Lissencephaly type I - subcortical band heterotopia spectrum
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Lissencephaly type I, also known as classic lissencephaly, is a heterogeneous group of disorders of cortical formation characterized by a smooth brain, with absent or hypoplastic sulci and is strongly associated with subcortical band heterotopia (see classification system for cortical malformations) and therefore the term lissencephaly type I - subcortical band heterotopia spectrum is probably a better choice.
This article focuses on the lissencephaly end of the lissencephaly - subcortical band heterotopia spectrum. For further discussion refer to the articles on lissencephaly (general overview) and band heterotopia.
Lissencephaly type I is rare, with a prevalence of 11.7 per million births in one study from the Netherlands 7. No strong gender predilection is reported 7.
In all forms of type I lissencephaly, infants present with marked hypotonia and paucity of movement and difficulty feeding. Although often these children have head circumference within normal limits at birth, head growth is slow, and most have microcephaly by one year of age 1,4.
Seizures are also a prominent feature, becoming apparent in 90% of children before the age of 6 months, usually initially in the form of infantile spasms (West syndrome). Later they progress to Lennox-Gastaut syndrome 4.
Type I lissencephaly results from any one of at least 5 (perhaps more) mutations 1,4,5:
- isolated: without a known genetic defect
PAFAH1B1 (LIS1) gene mutation
- isolated (LIS1)
- Miller-Dieker syndrome (MDS)
- doublecortin (DCX) gene mutation
- presents as lissencephaly usually in males
- presents as subcortical band heterotopia (double cortex) usually in females 4,5
Histological examination of the cortex reveals only 4 poorly organized layers (rather than the normal 6) 4:
- marginal zone: poorly defined with increased cellularity
- superficial cortical grey zone with diffusely scattered neurons
- relatively neuron-sparse zone
- deep cortical grey zone with neurons often oriented in columns
Although morphological changes are visible on all modalities able to image the brain (antenatal and perinatal ultrasound, CT and MRI), MRI is the modality of choice in assessing the changes of lissencephaly.
The brain is usually grossly abnormal in outline, with only a few shallow sulci and shallow Sylvian fissures, taking on an hourglass or figure-8 appearance on axial imaging. The cortex is markedly thickened measuring 12-20 mm (rather than the normal 3-4 mm) 6. Subcortical band heterotopia is also sometimes visible.
The subcortical heterotopia is usually diffuse and symmetric but sometimes an anterior-posterior predilection is present which suggests a specific underlying genetic abnormality 4:
- anterior predilection suggests mutations of DCX
- posterior predilection suggests mutations of LIS1
Additional features usually also present include 4:
- enlarged ventricles, especially posteriorly
- flattened/hypoplastic anterior corpus callosum
- cavum septum pellucidum et vergae
Treatment and prognosis
In both isolated lissencephaly or Miller-Dieker syndrome (MDS) developmental prognosis is poor, with individuals never achieving a developmental equivalent than 3-5 months age.
To make matters worse, epilepsy in these individuals is usually difficult to control.
Regarding actual survival, the prognosis is worse for children with Miller-Dieker syndrome (MDS), with most succumbing (most frequently to aspiration pneumonia) within the first two years of life. In children with isolated lissencephaly, survival is somewhat better with approximately half of individuals reaching 10 years of age, but most dying before the end of adolescence 4.
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- 2. Pilz DT, Quarrell OW. Syndromes with lissencephaly. J. Med. Genet. 1996;33 (4): 319-23. J. Med. Genet. (link) - Free text at pubmed - Pubmed citation
- 3. Allanson JE, Ledbetter DH, Dobyns WB. Classical lissencephaly syndromes: does the face reflect the brain? J. Med. Genet. 1998;35 (11): 920-3. J. Med. Genet. (link) - Free text at pubmed - Pubmed citation
- 4. Dobyns WB, Das S. LIS1-Associated Lissencephaly/Subcortical Band Heterotopia. NCBI bookshelf
- 5. Hehr U, Uyanik G et al. DCX-Related Disorders. NCBI bookshelf
- 6. Barkovich AJ, Koch TK, Carrol CL. The spectrum of lissencephaly: report of ten patients analyzed by magnetic resonance imaging. Ann. Neurol. 1991;30 (2): 139-46. doi:10.1002/ana.410300204 - Pubmed citation
- 7. de Rijk-van Andel JF, Arts WF, Hofman A, Staal A, Niermeijer MF. Epidemiology of lissencephaly type I. (1991) Neuroepidemiology. 10 (4): 200-4. doi:10.1159/000110270 - Pubmed