Walsh (1957) described 3 affected sibs with normal parents. At least 2 of the 3 were female. Mental defect and optic atrophy were present. In another family 2 sibs may have been affected. Distinguishing between macrocephaly and megalencephaly ... Walsh (1957) described 3 affected sibs with normal parents. At least 2 of the 3 were female. Mental defect and optic atrophy were present. In another family 2 sibs may have been affected. Distinguishing between macrocephaly and megalencephaly is necessary: in megalencephaly, the brain is enlarged. In achondroplasia (100800), macrocephaly has been thought to be accompanied by true megalencephaly. Capo-chichi et al. (2013) reported a brother and sister, born of consanguineous parents of North African descent, with megalencephaly (greater than 97th percentile) and intellectual disability. Both patients had a normal neonatal course, but showed delayed psychomotor development and cognitive impairment. The sibs were not dysmorphic, but had a broad forehead; the head of 1 child was scaphocephalic. Brain MRI showed normal ventricle and subarachnoid spaces, as well as a slightly enlarged corpus callosum, indicating that the macrocrania is secondary to an increase in brain volume and not due to hydrocephalus. Neither had overt seizures, but EEG in 1 patient showed some epileptic activity in the right temporal lobe. Neither had evidence of cortical tubers.
In 2 sibs, born of consanguineous parents, with megalencephaly and intellectual disability, Capo-Chichi et al. (2013) identified a homozygous truncating mutation in the TBC1D7 gene (612655.0001). The mutation was found by homozygosity mapping combined with exome sequencing. Patient ... In 2 sibs, born of consanguineous parents, with megalencephaly and intellectual disability, Capo-Chichi et al. (2013) identified a homozygous truncating mutation in the TBC1D7 gene (612655.0001). The mutation was found by homozygosity mapping combined with exome sequencing. Patient cells showed no TBC1D7 mRNA or protein, consistent with nonsense-mediated mRNA decay. Patient cells showed constitutive activation of the mTORC1 complex (see 601231) compared to controls, consistent with TBC1D7 playing the role of an upstream regulator of mTORC1.