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Lissencephaly Spectrum Disorders

1. Disease Information

2026-06-03
Falcon MONDO:0018838 Model: Edison Scientific Literature 30 citations

1. Disease Information

1.1 Concise overview

Lissencephaly spectrum disorders are malformations of cortical development (MCDs) characterized by abnormal cortical folding (reduced gyrification) due primarily to impaired neuronal migration and cortical lamination during embryonic development. (uctepe2024biallelictruncatingvariants pages 1-2, alsafh2024multiplexconsanguineousfamily pages 1-2)

A concise definition from a 2024 European Journal of Human Genetics report states: “Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri.” (uctepe2024biallelictruncatingvariants pages 1-2)

1.2 Spectrum terminology (key concepts/definitions)

A core concept is that “lissencephaly” is not a single pattern but a spectrum that includes: - Agyria (near absence of gyri) - Pachygyria (broad, reduced number of gyri) - Subcortical band heterotopia (SBH) (a.k.a. double cortex) (uctepe2024biallelictruncatingvariants pages 1-2, tsai2024novellissencephalyassociatedndel1 pages 1-2)

A 2024 paper explicitly defines this: “LIS spectrum disorder includes agyria, pachygyria and subcortical band heterotopia.” (uctepe2024biallelictruncatingvariants pages 1-2)

1.3 Key identifiers and coding systems

From the tools used here, the disease has: - MONDO: MONDO:0018838 (OpenTargets Search: lissencephaly)

Other identifiers (OMIM disease numbers, Orphanet IDs, ICD-10/ICD-11, MeSH IDs) were not directly retrieved in the available evidence in this run and therefore are not reported here.

1.4 Synonyms and alternative names

1.5 Evidence source type

The evidence in this report comes from: - Aggregated disease-level resources/knowledge graphs (Open Targets). (OpenTargets Search: lissencephaly) - Human clinical genomics cohort studies and gene discovery/expansion papers (exome sequencing, GeneMatcher collaborations). (kooshavar2024diagnosticutilityof pages 1-3, uctepe2024biallelictruncatingvariants pages 1-2) - Mechanistic human genetics with model-based functional validation (mouse in utero electroporation; scRNA-seq; spatial transcriptomics). (tsai2024novellissencephalyassociatedndel1 pages 1-2)

2. Etiology

2.1 Primary causal factors

Lissencephaly spectrum disorders are genetically heterogeneous, involving multiple pathways critical to neuronal migration, microtubule dynamics, dynein regulation, and cortical organization. Multiple papers emphasize microtubule/dynein/migration biology as central etiologic themes. (alsafh2024multiplexconsanguineousfamily pages 1-2, tsai2024novellissencephalyassociatedndel1 pages 1-2, pavone2023casereportstructural pages 1-2)

A 2024 NDEL1 paper highlights core upstream processes: “cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1.” (tsai2024novellissencephalyassociatedndel1 pages 1-2)

2.2 Genetic risk factors (causal genes and variant classes)

Open Targets provides disease–target associations for lissencephaly and for MONDO:0018838 lissencephaly spectrum disorders, including (not exhaustive): DCX, PAFAH1B1 (LIS1), TUBA1A, ARX, RELN, CEP85L, LAMB1, MACF1, KATNB1, TMTC3, DYNC1H1, NDE1. (OpenTargets Search: lissencephaly)

Recent (2023–2024) primary literature expands the gene spectrum and clarifies inheritance modes:

Autosomal recessive (AR) examples / emerging genes - CASP2: 2024 GeneMatcher-based series of 7 patients from 5 families with biallelic truncating/compound heterozygous variants, described as “compatible with an autosomal recessive pattern.” (uctepe2024biallelictruncatingvariants pages 1-2) - CLASP1: 2024 report of three affected siblings with a homozygous CLASP1 variant from a consanguineous family; the paper notes that segregation suggests “a possible autosomal recessive inheritance.” (alsafh2024multiplexconsanguineousfamily pages 1-2)

Autosomal dominant (AD), often de novo examples (notably tubulinopathies) - TUBA1A: a 2024 case report/literature review states that for TUBA1A “most cases show de novo autosomal dominant inheritance,” consistent with broader tubulinopathy patterns. (ren2024lissencephalycausedby pages 1-2)

