Novel NDE1 homozygous mutation resulting in microhydranencephaly and not microlyssencephaly.

Lissencephaly is characterized by deficient cortical lamination. Recently homozygous NDE1 mutations were reported in three kindred afflicted with extreme microcephaly with lissencephaly or microlissencephaly. Another severe developmental defect that involves the brain is microhydranencephaly which manifests with microcephaly, motor and mental retardation and brain malformations that include gross dilation of the ventricles with complete absence of the cerebral hemispheres or severe delay in their development. In the three related patients with microhydranencephaly that we had reported previously, we identified a homozygous deletion that encompasses NDE1 exon 2 containing the initiation codon. The mutation is predicted to result in a null allele. Herein we compare the clinical phenotypes of our research patients to those reported as microlissencephaly. The clinical findings in our patients having the fourth NDE1 mutation reported so far widen the spectrum of brain malformations resulting from mutations in NDE1.

Familial microhydranencephaly, a family that does not map to 16p13.13-p12.2: relationship with hereditary fetal brain degeneration and fetal brain disruption sequence.

Microhydranencephaly (MHAC) is a serious developmental brain anomaly characterized by microcephaly with severe reduction of brain hemispheres and intracranial space filled with cerebrospinal fluid without signs of intracranial hypertension. Clinical findings are very similar to fetal brain disruption sequence - severe microcephaly, scalp rugae, and profound developmental delay; however, although fetal brain disruption sequence is a sporadic condition caused by an external disruptive event, familial cases of MHAC presumably result from a process of progressive brain damage also termed as 'hereditary fetal brain degeneration'. Familial occurrence of this phenotype is very rare - only three reports on four families have been published so far. Here we present two new patients - affected brothers from Slovakia - and provide an update on a previously described case from a Turkish Anatolian family. We also present data excluding linkage to an MHAC locus 16p13.13-p12.2 in the Slovak family. We compare clinical and imaging findings in all five families and suggest genetic heterogeneity for this condition. In genetic counseling for this phenotype, especially in the absence of any known teratogenic factors in pregnancy, we suggest that the possibility of recurrence should be considered.