Alice Kuster

Excellent Response to a Ketogenic Diet in a Patient with Alternating Hemiplegia of Childhood

UNLABELLED Alternating hemiplegia of childhood (AHC) is a rare disorder caused by heterozygous mutations in ATP1A3. AHC is associated with early-onset plegic and tonic/dystonic attacks and permanent neurologic deficits. Attacks tend to persist through life. Flunarizine therapy occasionally reduces the severity, duration and frequency of attacks. A ketogenic diet/modified Atkins diet (KD/MAD) can attenuate paroxysmal movement disorders associated with GLUT1 deficiency syndrome (GLUT1DS), but there are no reports on the effect of KD/MAD in AHC. We describe the case of a young girl with AHC who had tonic/dystonic and plegic attacks, mostly triggered by exercise, together with mild permanent dystonia and mental retardation. Her family had a history of dominant (three affected generations) paroxysmal exercise-induced dystonia. A history of plegic attacks that ceased after childhood was retraced from the medical records of the three affected adults, leading to the diagnosis of familial AHC due to ATP1A3 p.Asp923Asn mutation (Roubergue et al 2013). KD/MAD was considered for the proband when she was 3½ years old, following initial misdiagnosis of GLUT1DS. MAD, a KD variant, was chosen because it is easier to manage than KD and is similarly effective to KD in most GLUT1DS patients. MAD resulted in complete disappearance of the attacks during 15 months of follow-up. CONCLUSIONS A modified Atkins diet had a sustained beneficial effect on attacks associated with AHC. Although preliminary, this observation suggests that a ketogenic diet might be a therapeutic option for paroxysmal disorders in some patients with alternating hemiplegia of childhood.

A Cause of Permanent Ketosis: GLUT-1 Deficiency.

GLUT-1-deficiency syndrome (GLUT1-DS; OMIM 606777) is a treatable metabolic disorder caused by a mutation of SLC2A1 gene. The functional deficiency of the GLUT1 protein leads to an impaired glucose transport into the brain, resulting in neurologic disorders.We report on a 6-month-old boy with preprandial malaises who was treated monthly by a sorcerer because of a permanent acetonemic odor. He subsequently developed pharmaco-resistant seizures with microcephaly and motor abnormalities. Metabolic explorations were unremarkable except for a fasting glucose test which revealed an abnormal increase of blood ketone bodies. At the age of 35 months, GLUT1-DS was diagnosed based on hypoglycorrhachia with a decreased CSF to blood glucose ratio, and subsequent direct sequencing of the SLC2A1 gene revealed a de novo heterozygous mutation, c.349A>T (p.Lys117X) on exon 4. It was noteworthy that the patient adapted to the deficient cerebral glucose transport by permanent ketone body production since early life. Excessive ketone body production in this patient provided an alternative energy substrate for his brain. We suggest a cerebral metabolic adaptation with upregulation of monocarboxylic acid transporter proteins (MCT1) at the blood-brain barrier provoked by neuroglycopenia and allowing ketone body utilization by the brain. This case illustrates that GLUT1-DS should be considered in the differential diagnosis of permanent ketosis.

WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.

Fluxomic evidence for impaired contribution of short-chain acyl-CoA dehydrogenase to mitochondrial palmitate β-oxidation in symptomatic patients with ACADS gene susceptibility variants

BACKGROUND Despite ACADS (acyl-CoA dehydrogenase, short-chain) gene susceptibility variants (c.511C>T and c.625G>A) are considered to be non-pathogenic, encoded proteins are known to exhibit altered kinetics. Whether or not, they might affect overall fatty acid β-oxidation still remains, however, unclear. METHODS De novo biosynthesis of acylcarnitines by whole blood samples incubated with deuterated palmitate (16-2H3,15-2H2-palmitate) is suitable as a fluxomic exploration to distinguish between normal and disrupted β-oxidation, abnormal profiles and ratios of acylcarnitines with different chain-lengths being indicative of the site for enzymatic blockade. Determinations in 301 control subjects of ratios between deuterated butyrylcarnitine and sum of deuterated C2 to C14 acylcarnitines served here as reference values to state specifically functional SCAD impairment in patients addressed for clinical and/or biological suspicion of a β-oxidation disorder. RESULTS Functional SCAD impairment was found in 39 patients. The 27 patients accepting subsequent gene studies were all positive for ACADS mutations. Twenty-six of 27 patients were positive for c.625G>A variant. Twenty-three of 27 patients harbored susceptibility variants as sole ACADS alterations (18 homozygous and 3 heterozygous for c.625G>A, 2 compound heterozygous for c.625G>A/c.511C>T). CONCLUSION Our present fluxomic assessment of SCAD suggests a link between ACADS susceptibility variants and abnormal β-oxidation consistent with known altered kinetics of these variants.