Somatic mosaicism - NDEL1 p.Arg105Pro: 2024 Acta Neuropathologica paper identified “the same de novo somatic mosaic NDEL1 variant” in two unrelated patients with pachygyria ± SBH. (tsai2024novellissencephalyassociatedndel1 pages 1-2)

X-linked - DCX is a major X-linked lissencephaly-spectrum gene in Open Targets. (OpenTargets Search: lissencephaly)

2.3 Environmental risk factors / protective factors / gene–environment interactions

While environmental insults can contribute to cortical malformations, quantitative environmental risk/protective factor evidence specific to “lissencephaly spectrum disorders” was not retrieved in the evidence set used here. The available evidence emphasizes genetic causation in most described cases and cohorts. (kooshavar2024diagnosticutilityof pages 1-3, uctepe2024biallelictruncatingvariants pages 1-2)

3. Phenotypes (clinical features)

3.1 Core phenotype set

Commonly reported features include: - Global developmental delay / intellectual disability (ID) (uctepe2024biallelictruncatingvariants pages 1-2) - Hypotonia (uctepe2024biallelictruncatingvariants pages 1-2) - Seizures / epilepsy, often early-onset and refractory (alsafh2024multiplexconsanguineousfamily pages 1-2, uctepe2024biallelictruncatingvariants pages 1-2) - Neurobehavioral phenotypes in subsets (ADHD, autistic traits, poor social skills) in CASP2-related cases (uctepe2024biallelictruncatingvariants pages 1-2)

Abstract quote (CASP2 series): “Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits.” (uctepe2024biallelictruncatingvariants pages 1-2)

3.2 Age of onset and progression

Lissencephaly-spectrum disorders typically present congenitally (structural brain malformation present at birth), with clinical manifestations in infancy (developmental delay and seizures often beginning early). In a long-term lissencephaly cohort, the median age at suspected diagnosis was reported as 5 months for LIS1/PAFAH1B1 and 9 months for DCX. (proepper2026genespecificlongtermcourse pages 6-11)

3.3 Phenotype frequencies and quantitative data (recent cohort statistics)

A long-term cohort study (published 2026) provides quantitative complication frequencies and supportive-care utilization; although slightly outside the requested 2023–2024 priority, these data are currently among the most detailed quantitative real-world outcomes located in the retrieved evidence: - Recurrent respiratory infections: 14/38 (37%) in LIS1/PAFAH1B1; 1/4 (25%) in DCX (proepper2026genespecificlongtermcourse pages 6-11) - Dysphagia/vomiting: 23/37 (62%) in LIS1/PAFAH1B1; 2/4 (50%) in DCX (proepper2026genespecificlongtermcourse pages 6-11) - Tube feeding required: 15/38 (40%) in LIS1/PAFAH1B1; 1/5 (20%) in DCX (proepper2026genespecificlongtermcourse pages 6-11) - Supportive therapies: median 8 therapies per patient (range 1–17) (proepper2026genespecificlongtermcourse pages 6-11)

3.4 HPO term suggestions (non-exhaustive)

Based on the phenotypes explicitly present in the evidence: - Lissencephaly (HP:0001339 appears as a disease entity in the Open Targets output) (OpenTargets Search: lissencephaly) - Microcephaly (mentioned as common and as a prenatal abnormality in cohorts) (hu2026prenataldiagnosisof pages 1-2, proepper2026genespecificlongtermcourse pages 6-11) - Seizures / epilepsy (alsafh2024multiplexconsanguineousfamily pages 1-2, uctepe2024biallelictruncatingvariants pages 1-2) - Hypotonia (uctepe2024biallelictruncatingvariants pages 1-2) - Developmental delay / intellectual disability (uctepe2024biallelictruncatingvariants pages 1-2) - Subcortical band heterotopia / double cortex (tsai2024novellissencephalyassociatedndel1 pages 1-2, uctepe2024biallelictruncatingvariants pages 1-2)

Frequency-by-HPO mapping beyond these qualitative statements was not available in the retrieved sources.

