SNP Shot: Genomic Insights

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a rare condition primarily impacting brain development. Individuals with MPPH are characterized by an abnormally large brain and head size at birth (megalencephaly), with rapid growth continuing for the first two years. A key feature of MPPH is bilateral perisylvian polymicrogyria (BPP), a brain malformation where the perisylvian region has excessive, small, and irregular folds (gyri) compared to the normal brain's ridges. Hydrocephalus, a buildup of fluid in the brain, can also occur.

These brain development issues result in various neurological problems. Individuals with MPPH syndrome experience developmental delays and intellectual disability, ranging in severity. Roughly half develop epilepsy with recurrent seizures early in childhood. Oromotor dysfunction, affecting mouth and tongue coordination, leads to drooling, difficulty swallowing (dysphagia), and delayed speech production (expressive language).

Approximately half of individuals with MPPH syndrome exhibit polydactyly, possessing an extra finger or toe on one or more hands or feet. This polydactyly is typically postaxial, meaning it occurs on the side of the hand or foot with the pinky finger or little toe.

The brain abnormalities seen in MPPH syndrome are also present in megalencephaly-capillary malformation syndrome (MCAP), a related disorder. However, MCAP is distinguished by abnormalities of small blood vessels in the skin (capillary malformations) and other features not commonly associated with MPPH syndrome.

Inheritance:

MPPH syndrome is typically inherited in an autosomal dominant manner, meaning only one copy of the mutated gene is needed to cause the condition. Almost all cases arise from new (de novo) gene mutations during the formation of eggs or sperm, or during early embryonic development. These individuals have no family history of the condition. In rare cases, individuals may inherit the altered gene from a parent who is unaffected but carries the mutation in their sperm or egg cells (germline mosaicism). Very rarely, somatic mosaicism can occur, where some cells have the mutation and others do not. Somatic mutations occur randomly in a single cell during embryonic development, and only cells descended from that initial cell will carry the mutation.