Disorders of Cortical Organization

Primary Microcephaly (Microcephaly Vera)

Diagnosis

Microcephaly is defined as a head circumference of 2 standard deviations below the mean or smaller. Congenital microcephaly is defined as birth occipitofrontal circumference (OFC) of 2 standard deviations below the mean or smaller. Many different types of brain disorders can result in congenital microcephaly, including malformations, metabolic disorders and various extrinsic factors such as teratogens,

hypoxia-ischemia or other injuries. Children with congenital microcephaly and otherwise normal brain structure have been classified as having primary microcephaly or microcephaly vera. Delayed myelinization and simplified gyral patterns may be seen.

Clinical Course and Management

The prognosis with primary microcephaly is remarkably variable. Even with very small head size, some children have only moderate developmental delay. Others have severe to profound mental retardation, which is often associated with spastic quadriparesis and epilepsy. These groups are difficult to recognize by MRI scans, although children with severe abnormalities often have delayed myelinization. Participation in early-intervention developmental programs should begin early in life and all should be watched closely for seizures.

Genetics

Familial recurrence in siblings of both sexes has been observed often in primary microcephaly, which is consistent with autosomal recessive inheritance in most families. However, families with X-linked inheritance have also been reported.

Hemimegalencephaly

Diagnosis

Hemimegalencephaly (HMEG) is a malformation characterized by enlargement and dysplasia of one cerebral hemisphere, but is not strictly limited to one hemisphere. The entire hemisphere appears to be enlarged in most patients, and all have enlargement of at least one lobe of the brain (Fig. 3), and abnormalities seen on an electroencephalogram (EEG) are often extensive throughout the abnormal hemisphere. Heterotopia is commonly seen and the ventricles are enlarged in most patients.

Figure 3. Hemimegalencephaly. MRI shows right hemimegalencephaly with dys-plastic gyral pattern, mildly thickened cortex, abnormal white matter and enlarged right lateral ventricle on coronal (left) and axial (right) images.

Clinical Course and Management

The clinical presentation for patients with HMEG includes hemiparesis, hemi-anopia, seizures and developmental delay with mental retardation, which vary greatly in severity. Most patients have isolated HMEG with no associated anomalies, although some have neurocutaneous disorders such as Klippel-Trenauney syndrome, the epidermal (sebaceous) nevus syndrome, hypomelanosis of Ito, or neurocutane-ous melanosis. The seizures in HMEG are severe and often intractable, and frequently result in deterioration in cognitive skills due to seizure frequency and required medications. They most often start within the first 6 months of life, typically arising from the megalencephalic hemisphere. Infantile spasms and drop attacks may be present in early childhood. When medical treatment appears to be inadequate, a hemispherectomy should be considered.

Genetics

No examples of familial recurrence of HMEG have ever been reported. Thus, parents of affected children should be given a very low recurrence risk. The most convincing hypothesis regarding cause suggests somatic mosaicism for a genetic mutation of unknown genes.

Lissencephaly and Subcortical Band Heterotopia

Diagnosis

Classic lissencephaly (LIS) or agyria-pachygyria is a severe malformation defined by a smooth cerebral surface, abnormally thick cortex with 4 abnormal layers, diffuse neuronal heterotopia, dysplastic and enlarged ventricles, and often hypoplasia of the corpus callosum (Fig. 4). Subcortical band heterotopia (SBH) consists of symmetric and circumferential bands of gray matter located just beneath the cortex and separated

Figure 4. Lissencephaly. MRI shows frontal agyriaand minimal posterior pachygyria, very thick 1-1.5 cm cortex and mildly enlarged lateral ventricles.

from it by a thin band of white matter. LIS and SBH comprise a single malformation spectrum caused by mutations of the same genes, which may be described as the agyria-pachygyria-band spectrum. In both LIS and SBH, the brainstem appears normal, while the cerebellum appears normal or mildly small. In a subset of atypical patients, LIS is associated with moderate or severe cerebellar hypoplasia.

Most patients with LIS have normal facial appearance, and are classified as having isolated lissencephaly sequence (ILS). However, several syndromes with LIS and craniofacial malformations have been described. The most common and best known of these is the Miller-Dieker syndrome (MDS), which is characterized by a prominent forehead, bitemporal narrowing, short nose with upturned nares, prominent upper lip and small jaw.