4. Genetic/Molecular Information

4.1 Causal genes (representative list)

High-confidence, widely established genes: PAFAH1B1 (LIS1), DCX, ARX, RELN, TUBA1A, DYNC1H1, NDE1. (OpenTargets Search: lissencephaly, tsai2024novellissencephalyassociatedndel1 pages 1-2)

Recently expanded/implicated genes (2023–2024 evidence): - NDEL1 (somatic mosaic) (tsai2024novellissencephalyassociatedndel1 pages 1-2) - CASP2 (biallelic truncating variants; PIDDosome component) (uctepe2024biallelictruncatingvariants pages 1-2) - CLASP1 (candidate AR lissencephaly) (alsafh2024multiplexconsanguineousfamily pages 1-2)

4.2 Variant classes and functional consequences

Examples from recent evidence: - Truncating / splice-disrupting loss-of-function (AR): CASP2 truncating and splice-site variants, including frameshift and nonsense; RNA studies showed cryptic splicing generating premature stop codons. (uctepe2024biallelictruncatingvariants pages 1-2) - Missense variants with dominant effects (often de novo): NDEL1 p.Arg105Pro (somatic mosaic missense) (tsai2024novellissencephalyassociatedndel1 pages 1-2); TUBA1A p.Arg402Cys in a de novo case report (ren2024lissencephalycausedby pages 1-2)

4.3 Modifier genes / epigenetic information

Specific validated modifier genes or disease-specific epigenetic mechanisms were not retrieved in the evidence set.

4.4 Chromosomal abnormalities

General MCD resources emphasize chromosomal abnormalities as part of the etiologic spectrum, and Kooshavar et al. required prior chromosomal microarray (CMA) with exclusion of pathogenic CNVs. However, lissencephaly-specific CNV frequencies were not provided in the extracted evidence snippets. (kooshavar2024diagnosticutilityof pages 1-3)

5. Environmental Information

No disease-specific environmental or lifestyle contributors were identified in the retrieved evidence set; the evidence emphasizes genetic causation and genomics-guided diagnosis. (kooshavar2024diagnosticutilityof pages 1-3, uctepe2024biallelictruncatingvariants pages 1-2)

6. Mechanism / Pathophysiology

6.1 Core causal chain (current understanding)

A broadly supported mechanism is: 1) Pathogenic variants disrupt proteins governing neuronal migration/cytoskeletal dynamics (microtubules, dynein regulators, microtubule-associated proteins). (alsafh2024multiplexconsanguineousfamily pages 1-2, pavone2023casereportstructural pages 1-2) 2) This impairs nucleokinesis and/or radial migration and cortical layer formation. (tsai2024novellissencephalyassociatedndel1 pages 1-2) 3) The resulting cortical malformation manifests as agyria/pachygyria/SBH and commonly leads to epilepsy and neurodevelopmental disability. (uctepe2024biallelictruncatingvariants pages 1-2)

6.2 Dynein–LIS1–NDE1/NDEL1 and nucleokinesis (major 2024 advance)

The 2024 Acta Neuropathologica study provides unusually direct mechanistic linkage from variant → molecular interaction → cellular process → phenotype: - “p.R105P expression alone strongly disrupted neuronal migration … and impaired nucleus–centrosome coupling, suggesting a failure in nucleokinesis.” (tsai2024novellissencephalyassociatedndel1 pages 1-2) - “Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1.” (tsai2024novellissencephalyassociatedndel1 pages 1-2)

This paper also incorporates modern profiling approaches: “single-cell RNA sequencing and spatial transcriptomic analysis,” which showed complementary expression patterns (NDE1 in neural progenitors; NDEL1 in post-mitotic neurons). (tsai2024novellissencephalyassociatedndel1 pages 1-2)

6.3 PIDDosome/caspase-2 pathway (CASP2, CRADD, PIDD1)

The 2024 CASP2 study ties an apoptosis/inflammasome-like signaling complex to cortical development: “Recently, biallelic pathogenic variants in CRADD and PIDD1 have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2.” (uctepe2024biallelictruncatingvariants pages 1-2)

6.4 Microtubule biology and tubulinopathies

A 2023 review of TUBA1A tubulinopathies describes tubulinopathies as a heterogeneous group of tubulin-gene disorders with severe cortical and subcortical malformations, emphasizing microtubules as fundamental to neuronal migration, axonal transport, and connectivity. (pavone2023casereportstructural pages 1-2)

