RT Journal Article SR Electronic T1 Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 303 OP 311 DO 10.1136/jmedgenet-2014-102952 VO 52 IS 5 A1 José-Mario Capo-Chichi A1 Sarah Boissel A1 Edna Brustein A1 Sarah Pickles A1 Catherine Fallet-Bianco A1 Christina Nassif A1 Lysanne Patry A1 Sylvia Dobrzeniecka A1 Meijiang Liao A1 Damian Labuda A1 Mark E Samuels A1 Fadi F Hamdan A1 Christine Vande Velde A1 Guy A Rouleau A1 Pierre Drapeau A1 Jacques L Michaud YR 2015 UL http://jmg.bmj.com/content/52/5/303.abstract AB Background The heterogeneous group of 3-methylglutaconic aciduria disorders includes several inborn errors of metabolism that affect mitochondrial function through poorly understood mechanisms. We describe four newborn siblings, from a consanguineous family, who showed microcephaly, small birth weight, severe encephalopathy and 3-methylglutaconic aciduria. Their neurological examination was characterised by severe hypertonia and the induction of prolonged clonic movements of the four limbs upon minimal tactile stimulation. Methods and results Using homozygosity mapping and exome sequencing, we identified a homozygous truncating mutation (p.I562Tfs*23) in CLPB segregating with the disease in this family. CLPB codes for a member of the family of ATPases associated with various cellular activities (AAA+ proteins) whose function remains unknown. We found that CLPB expression is abolished in fibroblasts from the patients. To investigate the function of this gene, we interfered with the translation of the zebrafish clpb orthologue using an antisense morpholino. The clpb morphants showed an abnormal touch-evoked response with increased swim velocity and tail beat frequency. This motor phenotype is reminiscent of that observed in the patients and is suggestive of increased excitability in neuronal circuits. Interestingly, knocking down clpb reduced the number of inhibitory glycinergic interneurons and increased a population of excitatory glutamatergic neurons in the spinal cord. Conclusions Altogether, our study suggests that disruption of CLPB causes a novel form of neonatal encephalopathy associated with 3-methylglutaconic aciduria.