Pafah1b1-Associated Lissencephaly/subcortical Band Heterotopia

Clinical characteristics.

PAFAH1B1-associated lissencephaly includes Miller-Dieker syndrome (MDS), isolated lissencephaly sequence (ILS), and (rarely) subcortical band heterotopia (SBH). Lissencephaly and SBH are cortical malformations caused by deficient neuronal migration during embryogenesis. Lissencephaly refers to a "smooth brain" with absent gyri (agyria) or abnormally wide gyri (pachygyria). SBH refers to a band of heterotopic gray matter located just beneath the cortex and separated from it by a thin zone of normal white matter. MDS is characterized by lissencephaly, typical facial features, and severe neurologic abnormalities. ILS is characterized by lissencephaly and its direct sequelae: developmental delay, intellectual disability, and seizures.

Diagnosis/testing.

MDS is caused by either small cytogenetically visible deletions or FISH-detectable microdeletions of 17p13.3 that include PAFAH1B1 (formerly LIS1) and YWHAE, and intervening genes. ILS is caused by smaller submicroscopic deletions of PAFAH1B1; intragenic deletions or duplications of PAFAH1B1; or sequence variants of PAFAH1B1.

Management.

Treatment of manifestations: Poor feeding may require nasogastric tube feedings in newborns and later placement of a gastrostomy tube. Seizures require prompt and aggressive management based on the specific seizure type and frequency; response to treatment is similar to that in children with seizures due to other causes.

Surveillance: Whenever any unusual spells or any developmental regression is noted, a child neurology consultation should be performed and EEG considered.

Genetic counseling.

Approximately 80% of individuals with MDS have a de novo deletion involving 17p13.3 and approximately 20% have inherited a deletion from a parent who carries a balanced chromosome rearrangement. If neither parent has a structural chromosome rearrangement detectable by high-resolution chromosome analysis, the risk to sibs is negligible. If a parent has a balanced structural chromosome rearrangement, the risk to sibs for MDS depends on the specific rearrangement. Although germline mosaicism in a parent could lead to familial recurrence of ILS, all PAFAH1B1 intragenic pathogenic variants reported to date have been de novo; thus, the risk to sibs for ILS is negligible if neither parent has mosaicism for the PAFAH1B1 pathogenic variant present in the proband. Prenatal testing for pregnancies at increased risk for MDS is possible if the familial chromosome rearrangement is known.

Clinical Diagnosis

Together, lissencephaly and subcortical band heterotopia (SBH) comprise the "agyria-pachygyria-band" spectrum of cortical malformations that are caused by deficient neuronal migration during embryogenesis [Barkovich et al 1991, Norman et al 1995]. The term lissencephaly refers to a "smooth brain" with absent (agyria) or abnormally wide gyri (pachygyria).

MRI Findings

Lissencephaly

• Cerebral gyri are absent or abnormally broad.
• The cerebral cortex is abnormally thick (12-20 mm; normal: 3-4 mm) [Barkovich et al 1991].
• Associated findings in the most common ("classic") form of lissencephaly include:
  • Enlarged lateral ventricles, especially posteriorly
  • Mild hypoplasia of the corpus callosum (the anterior portion often appears flattened)
  • Cavum septi pellucidi et vergae
  • Normal brain stem and cerebellum in most individuals, mild cerebellar vermis hypoplasia in a few

Subcortical band heterotopia (SBH)

• A subcortical band of heterotopic gray matter, present just beneath the cortex, is separated from it by a thin zone of normal white matter [Barkovich et al 1994]. SBH is most often symmetric, but may be asymmetric.
• In PAFAH1B1-associated SBH, the subcortical bands are restricted to the parietal and occipital lobes (diffuse or frontal predominant SBH are associated with mutation of DCX (see DCX-Related Disorders).
• The gyral pattern is normal or demonstrates mildly simplified shallow sulci; a normal cortical ribbon is present.

Lissencephaly and SBH are graded by anterior-posterior gradient and severity (Table 1 and Figure 1). When the lissencephaly or SBH is more severe posteriorly, it is referred to as a posterior to anterior (p>a) gradient. When more severe anteriorly, it is referred to as an anterior to posterior (a>p) gradient. PAFAH1B1 abnormalities give rise to diffuse or p>a gradients, whereas abnormalities of DCX generally give rise to diffuse or a>p gradients [Pilz et al 1998a, Dobyns et al 1999].

Figure 1.

Brain MRIs of lissencephaly, ranging from grade 1 (the most severe) to grade 6 (subcortical band heterotopia, the least severe). (P) indicates posterior; (A) indicates anterior. Lissencephaly that is more severe posteriorly than anteriorly (best observed (more...)

Table 1.

Grading System for Classic Lissencephaly and SBH

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Gradient	Grade of Severity
1a=p 1	Complete agyria
2p>a or 2a>p	Diffuse agyria with a few undulations at the frontal or occipital poles
3p>a or 3a>p	Mixed agyria and pachygyria
4p>a or 4a>p	Diffuse pachygyria, or mixed pachygyria and normal or simplified gyri
5a>p 2	Mixed pachygyria and subcortical band heterotopia
6p>a or 6a>p	Subcortical band heterotopia only

1.

