Introduction[edit | edit source]

"Smooth brain" appearance of lissencephaly.

Lissencephaly (LIS) is a spectrum that includes various brain malformations. [1] Its prevalence is estimated at 11.7 to 40 per million births. [2]

The prognosis depends on the severity of the syndrome. Most children remain in an early developmental level and have a short life expectancy, many dying before 10 years old. Aspiration and respiratory disease and the most common reasons for death.[3]

It is derived from the combination of two Greek words meaning soft ("lissos") and brain ("enkephalos"). [2] This smooth appearance of the brain, which can be observed in MRI imaging, is associated with malformations of cortical development such as agyria (absence of gyrus), pachygyria (extremely wide gyrus), and subcortical band heterotopia (SBH, double cortex). [1][4]

Lissencephaly is generally divided into two subtypes: type 1 (classical LIS / isolated lissencephaly sequence) and type 2 (cobblestone LIS). [5]

Type 1 can present in different forms such as isolated LIS, Miller-Dieker Syndrome (MDS), Norman-Roberts syndrome, and X-linked LIS with ambiguous genitalia (XLAG). [6][7]

Type 2 represents the severe end of a spectrum and can present in three syndromes: Walker-Warburg syndrome (WWS), muscle eye-brain (MEB) disease, and Fukuyama Congenital Muscular Dystrophy (FCMD). [8][9][7]

Clinically Relevant Anatomy[edit | edit source]

Whole Brain Sulci.png

The cerebral cortex is the outermost part of the brain surrounded by meninges. [10] It contains about 16 billion neurons, making up more than eighty per cent of the total weight of the brain. [11]

The development of the cerebral cortex, which is anatomically composed of the neocortex (or isocortex) and allocortex, [12] begins in the uterus at the rostral (anterior) portion of the neural tube. [13] With the proliferation of neurons in the forebrain, the 6-layer structure, which is the initial state of the neocortex, is formed. [14][12]

Later, as the volume of the brain grows, folding occurs, forming the gyrus and sulcus of the brain. [15] This process, called gyrification, is an adaptation of the brain to fit into the cranium, [5] starts in the 2nd trimester of gestation, [13] peaks in early adolescence, stabilise in adulthood and regresses with ageing. [16]

Gyrification is also important for the functional organization of the brain. [5] Prominent sulci such as Sylvian, central, parieto-occipital and calcarine divide the brain roughly into 4 lobes (frontal, parietal, temporal, occipital) each of which is specialized functions. [10][17]

As in lissencephaly, disruptions that occur in the gyrification process cause changes in the structure and thus function of the brain, leading to intellectual and motor disability, also intractable epilepsy. [13][5]

Pathological Process[edit | edit source]

MRI of a lissencephaly case with pachygria.

Lissencephaly is caused by genetic (mutations especially in LIS1 (PAFAH1B1) gene for classical LIS, [18] doublecortin (DCX) gene for SBH [7] and TUBA1A gene for microcephaly [19]) or non-genetic factors (viral infections, [7] [20] hypoxia, [7] preterm birth [21]). Pathological processes caused by genetic mutations can be summarized as follows;

Primitive neurons (neuroblasts) generated from the stem cells in the neural tube should migrate through the entire cortical thickness and stop precisely near the cortical surface, but instead, they fail to migrate and position properly. [22][5]

MRI of a lissencephaly case with SBH.

In type 1 LIS they accumulate below the preplate in only four layers, thus causing thickened cortex with reduced folding (pachygyria or agyria). [23][2]

Their accumulation in the cortical white matter just below the cortical grey matter and forming a thick grey layer called SBH. Reduction in the size of the cerebral cortex and some cases also microgyria accompany this. [24][25][26]

In type 2 LIS because of the impaired cortical basement membrane, they over-migrate into the subarachnoid space, causing a bumpy appearance as cobblestones on the cortical surface. [27][28]

Clinical Presentation[edit | edit source]

MRI of a micro-lissencephaly case.

Clinical symptoms/findings of lissencephaly can be various including:

  • Neurodevelopmental delay [20]
  • Intellectual disability [10]
  • Drug-resistant epilepsy [29]
  • Neonatal hypotonia later evolves into spastic quadriparesis with truncal hypotonia (in isolated lissencephaly sequence) [2]
  • Hypertonia [20]
  • Muscle spasms [30][10]
  • Facial dysmorphism: Usually MDS-related high forehead, small jaw, short upturned nose, protuberant upper lip and bitemporal hollowing. [31][32]
  • Microcephaly: If the brain size is ≥2.5 standard deviations below average for age and gender in LIS cases, it is called micro-lissencephaly. [7]
  • Macrocephaly [20]
  • Feeding difficulties such as dysphagia [33][10]
  • Low weight for age [20]

Diagnostic Procedures[edit | edit source]

Prenatal diagnosis is usually possible after 27 weeks of gestation with fetal Magnetic Resonance Imaging (MRI) or Ultrasound. [34] In the postnatal period, MRI is a reliable diagnostic method. [1]

Alongside neuroimaging methods, genetic testing is highly recommended as a modern diagnostic tool. [1] Considering that 31 genes providing almost 90% diagnostic yield associated with lissencephaly have been identified so far, [1] it is important in terms of prenatal diagnosis, prognostic information, risk of recurrence in the family, avoidance of unnecessary research, and personalized medicine. [2][7]

Outcome Measures[edit | edit source]

To measure the severity of impairment in classical lissencephaly and SBH, the 6-point grading system ranging from severe grade 1 (complete agyria) to mild grade 6 (SBH only) modified from Dobyns and Truwit [35] is developed.

Management[edit | edit source]

Clinical management is carried out by a multidisciplinary team. There is no specific treatment for LIS, treatment is individual and based on symptoms. [1] In this sense, some of the elements that can be included in the treatment are as follows:

  • Medication
  • Physiotheraphy
  • Occupational therapy
  • Speech and swallowing therapy

Differential Diagnosis[edit | edit source]

MRI of a lissencephaly case with cobblestone malformation.

During MRI analysis, lissencephaly needs to be well differentiated from other malformations of cortical developments (especially cobblestone and polymicrogyria). [1] Even a recent study [36] advocates that although Cobblestone malformation is often referred to as type 2 lissencephaly, this term should not be used due to its different pathological mechanisms. On the other hand, polymicrogyria is a characteristic malformation of schizencephaly and they were put together in a category of the classification system for malformations of cortical development [24].

In addition, major brain abnormalities (e.g., severe congenital microcephaly, agenesis of the corpus callosum, or cerebellar hypoplasia) are not found in classical LIS. [24] And compared to MDS, the face is less dysmorphic, and extracerebral malformations such as heart defects, omphalocele, cleft palate and genital anomalies, which are occasionally reported in MDS, are not generally encountered. [2]

Resources[edit | edit source]


References[edit | edit source]

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  2. 2.0 2.1 2.2 2.3 2.4 2.5 Fry AE, Cushion TD, Pilz DT. The genetics of lissencephaly. InAmerican Journal of Medical Genetics Part C: Seminars in Medical Genetics 2014 Jun (Vol. 166, No. 2, pp. 198-210).
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