SNP Shot: Genomic Insights

Isolated lissencephaly sequence (ILS) is a condition impacting brain development before birth. Typically, the outer layer of the brain, the cerebral cortex, has a complex, layered structure with many folds and grooves (gyri). In individuals with ILS, the cerebral cortex is disorganized, and the brain's surface becomes unusually smooth, showing a lack (agyria) or reduction (pachygyria) in these folds and grooves. This often hinders brain growth, leading to a smaller than normal brain size (microcephaly). Consequently, ILS results in severe intellectual disability, delayed development, and recurring seizures (epilepsy).

Epilepsy affects over 90% of people with ILS, frequently beginning within the first year of life. Infantile spasms, a severe type of seizure, occur in up to 80% of infants with ILS and can lead to significant brain dysfunction (epileptic encephalopathy). After the initial months, children with ILS typically experience various types of seizures, including persistent infantile spasms, brief losses of consciousness (absence seizures), sudden episodes of muscle weakness (drop attacks), rapid, uncontrollable muscle jerks (myoclonic seizures), and episodes involving muscle rigidity, convulsions, and loss of consciousness (tonic-clonic seizures).

Infants with ILS may exhibit weak muscle tone (hypotonia) and feeding difficulties, contributing to poor overall growth. Hypotonia also affects breathing muscles, frequently causing respiratory problems that can lead to aspiration pneumonia, a serious bacterial lung infection. Children with ILS commonly develop muscle stiffness (spasticity) in their limbs and an abnormal curvature of the spine (scoliosis). In rare instances, muscle stiffness can progress to paralysis (spastic paraplegia). Individuals with ILS typically cannot walk and rarely crawl. Most children with ILS do not develop communication skills.

Inheritance:

The inheritance pattern of ILS varies depending on the specific gene involved. ILS caused by mutations in the PAFAH1B1 or TUBA1A gene follows an autosomal dominant inheritance pattern, meaning that only one copy of the mutated gene is needed in each cell to cause the disorder. Most cases arise from new mutations in the gene, occurring in individuals without a family history of the condition. When mutations in the DCX gene cause ILS, it is inherited in an X-linked manner. X-linked conditions occur when the mutated gene is located on the X chromosome, one of the two sex chromosomes. In males, who have only one X chromosome, a single altered copy of the DCX gene in each cell is enough to cause the condition. Females, having two X chromosomes, may experience a less severe condition called subcortical band heterotopia with one altered copy of the DCX gene, or they may not show any symptoms. Notably, fathers cannot pass X-linked traits to their sons.