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.
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