Clinical Course and Management

Children with classic LIS may appear normal as newborns, or have apnea, poor feeding and hypotonia. Seizures are uncommon during the first few days of life, but most affected children will have onset of seizures, especially infantile spasms, during the first year. Later on, typical seizure types include myoclonic, tonic and tonic-clonic seizures. Other neurological manifestations include profound mental retardation, early hypotonia, later spastic quadruplegia that is usually mild and opisthotonus. Many patients require a gastrostomy because of poor nutrition and repeated aspiration pneumonia.

In contrast, most patients with subcortical band heterotopia have mild to moderate developmental delay, minimal pyramidal signs and dysarthria. Cognitive abilities vary considerably, ranging from severe mental retardation to normal. Seizures may begin in childhood or the early adult years, and multiple seizure types occur, which may be difficult to control.

Genetics

Classic LIS and SBH are most often associated with mutations of the LIS1 (or PAFAH1B1) and XLIS (or DCX) genes. All patients with MDS have large deletions on chromosome 17p13.3, which include LIS1. About 70% are cytogenetically visible, while the rest must be detected with fluorescence in situ hybridization (FISH). Balanced translocation carrier parents are seen in about 20% of families. Recurrence risks are determined according to which gene is involved, whether a parent is a balanced translocation carrier, and additionally gonadal mosaicism has been reported.

Among patients with classic LIS but no other anomalies, about 40% have microdeletions of chromosome 17p13.3 involving LIS1, another 24% have intragenic mutations of LIS1, and 12% have intragenic mutations of XLIS. Those patients with LIS1 deletions or mutations typically have more severe LIS posteriorly, while those with XLIS mutations have more severe LIS anteriorly.

Polymicrogyria

Diagnosis

Polymicrogyria is a heterogeneous brain malformation characterized by many small gyri separated by shallow sulci, mildly thickened cortex and often-enlarged ventricles. It is often superimposed on areas of apparently broad gyri that represent

fused gyri rather than true pachygyria. While the most readily recognized cause is intrauterine cytomegalovirus (CMV) infection, recent experience has shown that many different genetic causes of polymicrogyria exist.

Clinical Course and Management

The severity of the associated neurological disabilities depends on several factors including birth OFC, distribution and extent of the polymicrogyria, and severity of the associated epilepsy. The outcome is worse with smaller head size, more extensive polymicrogyria and more severe seizure disorder. Mental retardation is common, although patients with restricted polymicrogyria may have normal intelligence or only a mild handicap. More extensive polymicrogyria, especially if it involves the frontal region, mimics cerebral palsy with mental retardation, spastic hemiplegia, diplegia or quadriplegia and frequent epilepsy. Patients with bilateral perisylvian involvement often have difficulty feeding, and may need alternative feeding strategies. Seizure onset may occur early in life, or not until late childhood or even early adult life.

The genetics of polymicrogyria is proving to be complex and familial recurrence has been reported. Most families with multiple affected individuals have been consistent with X-linked inheritance, although a few families have had autosomal recessive or autosomal dominant inheritance. The first few polymicrogyria loci, based on observation in patients with chromosome microdeletions or microduplications, have been reported, including 22q11.2. No studies of the empiric recurrence risk for polymicrogyria have been reported.

Schizencephaly

Diagnosis

Schizencephaly (SCH) or "cleft brain" is a malformation in which one or more deep clefts lined by polymicrogyria extend from the pial surface to the ependymal surface of the lateral ventricles. They have been divided into open-lip and closed-lip SCH based on the size of the cleft. Most are located in the central region, but the clefts may occur in most other regions of the cerebral hemispheres. In most patients, SCH occurs as an isolated malformation, but it has also been associated with absent or hypoplastic septum pellucidum and optic nerve hypoplasia in the septo-optic dysplasia-schizencephaly syndrome.

Clinical Course and Management

The clinical manifestations of SCH include developmental delay and mental retardation, spastic hemiparesis or quadriparesis and epilepsy. However, the distribution and severity of the clinical abnormalities are related to the size and location of the clefts. Unilateral clefts cause less severe cognitive deficiency and hemiparesis compared to bilateral clefts. Also, open-lip SCH is consistently more severe than closed lip SCH. Seizures are usually focal and often intractable.

SCH has generally been considered to be sporadic, but a few families with multiple affected siblings have been reported. Several recent reports have implicated

Genetics

Genetics mutations of the EMX2 homeobox-containing gene and further studies looking at this gene are needed.

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