Clinical characteristics.

PAFAH1B1-related lissencephaly / subcortical band heterotopia (SBH) comprises a spectrum of severity. Affected newborns typically have mild-to-moderate hypotonia, feeding difficulties, and poor head control. During the first years, neurologic examination typically demonstrates poor visual tracking and response to sounds, axial hypotonia, and mild distal spasticity that can transition over time to more severe spasticity. Seizures occur in more than 90% of individuals with lissencephaly and often include infantile spasms. Seizures are often drug resistant, but even with good seizure control, the best developmental level achieved (excluding the few individuals with partial lissencephaly) is the equivalent of about age three to five months. In individuals with PAFAH1B1-related lissencephaly/SBH, developmental delay ranges from mild to severe. Other findings in PAFAH1B1-related lissencephaly/SBH include feeding issues and aspiration (which may result in need for gastrostomy tube placement), progressive microcephaly, and occasional developmental regression.

Diagnosis/testing.

The diagnosis of PAFAH1B1-related lissencephaly/SBH is established in a proband with a heterozygous pathogenic variant in PAFAH1B1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Standard treatment with anti-seizure medication based on the specific seizure type and frequency; polytherapy with valproic acid and lamotrigine appears most effective in reducing drug-resistant seizures; placement of a gastrostomy tube for those with failure to thrive, dysphagia, and/or recurrent aspiration pneumonia; treatment with stool softeners, prokinetics, osmotic agents, or laxatives for constipation; standard treatment for developmental delay/intellectual disability, spasticity, visual impairment, and hearing loss.

Surveillance: At each visit: measure growth parameters and evaluate nutrition status and safety of oral intake; monitor for signs and symptoms of constipation, aspiration, and respiratory insufficiency; monitor those with seizures as clinically indicated; assess for new manifestations, such as unusual spells or developmental regression; assessment of developmental progress and educational needs; assessment of mobility and self-help skills. Annually or as clinically indicated: ophthalmologic and audiologic evaluations.

Genetic counseling.

Individuals diagnosed with isolated PAFAH1B1-related lissencephaly/SBH typically have the disorder as the result of a de novo genetic alteration (an intragenic PAFAH1B1 pathogenic variant or, rarely, a chromosome rearrangement that disrupts PAFAH1B1). In rare families, an individual with PAFAH1B1-related lissencephaly/SBH has the disorder as the result of autosomal dominant inheritance of a PAFAH1B1 pathogenic variant from a parent. If the intragenic PAFAH1B1 pathogenic variant identified in the proband is not identified in either parent, the recurrence risk for a future pregnancy is slightly greater than that of the general population because of the possibility of parental germline mosaicism. If a parent of a proband is known to have the intragenic PAFAH1B1 pathogenic variant or a balanced translocation that disrupts PAFAH1B1, the recurrence risk is 50% with each future pregnancy. Once the causative genetic alteration has been identified in the proband, prenatal testing may be offered to parents of an affected child because of the recurrence risk associated with the possibility of parental mosaicism or a balanced chromosome rearrangement.

Suggestive Findings

PAFAH1B1-related lissencephaly/SBH should be suspected in individuals with the following clinical and MRI findings.

Clinical features (nonspecific)

• Generalized hypotonia
• Abnormal arching (opisthotonus) in infants transitioning to bilateral spastic cerebral palsy in older individuals
• Central visual impairment
• Developmental delay, intellectual disability, psychomotor delay, speech and language delay
• Behavioral difficulties
• Epilepsy ranging from infantile spasms to severe drug-resistant epilepsy
• Nonspecific dysmorphic features (See Clinical Description.)
  Note: Dysmorphic features are rare in individuals with intragenic pathogenic variants or intragenic deletions of PAFAH1B1 and are more commonly seen in those with larger deletions that include PAFAH1B1 and adjacent genes (see Genetically Related Disorders).

MRI findings (specific) (See Figure 1.)

Figure 1.

Left panel – axial T₂-weighted MRI image illustrating diffuse agyria-pachygyria with posterior-to-anterior (p>a) gradient. Right panel – axial T₁-weighted MRI image illustrating diffuse subcortical band heterotopia with posterior-to-anterior (more...)

