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PAFAH1B1-Associated Lissencephaly/Subcortical Band Heterotopia

Synonym: LIS1-Associated Lissencephaly/Subcortical Band Heterotopia

, MD and , PhD.

Author Information

Initial Posting: ; Last Update: August 14, 2014.

Estimated reading time: 27 minutes


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.


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.


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.

GeneReview Scope

PAFAH1B1-Associated Lissencephaly/Subcortical Band Heterotopia: Included Phenotypes
  • Miller-Dieker syndrome
  • Isolated 17-linked lissencephaly
  • 17-linked subcortical band heterotopia


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


  • 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).

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

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

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


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

Histologic Findings

Classic lissencephaly. The cortex is abnormally thick and poorly organized with four apparent layers consisting of the following [Crome 1956, Forman et al 2005]:

  • Poorly defined marginal zone with increased cellularity
  • Superficial cortical gray zone with diffusely scattered neurons
  • Relatively neuron-sparse zone
  • Deep cortical gray zone with neurons often oriented in columns. Neurons may be oriented with dendrites extending toward the pial surface or inverted, extending toward the ventricle.

SBH. The architecture of the cortex has not been studied in individuals with PAFAH1B1 pathogenic variants (see DCX-Related Disorders)


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.

Molecular Genetic Testing

Gene. Abnormalities of PAFAH1B1 (LIS1)* cause isolated PAFAH1B1-associated lissencephaly/SBH [Pilz et al 1998b, Pilz et al 1999, Fogli et al 1999, Cardoso et al 2000, Cardoso et al 2002, Sicca et al 2003, Saillour et al 2009].

* Note: PAFAH1B1 is the official gene designation; however, the former gene designation (LIS1) is still in common use in medical genetics.

Clinical testing. Abnormalities of PAFAH1B1 range from single-nucleotide variants to contiguous gene deletions. Clinical testing for PAFAH1B1 is available for the detection of these various abnormalities.

Table 2.

Molecular Genetic Testing Used in PAFAH1B1-Related Lissencephaly/SBH

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method 2
PAFAH1B1Deletion / duplication analysis 4See footnotes 5, 6100%~54%4 individuals 7
See footnote 80~68% 9Not described
Sequence analysis 1o0~32% 117 individuals 12

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Does not take into account individuals with pathogenic variants in DCX, TUBA1A, or other lissencephaly-associated genes, and those in whom no pathogenic variants have been identified.


As currently defined, MDS is associated with deletions that include both PAFAH1B1 and YWHAE (a region of about 1.3 Mb harboring many genes) in 17p13.3 [Pilz et al 1998a, Cardoso et al 2003].


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), targeted array CGH and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Detecting deletions of PAFAH1B1 and adjacent genes/regions.


Chromosomal microarray analysis as well as FISH testing can be performed using a probe containing PAFAH1B1 (e.g., PAC95H6). Chromosomal microarray analysis will detect microdeletions/contiguous gene deletions that involve PAFAH1B1, and may detect partial deletions of PAFAH1B1 depending on the size of the deletion and probe density of the array. FISH analysis will detect microdeletions/contiguous gene deletions that involve the entire gene but will not detect partial deletions of PAFAH1B1.


Mosaic deletions of 17p13.3 involving PAFAH1B1 have been observed in four individuals with SBH [WB Dobyns, personal communication].


Quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and targeted array CGH may be used to detect partial deletions of PAFAH1B1 that may be intragenic and may affect single or multiple exons, the promoter, or the 5’ untranslated region.


Intragenic deletions and duplications of PAFAH1B1 that range in size from a single exon to multiple exons to the entire gene are present in approximately 14% of individuals with PAFAH1B1-related ILS [Mei et al 2008, Haverfield et al 2009].


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Germline PAFAH1B1 pathogenic variants are present in approximately 32% of individuals with PAFAH1B1-related ILS. Rarely, mosaic pathogenic variants have been identified.


