A randomized, double-blind trial of triheptanoin for drug-resistant epilepsy in glucose transporter 1 deficiency syndrome.

OBJECTIVE: This study was undertaken to evaluate efficacy and long-term safety of triheptanoin in patients >1 year old, not on a ketogenic diet, with drug-resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS). METHODS: UX007G-CL201 was a randomized, double-blind, placebo-controlled trial. Following a 6-week baseline period, eligible patients were randomized 3:1 to triheptanoin or placebo. Dosing was titrated to 35% of total daily calories over 2 weeks. After an 8-week placebo-controlled period, all patients received open-label triheptanoin through Week 52. RESULTS: The study included 36 patients (15 children, 13 adolescents, eight adults). A median 12.6% reduction in overall seizure frequency was observed in the triheptanoin arm relative to baseline, and a 13.5% difference was observed relative to placebo (p = .58). In patients with absence seizures only (n = 9), a median 62.2% reduction in seizure frequency was observed in the triheptanoin arm relative to baseline. Only one patient with absence seizures only was present in the control group, preventing comparison. No statistically significant differences in seizure frequency were observed. Common treatment-emergent adverse events included diarrhea, vomiting, abdominal pain, and nausea, mostly mild or moderate in severity. No serious adverse events were considered to be treatment related. One patient discontinued due to status epilepticus. SIGNIFICANCE: Triheptanoin did not significantly reduce seizure frequency in patients with Glut1DS not on the ketogenic diet. Treatment was associated with mild to moderate gastrointestinal treatment-related events; most resolved following dose reduction or interruption and/or medication for treatment. Triheptanoin was not associated with any long-term safety concerns when administered at dose levels up to 35% of total daily caloric intake for up to 1 year.

An overview of inborn errors of metabolism affecting the brain: from neurodevelopment to neurodegenerative disorders.

Inborn errors of metabolism (IEMs) are particularly frequent as diseases of the nervous system. In the pediatric neurologic presentations of IEMs neurodevelopment is constantly disturbed and in fact, as far as biochemistry is involved, any kind of monogenic disease can become an IEM. Clinical features are very diverse and may present as a neurodevelopmental disorder (antenatal or late-onset), as well as an intermittent, a fixed chronic, or a progressive and late-onset neurodegenerative disorder. This also occurs within the same disorder in which a continuum spectrum of severity is frequently observed. In general, the small molecule defects have screening metabolic markers and many are treatable. By contrast only a few complex molecules defects have metabolic markers and most of them are not treatable so far. Recent molecular techniques have considerably contributed in the description of many new diseases and unexpected phenotypes. This paper provides a comprehensive list of IEMs that affect neurodevelopment and may also present with neurodegeneration.

Las enfermedades hereditarias del metabolismo (EHM) afectan con gran frecuencia al sistema nervioso. En sus formas neuropediátricas el neurodesarrollo se encuentra siempre afectado. En realidad, cualquier enfermedad monogénica cuya fisiopatología implique una alteración bioquímica puede ser considerada como una EHM. Las presentaciones clínicas son muy diversas en forma de trastorno del desarrollo antenatal o tardío, o bien de una enfermedad neurodegenerativa a brotes intermitentes, de carácter crónico o progresivo de debut tardío. En una misma enfermedad pueden darse diferentes espectros de gravedad. En general, las EHM que afectan a las moléculas pequeñas tienen marcadores metabólicos diagnósticos y muchas de ellas son tratables. Por contra, las EHM de las moléculas complejas tienen raramente marcadores metabólicos conocidos y la mayoría no tienen un tratamiento a día de hoy. Las técnicas de secuenciación masiva han permitido la descripción de numerosas nuevas enfermedades y fenotipos inesperados. Este artículo ofrece una lista completa de EHM que afectan el neurodesarrollo y pueden presentarse también como enfermedades neurodegenerativas.

Les maladies héréditaires du métabolisme (MHM) affectent très fréquemment le système nerveux. Dans leurs formes neuropédiatriques, le neurodéveloppement est toujours perturbé et dès l'instant qu'elle implique un mécanisme biochimique, toute maladie monogénique peut devenir une MHM. Les présentations cliniques sont très diverses et peuvent s'exprimer sous la forme d'un trouble du neurodéveloppement (anténatal ou à début tardif) ou d'une maladie neurodégénérative intermittente, chronique stable ou progressive à début tardif. Ceci peut aussi s'observer au sein d'une même maladie, ou un continuum de sévérité est fréquemment constaté. En général, les MHM affectant les petites molécules biochimiques ont des marqueurs métaboliques de dépistage et beaucoup sont traitables. Au contraire, les MHM affectant les molécules biochimiques complexes ont rarement des marqueurs métaboliques et la plupart d'entre elles ne sont pas traitables jusqu'à présent. Les techniques moléculaires récentes ont permis la description de nombreuses nouvelles maladies et de phénotypes inattendus. Cet article donne une liste complète des MHM affectant le neurodéveloppement et pouvant aussi se présenter comme des maladies neurodégénératives.

Encephalopathies with intracranial calcification in children: clinical and genetic characterization.

BACKGROUND: We present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses. METHODS: We collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification. RESULTS: We collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two. CONCLUSIONS: Genetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.

A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycaemia and lactic acidosis.

Mitochondrial respiratory chain complex III (ubiquinol-cytochrome c reductase) consists of 11 subunits, only one (cytochrome b) being encoded by the mitochondrial DNA. Disorders of complex III are comparatively rare but are nevertheless present as a clinically heterogeneous group of diseases. To date, no mutation in any of the nuclear-encoded subunits has been described. We report here a deletion in the nuclear gene UQCRB encoding the human ubiquinone-binding protein of complex III (QP-C subunit or subunit VII) in a consanguineous family with an isolated complex III defect. In the proband, a homozygous 4-bp deletion was identified at nucleotides 338-341 of the cDNA predicting both a change in the last seven amino acids and an addition of a stretch of 14 amino acids at the C-terminal end of the protein. Both parents were found to be heterozygous for the deletion, which was absent from 55 controls. Low temperature (-196 degrees C) spectral studies performed on isolated mitochondria from cultured skin fibroblast of the proband showed a decreased cytochrome b content suggestive of a role for the QP-C subunit in the assembly or maintenance of complex III structure.