Lissencephaly and Periventricular Heterotopia

Lissencephaly (LIS)

LIS is a neuronal migration disorder and represents a malformation spectrum resulting from mutations of either LIS1 or DCX genes. In severe LIS, the cortex lacks surface folds. At the same time, manifestations include abnormally broad folds or a heterotopic layer of gray matter embedded in the white matter below the cortex.

Fig.1 The classical lissencephaly spectrum. (Fry, 2014)

Key Factors for LIS

Malformation syndromes such as LIS have been recognized, and specific causative gene defects have been identified in recent years. Five genes have been identified that cause or contribute to LIS in humans: LIS1, DCX, RELN, ARX, and TUBA1A.

Fig.2 Genetic heterogeneity in lissencephaly. (Fry, 2014)

Periventricular Heterotopia

Periventricular nodular heterotopia (PH) is a heterogeneous group of malformations in which more profound heterotopic neurons are observed. PH features the subset of neurons that line the walls of lateral ventricles after failing to migrate completely into the cerebral cortex.

This malformation may involve both sides of the brain or be restricted to a single hemisphere less frequently. They can occur singly or combined with other findings, including polymicrogyria, microcephaly, hydrocephalus, and limb abnormalities. PH can be caused by genetic mutations (e.g., FilaminA, ARFGEF2) or extrinsic factors (e.g., irradiation, infection, injury). Seizures are the most common presenting feature.

Key Factors for PH

PH is caused by genetic mutations or extrinsic factors, such as infections or prenatal injuries; PH has previously been identified with amniotic band syndrome in some clinical cases. Two genes are already known to cause PH: filaminA (FLNA) and adenosine diphosphate-ribosylation factor guanine exchange factor 2 (ARFGEF2). FLNA mutations are reported in all familial X-linked PH and approximately 25% of sporadic cases. Rare patients of both genders with FLN1 mutations had unilateral PH. In addition, patients with mutations of the ARFGEF2 gene present microcephaly, slightly enlarged ventricles, and delayed myelination. The X-linked dominant form of PH is caused by mutations in FLNA, whereas mutations cause the autosomal recessive form of PH and microcephaly in ARFGEF2.

Fig.3 Representative MRI section of PH in a patient with FILNA mutations. (Nadia Bahi-Buisson, 2013)

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References

1. Fry, A. E.; et al. The genetics of lissencephaly. In American Journal of Medical Genetics Part C: Seminars in Medical Genetics (Vol. 166, No. 2, pp. 198-210). 2014, June.
2. Bahi-Buisson, N.; Guerrini, R. Diffuse malformations of cortical development. Handbook of clinical neurology. 2013, 111, 653-665.