On occasion, PAFAH1B1 pathogenic variants are identified in individuals with SBH. To date, pathogenic variants have been identified in seven individuals: four who had mosaic pathogenic variants and three with apparent germline 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, personal communication].

Issues with interpretation of test results

  • Normal results of FISH analysis using a PAFAH1B1-derived probe such as PAC95H6 do not exclude the presence of the following:
    • A submicroscopic deletion of 17p13 that includes partial deletions of PAFAH1B1. Partial deletions of PAFAH1B1 may affect single or multiple exons, the promoter or the 5’ untranslated region (UTR).
    • An intragenic pathogenic variant in PAFAH1B1
  • Normal results of chromosomal microarray analysis do not exclude the presence of PAFAH1B1 intragenic deletions or duplications that affect single or multiple exons. Targeted deletion/duplication analysis that contains probes to PAFAH1B1 can detect smaller PAFAH1B1 intragenic deletions/duplications.

Testing Strategy

Probands with Isolated Lissencephaly

Sequential single-gene testing. One strategy for the diagnosis of an individual suspected of having lissencephaly with a p>a gradient or lissencephaly with an unknown or uncertain gradient is sequential single-gene testing.

Lissencephaly with a p>a gradient

Lissencephaly with an unknown or uncertain gradient

Multigene panel. An alternative to single-gene molecular genetic testing is a panel in which a number of genes that lead to lissencephaly (see Differential Diagnosis) are represented. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative variant or variants in any given individual also varies. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Lissencephaly with an a>p gradient (see Differential Diagnosis)

  • Perform sequence analysis of DCX, ACTB, ACTG1, PAFAH1B1, RELN and VLDLR. While DCX is the most indicated in this category and can be sequenced first, the other genes can result in an overlapping phenotype. Note: PAFAH1B1 abnormalities are generally not associated with an a>p gradient but when severe can be difficult to differentiate.

Probands with SBH

Sequential single-gene testing. One strategy for the diagnosis of an individual suspected of having SBH is sequential single-gene testing.

Multigene panel. An alternative to single-gene molecular genetic testing is a panel in which a number of genes that lead to SBH (see Differential Diagnosis) are represented. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative variant or variants in any given individual also varies. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Characteristics

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.

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:

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]).


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.

Differential Diagnosis

The greatest difficulty in diagnosis of lissencephaly and subcortical band heterotopia (SBH) is recognizing the malformation. Several types of lissencephaly have been described, although they have overlapping features (Table 3). The most common are classic lissencephaly (including SBH) and cobblestone complex.

Table 3.

Types of Lissencephaly

TypeDescriptionGenesInheritance Pattern
Classic lissencephalyVery thick cortex (15-20 mm), normal corpus callosum, & cerebellar vermis (or mild hypoplasia)PAFAH1B1AD
Lissencephaly with cerebellar hypoplasia, tubulin typeDiffuse or posterior predominant lissencephaly w/moderate to severe cerebellar hypoplasiaTUBA1AAD
Lissencephaly with cerebellar hypoplasia, reelinopathy typeMild frontal lissencephaly w/severe cerebellar hypoplasiaRELNAR
Cobblestone cortical malformation (lissencephaly)Pebbled brain surface, moderately thick 5-10 mm cortex (unless thinned by hydrocephalus), diffuse or patchy white matter abnormality, brain stem & cerebellar hypoplasiaFKTNAR
Lissencephaly with agenesis of the corpus callosumLissencephaly w/total or severe partial agenesis of the corpus callosumARXX-linked
MicrolissencephalyBirth OFC -3 SD or small, thick cortexNANA

NA = not applicable

OFC = occipital frontal circumference

Several different cortical malformations that are sometimes mistaken for lissencephaly have been described, including severe congenital microcephaly with reduced number of gyri, cobblestone malformations as seen in Walker-Warburg and other syndromes, polymicrogyria, and polymicrogyria-like variants associated with pathogenic variants of tubulin genes. This leads to incorrect diagnosis, counseling, and testing.

