Lissencephaly and migration disorders

A spectrum of malformations of cortical development arising from disordered neuronal migration during the second trimester. The cortex is too smooth (agyria / pachygyria, "lissencephaly"), arranged in a band beneath the normal cortex (subcortical band heterotopia, "double cortex"), nodular and ectopic (heterotopia), too small and overfolded (polymicrogyria), or over-migrated past the pial surface (cobblestone). The clinical phenotype is dominated by global developmental delay, drug-resistant epilepsy (frequently infantile spasms), microcephaly, and hypotonia evolving to spasticity.

Imaging is the entry point. The right neuroradiologist makes more diagnostic progress in 20 minutes than a gene panel does in three weeks. Organize by MRI pattern, then by inheritance and extra-CNS clues.

1. Smooth cortex (lissencephaly / pachygyria): classical "agyria-pachygyria complex," gradient (anterior-worse vs posterior-worse) is a key clue.
2. Subcortical band ("double cortex"): a strip of gray matter between the cortex and the ventricles. Almost always DCX in females.
3. Nodules along the ventricles: periventricular nodular heterotopia.
4. Excessive small gyri: polymicrogyria. Symmetric vs asymmetric; bilateral perisylvian is the classic pattern.
5. Cobblestone cortex with overlying meningeal-pial breaches, brainstem kinking, cerebellar cysts, eye anomalies: alpha-dystroglycanopathy (over-migration).

Classical lissencephaly (smooth cortex, agyria-pachygyria)

• LIS1 / PAFAH1B1 (17p13.3 deletion or sequence variant): the most common classical lissencephaly gene. Lissencephaly worse posteriorly (posterior > anterior gradient). Miller-Dieker syndrome is a 17p13.3 contiguous deletion encompassing LIS1 plus YWHAE; presents with lissencephaly plus dysmorphic facial features (bitemporal hollowing, short nose with upturned nares, prominent upper lip with thin vermilion border, micrognathia). CMA picks it up.
• DCX lissencephaly / subcortical band heterotopia (X-linked): males have lissencephaly worse anteriorly (anterior > posterior gradient, opposite of LIS1). Female carriers have subcortical band heterotopia (double cortex) with milder epilepsy and ID. Mother-to-son segregation; counsel female carriers carefully.
• TUBA1A, TUBB2B, TUBA8 (tubulinopathies): lissencephaly + brainstem / cerebellar hypoplasia + corpus callosum dysgenesis + basal ganglia dysmorphism. Highly variable; AD or X-linked.
• RELN, VLDLR: recessive lissencephaly with cerebellar hypoplasia (lissencephaly + cerebellar hypoplasia + areflexia = LCH).
• ARX (X-linked): lissencephaly + abnormal genitalia in males (XLAG syndrome); also a major cause of X-linked infantile spasms.

Heterotopia (gray matter where it shouldn't be)

• Periventricular nodular heterotopia (FLNA, X-linked): female-predominant (often lethal in males in utero); bilateral periventricular nodules; seizures with normal-to-mild ID; aortic dissection and joint laxity (vascular Ehlers-Danlos overlap) in some.
• Subcortical band heterotopia: DCX in females (see above).

Polymicrogyria

• Bilateral perisylvian polymicrogyria: the most recognizable PMG syndrome; "congenital bilateral perisylvian syndrome" with pseudobulbar palsy, dysarthria, seizures, variable ID. Multiple genes; consider 22q11.2 deletion which can cause PMG.
• Schizencephaly + polymicrogyria (EMX2, COL4A1): structural clefts lined by polymicrogyric cortex.
• Congenital CMV is a common acquired mimic of genetic PMG; always send CMV PCR / NAT.

Cobblestone lissencephaly (over-migration; alpha-dystroglycanopathies)

The cortex extends past the pial surface in disorganized "cobbles." Recessive congenital muscular dystrophy with brain and eye involvement. From severe to milder:

• Walker-Warburg syndrome: the most severe end. Cobblestone lissencephaly + cerebellar / brainstem malformation + congenital muscular dystrophy + ocular anomalies (microphthalmia, cataract, retinal dysplasia) + hydrocephalus. Usually fatal in infancy.
• Muscle-eye-brain disease (Finnish): intermediate severity; survives infancy with profound ID, myopia, retinal dysplasia, glaucoma, congenital muscular dystrophy.
• Fukuyama congenital muscular dystrophy (FKTN, Japanese founder): less severe brain malformation, congenital muscular dystrophy, ID, seizures.
• Causal genes (alpha-dystroglycanopathy panel): POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, ISPD, GMPPB, others.

Other migration / cortical phenotypes worth knowing

• Aicardi syndrome (X-linked dominant, lethal in males): female-only; agenesis of the corpus callosum + chorioretinal lacunae + infantile spasms. Polymicrogyria and heterotopia coexist.
• Lissencephaly + cerebellar hypoplasia + immune deficiency: consider RELN and ciliopathies.

1. Brain MRI read by a neuroradiologist comfortable with malformations of cortical development. Specify the question: gradient, gyration pattern, cerebellar / brainstem involvement, corpus callosum, basal ganglia.
2. CMA as first-tier; catches Miller-Dieker (17p13.3), 22q11.2, and other contiguous deletions.
3. Targeted single-gene testing when the pattern is classical: LIS1 for posterior-worse lissencephaly with dysmorphism, DCX for anterior-worse lissencephaly or female double cortex, FLNA for female periventricular nodular heterotopia.
4. Migration / lissencephaly gene panel or exome when imaging is non-classical.
5. CK in any cortical malformation with hypotonia or weakness; dystroglycanopathy panel if elevated or cobblestone pattern.
6. Congenital CMV testing (CMV PCR / NAT from blood or, ideally, newborn dried blood spot) in any polymicrogyria or periventricular calcification phenotype.
7. EEG for infantile spasms and other epilepsy phenotypes; treatment with vigabatrin / ACTH does not wait on the genetic diagnosis.