Early myoclonic encephalopathy caused by a disruption of the neuregulin-1 receptor ErbB4

Abstract

The tyrosine kinase receptor ErbB4 (erythroblastic leukemia viral oncogene homolog 4) plays a crucial role in numerous neurobiological processes in the developing and adult brain. Moreover, recent molecular genetics studies implicate ErbB4 in the pathophysiology of schizophrenia. However, the phenotypic consequences of haploinsufficiency of ErbB4 are not known, as no coding mutations have been identified until now. Here, we present a patient with early myoclonic encephalopathy and profound psychomotor delay with a de novo reciprocal translocation t(2;6)(q34;p25.3), disrupting the ErbB4 gene. This patient represents the first case of haploinsufficiency for one of the ErbB family members of tyrosine kinase receptors.

Figure 1

EEG taken during sleep at the age of 18 months showing hypsarrhythmia with periods of suppression-burst pattern. Longitudinal montage calibration 70 μV, 1 sec between lines.

Figure 2

Clinical pictures of the patient at age 18 months (left), and 4 years and 10 months (right).

Figure 3

Schematic representation of the translocation and the two breakpoints on 2q34 and 6p25.3: (a) Partial karyotype of the patient showing the reciprocal translocation between chromosomes 2q and 6p. (b) FISH analysis on metaphase spreads of the patient with BAC clone RP11-694B12 spanning the 2q34 breakpoint showing signals on chromosome 2, and derivatives 2 and 6. (c) Schematic representation of the 2q34 breakpoint. The breakpoint-spanning clone, RP11-694B12, maps within the first intron of the ErbB4 gene, and therefore disrupts the ErbB4 gene (forward slash). The orientation of ErbB4 is indicated by the black arrow. The exons are indicated as black boxes. (d) Schematic representation of the 6p25.3 breakpoint. The breakpoint resides in the region covered by the BAC clones RP11-323F15 (signal on the derivative chromosome 2) and RP11-707D01 (signal on the derivative chromosome 6), and interrupts the GMDS gene between exons 4 and 8 (brackets). The orientation of GMDS is indicated by the arrow. The exons are indicated as black boxes. Positions of the genes and BAC clones are indicated in Mb and are based on the Ensembl view release 43, Feb 2007 (http://www.ensembl.org/Homo_sapiens/). EX exon.