Clinical features can help distinguish children who have lissencephaly from those who have other brain malformations. Children with lissencephaly usually have normal or slightly small OFC at birth (> -3 SD) and diffuse hypotonia except for mildly increased tone at the wrists and ankles. Children with severe congenital (i.e., primary) microcephaly and gyral abnormalities have smaller birth OFC (≤ -3 SD) and may be hypotonic or spastic. Infants with polymicrogyria, especially when the frontal lobes are involved, frequently have spastic quadriparesis.

The differential diagnosis of classic lissencephaly includes the PAFAH1B1-related malformations, DCX-related malformations, TUBA1A-related malformations and the rare Baraitser-Winter syndrome (BWS) [Dobyns et al 1991, Dobyns et al 1992, Pilz et al 1998a, Pilz et al 1998b, Dobyns et al 1999, Matsumoto et al 2001, Ross et al 2001, Rossi et al 2003, Poirier et al 2007]. These disorders are distinguished by mode of inheritance, grade and gradient of lissencephaly or SBH (Table 1), presence of other congenital anomalies, and results of molecular genetic testing.

  • Classic lissencephaly associated with deletions or intragenic pathogenic variants in PAFAH1B1 is more common than classic lissencephaly associated with pathogenic variants in DCX, located on the X chromosome [Pilz et al 1998b], and classic lissencephaly associated with pathogenic variants in TUBA1A codon Arg402.
  • SBH in females associated with pathogenic variants in DCX is far more common than SBH in females with PAFAH1B1 pathogenic variants [Pilz et al 1999, D’Agostino et al 2002, Sicca et al 2003].
  • PAFAH1B1-related malformations are characterized by a p>a gradient (see Table 1). DCX-related malformations are associated with an a>p gradient [Pilz et al 1998b, Dobyns et al 1999]. However, in severe classic lissencephaly or SBH the gradient may be difficult to discern.
  • TUBA1A-related malformations, like PAFAH1B1-related malformations, are characterized by a p>a gradient. The lissencephaly phenotype associated with PAFAH1B1 and TUBA1A Arg402 pathogenic variants may be indistinguishable. Pathogenic variants elsewhere in TUBA1A result in a spectrum of malformations that vary from polymicrogyria-like cortical malformation with cerebellar hypoplasia and callosal dysgenesis to the most severe forms of lissencephaly with cerebellar hypoplasia (also called 2-layer lissencephaly) [Poirier et al 2007, Kumar et al 2010, Cushion et al 2013].
  • Baraitser-Winter syndrome is characterized by: lissencephaly with an a>p gradient similar to that of DCX-related malformations; trigonocephaly; shallow orbits; ptosis; and colobomas of the iris, choroid, or both [Ramer et al 1995, Rossi et al 2003].

Lissencephaly with agenesis of the corpus callosum is typically associated with pathogenic variants in ARX. The XLAG (X-linked lissencephaly with abnormal genitalia) phenotype in severely affected individuals with a 46,XY karyotype differs significantly from the phenotype associated with pathogenic variants in either PAFAH1B1 or DCX. XLAG is characterized by congenital or postnatal microcephaly, neonatal-onset intractable epilepsy, poor temperature regulation, chronic diarrhea, and abnormal genitalia [Kato & Dobyns 2003, Kato et al 2004].

The cobblestone cortical malformation (lissencephaly) syndromes (Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy) differ clinically in a number of ways, including the frequent presence of hydrocephalus and cerebellar hypoplasia, multiple different eye anomalies, and congenital muscular dystrophy manifest by hypotonia and elevated serum creatine kinase concentrations.


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.

