Macrocephaly/megalencephaly Syndrome, Autosomal Recessive
A number sign (#) is used with this entry because of evidence that autosomal recessive macrocephaly/megalencephaly syndrome (MGCPH) is caused by homozygous mutation in the TBC1D7 gene (612655) on chromosome 6p24.
DescriptionMacrocephaly refers to an abnormally enlarged head inclusive of the scalp, cranial bones, and intracranial contents. Macrocephaly may be due to megalencephaly (true enlargement of the brain parenchyma), and the 2 terms are often used interchangeably in the genetic literature (reviews by Olney, 2007 and Williams et al., 2008). Autosomal recessive macrocephaly/megalencephaly syndrome is characterized by an enlarged cranium apparent at birth or in early childhood. Affected individuals have intellectual disability and may have dysmorphic facial features resulting from the macrocephaly (summary by Alfaiz et al., 2014).
Clinical FeaturesWalsh (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.
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.
Alfaiz et al. (2014) reported 2 sisters, born of Italian parents from 2 distant villages, with macrocephaly and intellectual disability. They showed mildly delayed psychomotor development and had severe learning disabilities in school. Dysmorphic features included scaphocephaly/dolichocephaly, prognathism, and pointed chin. Both developed celiac disease and renal oxalate stones in childhood, and depression with psychosis as young adults. Additional features included myopia, astigmatism, and bilateral and patellar dislocation with flat trochlea. Brain MRI of 1 patient showed cerebral calcifications, whereas brain imaging of the other patient was normal. Neither had seizures or evidence of tuberous sclerosis.
InheritanceDe Almeida and Debarros (1964) observed parental consanguinity in cases of megalencephaly.
The transmission pattern of megalencephaly in the family reported by Capo-Chichi et al. (2013) was consistent with autosomal recessive inheritance.
Molecular GeneticsIn 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.
In 2 Italian sisters with macrocephaly and intellectual disability, Alfaiz et al. (2014) identified a homozygous truncating mutation in the TBC1D7 gene (612655.0002). The mutation was found by exome sequencing. Patient cells showed no detectable TBC1D7 protein on Western blot analysis, suggesting a loss of function. Loss of the TBC1D7 protein was associated with activation of mTORC1, and cellular studies showed a delay in initiation of the autophagy process.
HistoryWeil (1933) described the case of a male in which at autopsy the brain (at age 7 years) weighed 1,856 gm. The precentral area was underdeveloped, as were skeletal musculature and the adrenal medullae. Mental development had been normal until age 6. A brother had a large head but was well at age 12 years.