type 1. This porphyria is tentatively attributed to a secondary accumulation of coproporphyrins due to cholestasis, as reported in the bronze baby syndrome and recently described in neonates with purpuric phototherapy-induced eruption, rather than to a primary defect of porphyrin metabolism. The hypothesis of a direct effect of tyrosinaemia type 1 on porphyrin excretion is also discussed.

Alternative ketogenic diets in glucose transporter type 1 deficiency syndrome

Ketogenic diet is currently the treatment of choice for glucose transport type 1 deficiency syndrome (GLUT1-DS). It stimulates the synthesis of ketones that provide an alternative fuel to compensate for impaired glucose transport into the brain. The classical ketogenic diet (a fat:non-fat ratio of 4:1 and 3:1) can often help to manage epilepsy and to a lesser extent movement disorders. The impact of the diet on developmental delay is more debatable. The ketogenic diet is only maintained for 2 years in the treatment of intractable epilepsy; in GLUT1-DS the diet should be maintained throughout adolescence and sometimes into adulthood. Therefore, the burden of such restricted diets on patients and families, and their adverse effects are of even more concern. Alternative ketogenic diets have been proposed to improve treatment compliance and quality of life, including the Modified Atkins Diet (MAD), medium chain triglycerides, and low glycaemic index treatment. Their effectiveness in treating GLUT1DS has yet to be demonstrated. Amalou et al. report 10 patients with GLUT1-DS treated with MAD for 2.5 years. The outcomes they observed are similar, even in infants, to reports of treatment with the classical ketogenic diet. Two of their patients were successfully switched from the classical ketogenic diet to MAD and showed improvement in growth parameters. This study of a relatively larger group reinforces previous reports suggesting that MAD could be an interesting, alternative therapeutic approach in GLUT1-DS. Fujii et al. recently presented the outcome of patients with GLUT1-DS treated in Japan. The MAD and classical ketogenic diet were used respectively in 17 (55%) and 11 patients (35%). The ketogenicity of the diets was comparable and both were effective on seizure and movement disorders. Low ketone concentrations (e.g. 0.25mM serum b–hydroxybutyrate) seem to be enough to control neurological symptoms, but the relationship between ketosis and long-term intellectual development is still unknown. Ketone body levels were not reported by Amalou et al. Introduction of the ketogenic diet at an early age at is now expected to favourably affect neurocognitive development. Unfortunately, the delay in diagnosing GLUT1-DS continues in clinical practice. Amalou et al. reported a mean age at diagnosis of 6.2 years (standard deviation [SD] 1.7), whereas the first signs were noted at the age of 1.5 years (SD 0.4). If the neurological symptoms clearly improve under treatment, the long-term impact of introduction of the ketogenic diet on physical health remains undetermined. Growth can be impaired, particularly in young patients. Decrease in insulin-like growth factor 1 during ketosis may affect height velocity, bone acquisition, and increase fat mass. In 15 patients with epilepsy responding to the introduction of the classical ketogenic diet, the height z-score decreased after 15 months of treatment, while the weight status and resting energy expenditure were unchanged, and fat mass increased. The limited protein content of the diet