With severe grade 1 lissencephaly, it is difficult to determine if a gradient is present.

2.

The reverse (5p>a) has not been observed.

Testing

Chromosome analysis

• High-resolution chromosome studies at the 450-band level or higher identify cytogenetically visible deletions or other structural rearrangements of 17p13.3 in approximately 70% of individuals with Miller-Dieker syndrome (MDS), but not in individuals with isolated lissencephaly sequence (ILS) or SBH [Dobyns et al 1991].
• Rarely, individuals with ILS have a balanced reciprocal translocation disrupting PAFAH1B1.
• Rarely, individuals with posterior-predominant SBH have mosaic deletions of 17p13.3 visible on cytogenetic analysis.

Testing Strategy

Clinical Description

The phenotypes associated with mutation of PAFAH1B1 comprise a spectrum of severity that can be separated into Miller-Dieker syndrome (MDS), posterior predominant ILS (or isolated lissencephaly) and, on rare occasion, posterior predominant subcortical band heterotopia (SBH).

MDS consists of severe lissencephaly (grade 1-2) (see Table 1 and Figure 1), characteristic facial changes, other more variable malformations, and severe neurologic and developmental abnormalities [Dobyns et al 1991, Cardoso et al 2003]. The facial changes consist of high and prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip with downturned vermilion border, and small jaw (Figure 2). Other malformations seen on occasion include omphalocele and congenital heart defects.

Figure 2.

Two children with Miller-Dieker syndrome showing typical facial features Photographs obtained with consent of the families.

ILS consists of more variable lissencephaly (grades 2-4) (see Table 1 and Figure 1), minor facial changes, rare malformations outside of the brain, and similar neurologic and developmental handicaps as in MDS [Dobyns et al 1992].

In both MDS and ILS, the pregnancy may be complicated by polyhydramnios. Affected newborns may appear normal or may have mild to moderate hypotonia, poor feeding, and transient elevations in bilirubin likely related to feeding difficulties [Dobyns et al 1991, Dobyns et al 1992]. At birth, the occipitofrontal circumference (OFC) is typically normal (between the mean and 2 SD below the mean). However, postnatal head growth is slow; most children develop microcephaly by age one year. Prior to the onset of seizures, most infants have mild delay in development and mild hypotonia including poor head control. Some have difficulty with feeding.

Children with lissencephaly have epileptic encephalopathies that typically evolve from infantile spasms (West syndrome) to Lennox-Gastaut syndrome of mixed epilepsy with a slow spike and wave pattern on EEG. Overall, seizures occur in more than 90% of children with lissencephaly with onset usually before age six months. Approximately 80% have infantile spasms, although the EEG does not always show the typical hypsarrhythmia pattern. The onset of infantile spasms may be associated with a decline in function. After the first months of life, most children have mixed seizure disorders including persisting infantile spasms, focal motor and generalized tonic seizures [Guerrini 2005], complex partial seizures, atypical absences, and atonic and myoclonic seizures. Some children with lissencephaly have characteristic EEG changes, including diffuse high-amplitude fast rhythms that are considered to be highly specific for this malformation [Quirk et al 1993].

The developmental prognosis is poor for all children with MDS and for the majority with isolated lissencephaly. Even with good seizure control, the best developmental level achieved by children with MDS or isolated lissencephaly (excluding the few with partial lissencephaly) is the equivalent of about age three to five months. This may include brief visual tracking, rolling over, limited creeping, and very rarely, sitting. With poor seizure control, children with lissencephaly may function at or below the level of a newborn. A few individuals with less severe (grade 4) lissencephaly, especially partial posterior lissencephaly or pachygyria, have a better developmental outcome [Leventer et al 2001].

During the first years, neurologic examination typically demonstrates brief visual tracking and response to sounds, axial hypotonia, and mild distal spasticity. Infants often demonstrate abnormal arching (opisthotonus). Later, distal spasticity becomes more prominent, although hypotonia remains. Rarely, affected individuals develop moderate spastic quadriplegia and scoliosis.

Feeding often improves during the first few months of life, but typically worsens again with seizure onset during the first year of life, and then again at several years of age for various reasons.

Children with lissencephaly have poor control of their airway, which predisposes to aspiration pneumonia, the most common terminal event.

The prognosis differs somewhat between MDS and isolated lissencephaly. In MDS, death occurs within the first two years in many children, and only a few reach age ten years. The oldest known individual with MDS died at age 17 years. In isolated lissencephaly, approximately 50% live to age ten years, and very few reach age 20 years. The oldest known individual lived to age 30 years. These estimates apply only to individuals with typical lissencephaly affecting the entire brain (the large majority of those with lissencephaly). In general, life expectancy is related to the severity of the lissencephaly on neuroimaging [de Wit et al 2011].