6.5 Ontology suggestions

GO biological process (examples): neuronal migration; nucleokinesis; microtubule-based process; cortical layer formation (supported conceptually by dynein/migration mechanism and explicitly by the NDEL1 paper’s focus on neuronal migration and nucleokinesis). (tsai2024novellissencephalyassociatedndel1 pages 1-2)

Cell Ontology (CL) suggestions (examples): - Radial glial cells / neural progenitors (the NDEL1 paper explicitly discusses neural progenitors and radial glial cells in the ventricular zone) (tsai2024novellissencephalyassociatedndel1 pages 1-2) - Post-mitotic neurons (explicitly referenced in expression analysis) (tsai2024novellissencephalyassociatedndel1 pages 1-2)

UBERON suggestions: cerebral cortex; ventricular zone; subventricular zone; cortical plate (explicitly referenced anatomical compartments in the NDEL1 study). (tsai2024novellissencephalyassociatedndel1 pages 1-2)

7. Anatomical Structures Affected

7.1 Organ/system level

Primary system: central nervous system, particularly the cerebral cortex (six-layered neocortex) and its gyral/sulcal architecture. (tsai2024novellissencephalyassociatedndel1 pages 1-2, uctepe2024biallelictruncatingvariants pages 1-2)

7.2 Tissue/cell level

Key developmental compartments and cell types include ventricular zone progenitors (radial glial cells) and migrating post-mitotic neurons. (tsai2024novellissencephalyassociatedndel1 pages 1-2)

8. Temporal Development

8.1 Onset

Structural malformation is congenital; clinical recognition often occurs in infancy. In one cohort, median suspected diagnosis age was 5–9 months depending on gene subgroup (LIS1 vs DCX). (proepper2026genespecificlongtermcourse pages 6-11)

8.2 Course

Neurodevelopmental impairment and epilepsy frequently persist long-term; supportive therapies are heavily used by families. (proepper2026genespecificlongtermcourse pages 6-11)

9. Inheritance and Population

9.1 Epidemiology (statistics)

A recent cohort study reports incidence estimates for classic lissencephaly of 11.7–40 per million births and cites substantial mortality burden (approximately 50% mortality by age 10 years). (proepper2026genespecificlongtermcourse pages 6-11)

9.2 Inheritance patterns (summary)

9.3 Consanguinity

The CLASP1 report explicitly involves a “multiplex consanguineous” family and demonstrates a recessive segregation pattern, supporting consanguinity as a practical risk factor for AR forms. (alsafh2024multiplexconsanguineousfamily pages 1-2)

10. Diagnostics

10.1 Imaging

MRI is foundational for diagnosis and for defining the malformation subtype. Kooshavar et al. recruited only children with MRI-defined malformations. (kooshavar2024diagnosticutilityof pages 1-3)

10.2 Genetic testing strategy and real-world yields (key 2024 dataset)

Kooshavar et al. (Brain Communications; accepted Feb 2024; advance access publication Feb 28, 2024) provides “real-world” yield data for exome sequencing in pediatric brain malformations, including lissencephaly and tubulinopathies:

Direct abstract quotes: - “The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up.” (kooshavar2024diagnosticutilityof pages 1-3) - “The main source of increased diagnostic yield was the reanalysis of the singleton exome data to include newly discovered gene–disease associations. One additional diagnosis was made by trio exome sequencing.” (kooshavar2024diagnosticutilityof pages 1-3)

This cohort also provides subtype frequencies in their 102-patient series: polymicrogyria 36%, tubulinopathy 10%, lissencephaly 10%, among others. (kooshavar2024diagnosticutilityof pages 1-3)

The study required CMA first and excluded cases with pathogenic CNVs, highlighting the common diagnostic workflow: CMA → exome → research reanalysis/trio when indicated. (kooshavar2024diagnosticutilityof pages 1-3)

10.3 Prenatal diagnostics

A 2026 prenatal MCD review quantifies the high de novo burden and limitations of routine prenatal screening: - “De novo mutations account for the majority of pathogenic genetic alterations identified in MCD (50.6%); up to 75.1% of pathogenic mutations cannot be detected by routine prenatal screening.” (hu2026prenataldiagnosisof pages 1-2)

