Continuing Education Activity

Lissencephaly is a spectrum of severe and rare brain malformations. It is caused by non-genetic and genetic factors. Treatment of children with lissencephaly is supportive and aims to reduce symptoms severity. This activity reviews the etiology, epidemiology, evaluation, and treatment options and highlights the role of the professional team in the care of patients with this condition.

Objectives:

• Identify the etiology of lissencephaly.
• Describe the evaluation of lissencephaly.
• Outline the management options available for lissencephaly.
• Summarize interprofessional team strategies for improving care coordination and improving outcomes in patients with lissencephaly.

Introduction

Lissencephaly includes a range of severe brain malformations, including agyria (absent gyri), pachygyria (broad gyri), and subcortical band heterotopia.[1] In lissencephaly (which literally means smooth brain), the surface of the brain appears smooth.[2] It may occur as an isolated lissencephaly or in association with certain syndromes (Miller-Dieker syndrome).[3]

Lissencephaly is caused by a defect in neuronal migration during embryonic development between 12 and 24 weeks of gestation that results in the absence of normal development of brain gyri and sulci.[4] Children with lissencephaly present with significant developmental delays and mental disability, but these vary from child to child depending on the degree of brain malformation and intractable epilepsy.[5]

Etiology

Lissencephaly can be caused by non-genetic and genetic factors. Non-genetic factors include viral infections of the mother or the fetus, especially during the first trimester and insufficient supply of oxygenated blood to the brain during fetal development.[6] There are several genetic causes also.[2][7]

Some of the known genetic causes are listed below:

• LIS1

LIS1 (PAFAH1B1) is the most studied. This gene is located on chromosome 17p13.3.[8] LIS1 regulates the motor protein dynein, which is linked to neuronal nuclei movement along microtubules.[9] The mutation or deletion in the LIS1 gene is associated with both isolated Lissencephaly syndrome and Miller-Dieker syndrome.[8]

• DCX

DCX is located on the X chromosome.[10] DCX encodes for the doublecortin protein, which encodes a neuronal microtubule-associated protein, which is known to be essential for neuronal migration. DCX mutation causes defects in neuronal migration and reduced folding in the cerebral cortex.[11][12] Males with DCX mutation are more likely to be severely affected, while females with the same mutation have a milder version of the syndrome.[13]

• ARX

The ARX gene encodes for the aristaless related homeobox protein, which is a transcription factor with an important role in the forebrain and other tissue.[14] Children with ARX mutation present with other symptoms such as the absence of portions of the brain (corpus callosum agenesis), abnormal genitalia, and severe epilepsy.[15][16]

• RELN

RELN gene encodes reelin, an extracellular matrix glycoprotein. The mutation of this gene is involved in lissencephaly associated with cerebellar hypoplasia and hippocampal abnormalities.[17]

• Other genes:

Several genes have established a relationship with lissencephaly. Those genes are VLDLR, ACTB, ACTG1, TUBG1, KIF5C, KIF2A, and CDK5.[18]

Cytomegalovirus (CMV) has been associated with developing lissencephaly by reducing blood supply to the fetal brain. The severity of CMV infection depends on the gestational age. Early infection is more likely to cause lissencephaly because neuronal migration takes place early in the pregnancy.[19]

Epidemiology

Lissencephaly is a relatively rare disorder of the brain and the incidence of which is not known. A study of lissencephaly in the Netherlands estimated the prevalence of around 1.2/100,000 births.[20][21] The diagnosis and the prevalence of lissencephaly will increase with improving imaging technology.

Genetic studies of 17 genes associated with lissencephaly revealed that LIS1 mutation or deletion accounts for 40% of the patients, and 23% was associated with DCX mutation, followed by TUBA1A (5%), and DYNC1H1 (3%).[22]

Pathophysiology

The genetic and non-genetic causes lead to an absent migration of the newly formed neurons to the surface of the brain. This results in an absent infolding of the cerebral cortex in addition to the reduced number of cellular layers in the cortex.