SFP-P135 – Métabolisme – Réversibilité d’anomalies de signal à l’IRM après coma hyperammoniémique néonatal

Le cycle de l’uree permet l’excretion d’azote issu du metabolisme des acides amines par la conversion d’ammoniaque en uree dans le foie. Les deficits enzymatiques du cycle de l’uree (incidence cumulee : 1/8.000) se manifestent le plus souvent par une encephalopathie liee a la toxicite cerebrale de la glutamine au niveau des astrocytes. Le diagnostic precoce d’une hyperammoniemie neonatale avec mise en place de traitements epurateurs de l’azote (hemofiltration, chelateurs) peut permettre la survie de ces enfants. Une difficulte est alors l’evaluation des sequelles de cette decompensation. En dehors des criteres de gravite du coma et de l’EEG, l’IRM est mise a contribution. Il n’existe cependant que tres peu de documentations neuroradiologiques notamment en periode neonatale. Cas clinique Nous rapportons ici le cas clinique d’E.-G., nee a terme, qui a ete admise pour un tableau digestif en reanimation a J2, evoluant rapidement vers un coma. L’ammoniemie retrouvee elevee (max. 600 μmol/l) a pu etre corrigee en 48 h par hemofiltration et traitement medicamenteux. L’analyse des acides amines plasmatiques a permis le diagnostic de deficit en argininosuccinate synthetase (citrullinemie type I), confirmee par l’etude moleculaire. L’IRM a J13 montrait des anomalies en T1 et T2 des noyaux gris centraux avec hypersignal des noyaux lenticulaires predominant sur les regions pallidales associe a des anomalies de signal bilaterales symmetriques corticosouscorticales predominant en regions insulaires ayant fait evoquer la possibilite d’une necrose hemorragique. L’imagerie de controle realisee a 6 mois montrait cependant une quasi disparition de ces anomalies de signal. Le developpement psychomoteur de l’enfant a l’âge de 1 an est excellent. Conclusion Alors que l’aspect des lesions en phase precoce est assez specifique de l’atteinte neurologique par hyperammoniemie, il n’est pas forcement associe a un mauvais pronostic neurologique et peut regresser de facon quasi complete.

SFP-P184 – Métabolisme – Mode de révélation atypique d’un déficit du cycle de l’urée avec hyperlactacidémie majeure

Le cycle de l’uree permet l’elimination de l’ammoniaque issu du catabolisme proteique par sa transformation en uree. Le deficit d’une de ses enzymes se revele typiquement a la naissance apres un intervalle libre par une detresse neurologique avec hyperammoniemie sans acidocetose. Une alcalose respiratoire est frequemment retrouvee. Nous rapportons le cas d’un mode de revelation atypique d’un deficit du cycle de l’uree avec hyperlactacidemie majeure. Cas clinique Il s’agit d’une deuxieme enfant de parents caucasiens non consanguins, nee a terme. Une hypotonie et des mouvements de peda-lage apparaissent a J3 puis rapidement une degradation neurologique necessitant une ventilation mecanique. Deux arrets cardiorespiratoires surviennent lors du transfert en reanimation. Le bilan biologique montre une hyperlactacidemie majeure > 15Mm/l, mais une SvO2 > 60 %. On retrouve une ammoniemie a 609 μmol/l, une acidose metabolique avec pH a 7,10 ainsi qu’une insuffisance hepatocellulaire (TP 16 %, FV 32 %). Il n’existe pas de cetonurie. Un traitement medicamenteux epurateur et vitaminique est instaure avec arret transitoire des apports protidiques. L’hemofiltration ne sera pas debutee devant la survenue d’un troisieme arret cardiorespiratoire a l’amorcage du circuit. L’ammoniemie se normalise en 36 heures, l’hyperlactacidemie persistera pendant 5 jours alors que l’hemodynamique a ete rapidement restauree. Le diagnostic de deficit en argininosuccinate synthetase ou citrullinemie type I sera porte par la chromatographie des acides amines et confirme en biologie moleculaire. La presentation est inhabituelle par une defaillance hemodynamique au premier plan et une hyperlactacidemie majeure et prolongee.