Seven individuals with SBH associated with PAFAH1B1 pathogenic variants have been reported/identified, three with germline pathogenic variants and four with mosaic pathogenic variants [Pilz et al 1999; D’Agostino et al 2002; Sicca et al 2003; Uyanik et al 2007; Mineyko et al 2010; Pagnamenta et al 2012; WB Dobyns & S Das, unpublished review]. Two other unreported individuals have had mosaic deletions of chromosome 17p13.3 [WB Dobyns, personal observation].

SBH is characterized by normal facial appearance, epilepsy, and intellectual disability. Four of the seven individuals with PAFAH1B1-related SBH had frequent seizures. One had an IQ of 107 at age seven years that declined to 60 by age 13 years, most likely as a result of severe seizures; one had an IQ of approximately 60; one had severe intellectual disability; two had global developmental delay.

In general individuals with SBH live into adult life. No reliable data regarding life span exist; it is likely to be shortened in those with severe intellectual disability, intractable epilepsy, or both.

Genotype-Phenotype Correlations

MDS. The most severely affected individuals with MDS have large cytogenetically visible deletions of 17p13.3 and unbalanced chromosome rearrangements associated with duplication of another chromosome segment.

The next-most severe abnormality is deletion of 17p13.3 that includes both PAFAH1B1 and YWHAE [Cardoso et al 2003], the latter located telomeric to PAFAH1B1 in the MDS chromosome region.

ILS. Smaller deletions, including intragenic deletions and duplications of PAFAH1B1, cause ILS that is less severe than MDS, ranging in severity from grade 2 to 4.

• Most individuals with a telomeric deletion including the 5’ end of PAFAH1B1 have grade 2 to 3 lissencephaly.
• Most individuals with a deletion of the 3’ end of PAFAH1B1 have grade 3 to 4 lissencephaly [Chong et al 1997; unpublished data].
• The vast majority of individuals with intragenic deletions and duplications of PAFAH1B1 have grade 3 lissencephaly [Haverfield et al 2009].

Intragenic pathogenic variants in PAFAH1B1 usually result in ILS grade 3 or 4. In general:

• Intragenic pathogenic variants that predict premature termination of the PAFAH1B1 protein tend to result in a more severe lissencephaly phenotype than missense variants in PAFAH1B1 [Cardoso et al 2000, Leventer et al 2001, Cardoso et al 2002].
• Pathogenic variants near the beginning of the gene in the coiled-coil domain that result in truncation/deletion may cause a more severe lissencephaly phenotype than the similar variants that occur in other downstream regions of the gene [Cardoso et al 2000, Cardoso et al 2002].

Note: These generalizations notwithstanding, severity of the phenotype does not always appear to correspond to location and type of pathogenic variant, as a more severe phenotype has been observed in some individuals with pathogenic missense variants and more severe grades (2 and 3) of lissencephaly have been observed in individuals with truncation/deletion variants in the coiled-coil domain toward the 3’ end of PAFAH1B1 [Uyanik et al 2007].

SBH. Two PAFAH1B1 pathogenic missense variants, one frameshift variant, and somatic mosaicism for a PAFAH1B1 missense, nonsense, in-frame, and splice site variant have been identified in seven individuals with a milder phenotype of SBH [Pilz et al 1999; D’Agostino et al 2002; Sicca et al 2003; Uyanik et al 2007; Mineyko et al 2010; Pagnamenta et al 2012; WB Dobyns & S Das, unpublished review].

Somatic mosaicism for a PAFAH1B1 deletion also results in the milder phenotype SBH (seen in two individuals [WB Dobyns, unpublished observation]).

Prevalence

Classic lissencephaly is rare. Birth prevalence is estimated to range from 11.7 to 40 per million births [personal communication with Metropolitan Atlanta Congenital Defects Program Personnel, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, 2002]. Even the latter is likely to be an underestimate as the CDC program ascertains only hospitalized children in the first several years of life.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PAFAH1B1-associated lissencephaly/ subcortical band heterotopia (SBH), the following are recommended:

• Evaluation of:
  • Growth
  • Feeding and nutrition
  • Respiratory status
  • Development
  • Seizures
• Clinical genetics consultation

MRI should be interpreted carefully to provide as much prognostic information as possible. Note: Although most affected individuals have severe to profound intellectual disability, a minority have less extensive lissencephaly that results in only moderate intellectual disability, and a few have limited malformations that allow near-normal development. In the latter, the lissencephaly or SBH is typically less severe and less extensive on MRI. The resolution of brain CT scan is not usually sufficient to allow this.

Treatment of Manifestations

Parents seem best able to deal with this severe disorder when accurate information regarding the prognosis is given as soon as possible after the diagnosis is recognized. For those with severe lissencephaly, it is usually appropriate to discuss limitations of care, such as "do not resuscitate" (DNR) orders, in the event of severe illnesses.

Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life. But they often worsen again with intercurrent illnesses and with advancing age and size. At least 50% of children with PAFAH1B1-related lissencephaly (but not SBH) eventually have a gastrostomy tube placed for feeding