• Lissencephaly, characterized by absent or abnormally broad cerebral gyri with abnormally thick cerebral cortex (10-20 mm; normal: 3-4 mm) [Di Donato et al 2017]
• Subcortical band heterotopia, characterized by either a symmetric or an asymmetric subcortical band of heterotopic gray matter restricted to the parietal and occipital lobes with a posterior-to-anterior gradient

Establishing the Diagnosis

The diagnosis of PAFAH1B1-related lissencephaly/SBH is established in a proband with a heterozygous pathogenic (or likely pathogenic) variant in PAFAH1B1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous PAFAH1B1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA).

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including PAFAH1B1) that cannot be detected by sequence analysis.

If CMA is not diagnostic, molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires clinical suspicion of a particular genetic cause, based on the clinical and imaging phenotype. This also implies that the clinician is familiar with rare disorders such as lissencephaly/SBH. In contrast, genomic testing can be used when clinical findings are nonspecific, as this does not require preliminary suspicion of a defined genetic cause. Because the phenotype of lissencephaly/SBH is broad, individuals with the distinctive MRI findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with lissencephaly and/or epileptic encephalopathy are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Together, isolated lissencephaly sequence (ILS) and subcortical band heterotopia (SBH) comprise the "agyria-pachygyria-band" spectrum of cortical malformations that are caused by deficient neuronal migration during embryogenesis. The term lissencephaly refers to a "smooth brain" with absent (agyria) or abnormally wide gyri (pachygyria).

To date, almost 200 individuals have been identified with an intragenic pathogenic variant in PAFAH1B1 [De Vita et al 2018, Di Donato et al 2018] causative of ILS and SBH. The following description of the phenotypic features associated with this condition is based on these reports.

Genotype-Phenotype Correlations

ILS

• Most individuals with a telomeric deletion including the 5' end of PAFAH1B1 have grade 2 to 3 lissencephaly.
• The vast majority of individuals with intragenic deletions and duplications of PAFAH1B1 have grade 3 lissencephaly [Haverfield et al 2009].
• Most individuals with a deletion of the 3' end of PAFAH1B1 have grade 3 to 4 lissencephaly [Chong et al 1997; Author, unpublished data].
• Intragenic pathogenic variants in PAFAH1B1 usually result in ILS grade 3 or 4.
  • 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 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 nine individuals with a milder imaging phenotype consisting of posterior-predominant 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, Damiano et al 2017, González-Morón et al 2017].
• Somatic mosaicism for a PAFAH1B1 deletion results in a variable clinical phenotype, ranging from mild to severe developmental delay.
• Seizures are intractable in most affected individuals and can cause regression of the developmental stage.

Prevalence

Classic lissencephaly from any cause 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.

Classic Lissencephaly

The differential diagnosis of classic lissencephaly is summarized in Table 3. These disorders are distinguished by mode of inheritance, grade and gradient of lissencephaly or SBH (see Clinical Description, Neuroimaging), presence of other congenital anomalies, clinical features, and results of molecular genetic testing.

Lissencephaly with Agenesis of the Corpus Callosum

Lissencephaly with agenesis of the corpus callosum is typically associated with pathogenic variants in ARX. Pathogenic variants in ARX cause X-linked lissencephaly with abnormal genitalia (XLAG; OMIM 300215). The XLAG 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 et al 2004].

Females who are heterozygous for an ARX pathogenic variant may be asymptomatic or may present with variable clinical features including: developmental delay, intellectual disability (55% of heterozygous females), learning disabilities, and behavioral abnormalities. Seizures were reported in 64% of affected females who also presented with intellectual disability [Mattiske et al 2017]. Brain imaging often shows agenesis of the corpus callosum, although lissencephaly has not been reported [Marsh et al 2009].

Tubulin-Related Dysgyria

Cortical malformations resembling lissencephaly and caused by mutation of an α-tubulin (TUBA1A or TUBA8), β-tubulin (TUBB2A, TUBB2B, TUBB3, TUBB [TUBB5]), or γ-tubulin (TUBG1) gene are referred to as tubulin-related dysgyria. Tubulinopathies often cause associated brain malformations including hypoplasia/agenesis of the corpus callosum, dysmorphic basal ganglia, and hypoplasia of the cerebellar vermis and brain stem (see Tubulinopathies Overview). Affected individuals present with variable degrees of developmental delay and often with epilepsy [Romaniello et al 2019]. Of note, the p.Arg402Cys variant in TUBA1A results in an agyria-pachygyria (posterior more severe than anterior on imaging) phenotype that is highly similar to that caused by pathogenic variants in PAFAH1B1 [Bahi-Buisson et al 2014].