A large majority of children with lissencephaly have seizures, including frequent infantile spasms, which can be difficult to control. Management of seizures in children with ILS or SBH is based on the specific seizure type and frequency. In general, seizures should be treated promptly and aggressively by specialists, as poor seizure control frequently results in decline in function and health. Specifically, poor seizure control worsens feeding and increases the likelihood that a gastrostomy tube will be needed, and increases the risk for pneumonia.


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

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

PAFAH1B1-associated lissencephaly/subcortical band heterotopia (SBH) is inherited in an autosomal dominant manner, although most deletions and all intragenic pathogenic variants reported to date have been de novo.

Risk to Family Members

Parents of a proband

  • Approximately 80% of probands with Miller-Dieker syndrome (MDS) have a de novo deletion involving 17p13.3.
  • Approximately 20% of probands with MDS have inherited a deletion from a parent who carries a balanced chromosome rearrangement [Dobyns et al 1991; Dobyns, unpublished data]
    • Parents of a proband with a structural unbalanced chromosome constitution (e.g., deletion or duplication) are at increased risk for balanced chromosome rearrangements and should be offered chromosome analysis.
  • Most PAFAH1B1 intragenic pathogenic variants are de novo.
    • Parental studies are recommended to exclude mosaicism in one parent.

Sibs of a proband

  • Proband with a cytogenetic deletion
    • 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 is increased and depends on the specific rearrangement, and possibly other variables.
  • Proband with an intragenic pathogenic variant in PAFAH1B1

Offspring of a proband. Individuals with PAFAH1B1-associated lissencephaly/SBH do not reproduce.

Other family members. The risk to other family members depends on the genetic status of the proband's parents. If a parent has a chromosome rearrangement, his or her family members are at risk and can be offered chromosome analysis.

Related Genetic Counseling Issues

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the PAFAH1B1 pathogenic variant in the family.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or deletion, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the PAFAH1B1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Fetal ultrasound examination. Prenatal testing by level 2 ultrasound examination does NOT detect lissencephaly, as normal fetal brains have a smooth surface until late in gestation.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • American Epilepsy Society (AES)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

PAFAH1B1-Associated Lissencephaly/Subcortical Band Heterotopia: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for PAFAH1B1-Associated Lissencephaly/Subcortical Band Heterotopia (View All in OMIM)


Gene structure. PAFAH1B1 (often referred to as LIS1) is approximately 92 kb in size and consists of 11 exons. The coding region is 1230 bp, with the AUG start codon located in exon 2, and it encodes a protein of 410 amino acids called PAFAH1B1 (platelet-activating factor acetylhydrolase IB alpha subunit, also known as brain isoform 1b) [Reiner et al 1993]. There are two alternative transcripts (5.5 kb and 7.5 kb) that differ in the length at their respective 3’ UTR regions; both transcripts are expressed ubiquitously [Hattori et al 1994, Lo Nigro et al 1997]. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. To date, several different polymorphisms have been identified in PAFAH1B1 (not all have been published). The polymorphic changes that have been identified are thought to be benign, as they have been found either in individuals in whom a clearly deleterious variant is also present or in individuals without the disease. Most represent rare variants, with the exception of two polymorphisms in the 3’ UTR (c.*3G>T and c.*17C>T; see Table 4) that occur at frequencies of approximately 10% and 40% respectively [Koch et al 1996, Cardoso et al 2000].

Pathogenic variants. More than 130 different PAFAH1B1 (formerly LIS1) pathogenic variants have been described [Cardoso et al 2000; Cardoso et al 2002; Uyanik et al 2007; Saillour et al 2009; Author, unpublished]. Most are private variants; however, a few recurrent variants have been described, including c.162delA and c.162dupA, which occur in a small stretch of adenine residues, and c.1050delG and c.1050dupG, which occur in a small stretch of guanine residues. Pathogenic variants appear to be evenly distributed throughout the gene. No predominant common pathogenic variant has been identified in any population.