History and Physical

Lissencephaly has different levels of severity and symptoms.[23]

Symptoms may include seizures, feeding difficulty, muscle spasm, mental disability, severe psychomotor impairment, failure to thrive, developmental delays, and sometimes hands, finger, or toe anomalies. However, some children may develop normally with a mild learning disability.[24][25]

Epilepsy develops in the first year of life in 9 out of 10 lissencephaly cases.

Evaluation

Lissencephaly is usually diagnosed at birth through clinical evaluation and head imaging (ultrasound, computed tomogram (CT), or magnetic resonance imaging (MRI)). It is characterized by the absence or reduction of the sulci and gyri of the cerebral surface and a thickened cortex. To confirm the diagnosis, DNA studies like chromosomal analysis or/and specific gene mutational analysis are needed to find a mutation.[26][27] Another test that can aid in the diagnosis is the electroencephalogram (EEG).[28]

Treatment / Management

Management for children with lissencephaly is symptomatic and supportive. Treatment aims to improve the intake of nutrients in patients with feeding difficulties and the use of anticonvulsant drugs to prevent or control seizures. Genetic counseling is usually offered to families of affected children, coupled with genetic studies.[25]

Differential Diagnosis

There are more than 20 types of lissencephaly, most of them are listed under 2 main categories: Classic lissencephaly (Type 1) and Cobblestone lissencephaly (Type 2). Each category shares similar clinical presentations but different genetic mutations.[20][29]

Examination of the brain in type I lissencephaly shows a cerebral cortex with four layers instead of six layers as in normal patients, while in type 2 lissencephaly the cerebral cortex is disorganized, and appears pebbled or nodular due to complete displacement of the cerebral cortex with clusters of cortical neurons separated by glio-mesenchymal tissue. The patients also had abnormalities of muscle and eyes.[20]

• Classic lissencephaly (type 1):

1. LIS1: Isolated lissencephaly and Miller-Dieker syndrome (lissencephaly associated with facial dysmorphism).[30]
2. LISX1: DCX gene mutation. Compared to lissencephaly caused by LIS1 mutations, DCX shows a six-layered cortex instead of four.
3. Isolated lissencephaly without other known genetic defects

• Cobblestone lissencephaly (type 2):

1. Walker-Warburg syndrome
2. Fukuyama syndrome
3. Muscle-eye-brain disease

• Other types cannot be placed in one of the two aforementioned groups:

1. LIS2: Norman-Roberts syndrome, similar to type I lissencephaly or Miller-Dieker syndrome, but without deletion of the chromosome 17.
2. LIS3
3. LISX2
4. Microlissencephaly: It is a combination of the absence of normal cerebral cortex folding and an abnormally small head. Children with usual lissencephaly have a normal head size at birth. In children with reduced head size at birth, microlissencephaly is typically diagnosed.

It is also important to differentiate between lissencephaly and polymicrogyria, which is a different developmental malformation of the brain.

Prognosis

The prognosis varies depending on the severity of the syndrome. Many children may remain in an early developmental level. Life expectancy is short, and many will die before the age of 10 years. The most common cause of death among lissencephaly patients is aspiration and respiratory disease.

Lissencephaly may affect some areas of the brain more severely than others. The gradient of severity is dependent on the lissencephaly type and gene mutations.[31]

Complications

Every case is different, but the most common complications in patients with lissencephaly are breathing problems, feeding difficulty, and seizures.[32]

Deterrence and Patient Education

It is very important to teach the patient's family how to care for patients with feeding problems, learning disabilities, and seizures. It is also important to do genetic counseling when there is a risk for lissencephaly.

Enhancing Healthcare Team Outcomes

An interprofessional approach to lissencephaly is recommended. Lissencephaly is a spectrum of disorders characterized by severe mental insult. Patients with lissencephaly are at an increased risk of having learning disabilities, developmental delays, seizures, and muscle spasms. An interprofessional team consisting of a geneticist, primary clinicians, physiatrist, and neurologist is recommended to decrease the morbidity and mortality of this disease. The primary clinicians should refer these patients to the appropriate specialist as soon as the diagnosis is made.[24]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

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Disclosure: Mohammad Kattuoa declares no relevant financial relationships with ineligible companies.

Disclosure: Joe Das declares no relevant financial relationships with ineligible companies.