Cobblestone Cortical Malformation (Lissencephaly) Syndromes

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 ventriculomegaly, white matter changes, and cerebellar hypoplasia, multiple different eye anomalies, and congenital muscular dystrophy manifested 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-related lissencephaly/SBH, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

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" orders, in the event of severe illnesses.

Surveillance

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 ClinicalTrials.gov in the US and EU Clinical Trials Register 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.

Mode of Inheritance

PAFAH1B1-related lissencephaly / subcortical band heterotopia (SBH) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Note: Genetic counseling for the families of individuals diagnosed with Miller-Dieker syndrome is not addressed in this section (see Genetically Related Disorders).

Risk to Family Members

Parents of a proband

• Individuals diagnosed with isolated PAFAH1B1-related lissencephaly/SBH typically have the disorder as the result of a de novo genetic alteration (an intragenic PAFAH1B1 pathogenic variant or, rarely, a chromosome rearrangement that disrupts PAFAH1B1).
• In rare families, an individual with PAFAH1B1-related lissencephaly/SBH has the disorder as the result of a PAFAH1B1 pathogenic variant inherited from a parent. Maternal vertical transmission of a PAFAH1B1 pathogenic variant has been reported in three unrelated families:
  • A boy with ILS (with posterior more severe than anterior gradient) and epilepsy inherited a PAFAH1B1 missense variant from his mother who presented with similar clinical features [De Vita et al 2018].
  • Two girls with severe intellectual disability, epilepsy, and anterior-predominant lissencephaly and calcifications of the basal ganglia were born to a mother also presenting with anterior-predominant lissencephaly (the affected daughters and their mother were all heterozygous for the same missense variant in PAFAH1B1, which was absent in unaffected family members [Shi et al 2019]).
  • A boy who presented with ILS/SBH inherited a PAFAH1B1 missense variant from his mother, who was mosaic for the missense variant [Mineyko et al 2010].
• Molecular genetic testing for the intragenic PAFAH1B1 pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. (If the proband has a chromosome rearrangement that disrupts PAFAH1B1, chromosome analysis [a karyotype] is recommended for the parents of the proband.)
• If the genetic alteration identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be mildly affected [Mineyko et al 2010].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the intragenic PAFAH1B1 pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If a parent of the proband has a structural chromosome rearrangement involving PAFAH1B1, the risk to sibs is increased and depends on the specific chromosome rearrangement.
• If the proband has a known PAFAH1B1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Mineyko et al 2010].
• If the parents have not been tested for the PAFAH1B1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for PAFAH1B1-related lissencephaly/SBH because of the possibility of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with PAFAH1B1-related lissencephaly/SBH has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the PAFAH1B1 genetic alteration, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the PAFAH1B1 genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing 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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Platelet-activating factor acetylhydrolase IB subunit alpha (PAFAH1B1) is highly conserved among species. The main functional domains of this protein are a LisH motif at the N terminus and a coiled-coil region, which are important for protein dimerization. Seven WD40 repeats at the C terminus are necessary for protein-protein interactions [Cardoso et al 2000, Reiner 2013].

The PAFAH1B1 protein has several functions. PAFAH1B1 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]. Additionally, PAFAH1B1 interacts directly with tubulin proteins and indirectly with microtubulin-associated proteins (MAP), such as dynein, DCX, or NDE1, to facilitate cytoskeleton organization during mitotic spindle cell orientation. Normal interaction of PAFAH1B1 with microtubules and MAPs is also crucial for interkinetic motility, nucleokinesis, and radial and tangential migration of neurons [Markus et al 2020].

Proliferation of neuronal progenitors and astrocytes has been shown to be impaired in individuals with pathogenic variants in PAFAH1B1. Additionally, cortical layering is disturbed due to abnormal migration of neuronal precursors from the ventricular and subventricular zone to the cortical plate during cortical development [Reiner & Sapir 2013].

Mechanism of disease causation. Loss of function

PAFAH1B1-specific laboratory technical considerations. 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.

Author Notes

Stefanie Brock: researchportal.vub.be

William B Dobyns: med.umn.edu

Anna Jansen: researchportal.vub.be, @jansen_ac

Author History

Stefanie Brock, MD (2021-present)
Soma Das, PhD; University of Chicago (2009-2021)
William B Dobyns, MD (2009-present)
Anna Jansen, MD, PhD (2021-present)

Revision History

• 25 March 2021 (ma) Comprehensive update posted live
• 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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