Intragenic deletions and duplications of PAFAH1B1 that range from single-exon deletions or duplications to deletions of the entire coding region have been described; to date, approximately 35 partial deletions and duplications of PAFAH1B1 have been identified [Mei et al 2008, Haverfield et al 2009, Saillour et al 2009]. These partial deletions and duplications appear to be spread throughout the gene. Microdeletions of the 17p13.3 region that delete all of PAFAH1B1 have been described in approximately 40% of individuals with ILS and differ with regard to size and break points. 17p13.3 microdeletions have been identified in affected individuals of different ethnic groups.

Table 4.

Selected PAFAH1B1 (LIS1) Recurrent Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions

Normal gene product. Platelet-activating factor acetylhydrolase IB subunit alpha (PAFAH1B1) is a 45-kd protein that contains 410 amino acids and is highly conserved among species. The main functional domains of this protein are a LisH motif at the N terminus, followed by a coiled-coil region and seven WD40 repeats at the C terminus [Reiner et al 1993, Cardoso et al 2000]. The LisH domain, coiled-coil domain, and WD40 repeats are important for dimerization, involved in protein/protein interactions, and essential for PAFAH1B1 function [Sapir et al 1999, Efimov & Morris 2000, Sweeney et al 2000, Ahn & Morris 2001, Cahana et al 2001, Kim et al 2004].The PAFAH1B1 protein has two main functions: (1) it forms a trimeric complex with the PAFAH1B2 and PAFAH1B3 proteins to regulate the level of platelet activating factor in the brain [Albrecht et al 1996, Bix & Clark 1998]; (2) more importantly, it has been shown to play a central role in the organization of the cytoskeleton by the interaction with proteins including tubulin (the major component of microtubules) as well as proteins associated with the centrosome and involved in microtubule dynamics (e.g., cyoplasmic dynein, dynactin, NUDE, and NUDEL), in turn affecting neuronal proliferation and migration [Faulkner et al 2000, Feng et al 2000, Niethammer et al 2000, Smith et al 2000, Suzuki et al 2007, Torisawa et al 2011, Egan et al 2012, Huang et al 2012, Dix et al 2013] and playing an important role in mitotic spindle regulation [Wang et al 2013, Moon et al 2014]. PAFAH1B1 also interacts with components of the Reelin signaling pathway [Assadi et al 2003].

Abnormal gene product. Pathogenic variants in PAFAH1B1 result in a reduction in the amount of correctly folded PAFAH1B1 protein [Sapir et al 1999]. Modeling studies of PAFAH1B1 pathogenic variants have shown that they abolish the binding of PAFAH1B1 with protein partners such as PAFAH1B2, PAFAH1B3, NUDE, or NUDEL [Sapir et al 1999, Feng et al 2000, Sasaki et al 2000, Sweeney et al 2000]. This in turn interferes with functions such as neuroblast proliferation and migration. PAFAH1B1 RNA interference studies indicate that an abnormal PAFAH1B1 gene product disrupts the production of neurons in the developing brain as well as their migration [Tsai et al 2005]. Both non-radial cell migration (inhibitory interneurons) and radial migration (excitatory projection neurons) appear to be affected [Fleck et al 2000, Pancoast et al 2005].


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Suggested Reading

  • Guerrini R, Marini C. Genetic malformations of cortical development. Exp Brain Res. 2006;173:322–33. [PubMed: 16724181]
  • Kerjan G, Gleeson JG. Genetic mechanisms underlying abnormal neuronal migration in classical lissencephaly. Trends Genet. 2007;23:623–30. [PubMed: 17997185]
  • Wynshaw-Boris A. Lissencephaly and LIS1: insights into the molecular mechanisms of neuronal migration and development. Clin Genet. 2007;72:296–304. [PubMed: 17850624]

Chapter Notes

Revision History

  • 14 August 2014 (me) Comprehensive update posted live
  • 3 March 2009 (me) Review posted live
  • 22 August 2008 (wd) Original submission
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