Although not lissencephaly-specific, this is directly relevant to prenatal detection of lissencephaly-spectrum malformations because gyral/sulcal abnormalities are linked to microtubule/migration genes in that review. (hu2026prenataldiagnosisof pages 1-2)

11. Outcome/Prognosis

Quantitative real-world morbidity and family impact includes high complication burdens (feeding difficulties, respiratory infections) and substantial caregiver HRQL impact. In one cohort, parental HRQL mean was 61.23 (SD 16.79) by PedsQL Family Impact Module. (proepper2026genespecificlongtermcourse pages 6-11)

12. Treatment

12.1 Current applications and real-world management

There are no established disease-modifying therapies in the retrieved evidence set; care is multidisciplinary and supportive: - Antiseizure medications (illustrated by a TUBA1A case with infantile spasms treated with valproate and vigabatrin) (ren2024lissencephalycausedby pages 1-2) - Feeding and dysphagia management including tube feeding/PEG when needed (quantified in a cohort) (proepper2026genespecificlongtermcourse pages 6-11) - Respiratory therapy and infection management (proepper2026genespecificlongtermcourse pages 6-11) - Physiotherapy and other developmental therapies (proepper2026genespecificlongtermcourse pages 6-11)

In a lissencephaly cohort, “physiotherapy and respiratory therapy [were] considered the most effective,” and families used a median of eight supportive therapies per patient. (proepper2026genespecificlongtermcourse pages 6-11)

12.2 MAXO suggestions (examples)

Based on management described: - Antiepileptic drug therapy (seizure management) (ren2024lissencephalycausedby pages 1-2) - Enteral feeding / tube feeding (proepper2026genespecificlongtermcourse pages 6-11) - Physiotherapy (proepper2026genespecificlongtermcourse pages 6-11) - Respiratory therapy (proepper2026genespecificlongtermcourse pages 6-11)

13. Prevention

Primary prevention is generally not feasible for monogenic lissencephaly-spectrum disorders, but genetic counseling and reproductive options (prenatal diagnosis, preimplantation genetic testing) are practical prevention strategies once a familial pathogenic variant is known. This is supported indirectly by the emphasis on the importance of a precise genetic diagnosis for counseling and reproductive planning in genomic-diagnostic cohort work. (kooshavar2024diagnosticutilityof pages 1-3)

14. Other Species / Natural Disease

Evidence for naturally occurring non-human disease was not retrieved in this run.

15. Model Organisms and Experimental Systems

Mechanistic validation in modern lissencephaly genetics increasingly uses functional neurodevelopmental assays and advanced transcriptomics: - The 2024 NDEL1 study used “single-cell RNA sequencing and spatial transcriptomic analysis” and in utero electroporation knockdown to test neuronal migration phenotypes. (tsai2024novellissencephalyassociatedndel1 pages 1-2)

This supports the use of mouse neurodevelopmental systems and multi-omic profiling as key current research implementations for lissencephaly-spectrum gene discovery and mechanism elucidation. (tsai2024novellissencephalyassociatedndel1 pages 1-2)

Clinical trials (real-world implementation of research)

ClinicalTrials.gov includes an interventional study explicitly focused on genetic/transcriptomic diagnosis of lissencephalies: - NCT05185414 “Combining Exome and Transcriptome Data to Unravel the Genetic Basis of the Lissencephalies” (Universitair Ziekenhuis Brussel; enrollment 50; status unknown). (OpenTargets Search: lissencephaly)

Summary artifact (high-yield structured facts)

Table (click to expand)
Item Key details Evidence/PMID/DOI/URL Publication date Context citation id(s)
Disease spectrum / definition Lissencephaly spectrum disorders are malformations of cortical development caused chiefly by defective neuronal migration; the spectrum includes agyria, pachygyria, and subcortical band heterotopia (SBH, “double cortex”). Clinical comorbidity commonly includes developmental delay/intellectual disability, hypotonia progressing to spasticity, and seizures. Uctepe et al., Eur J Hum Genet 2024, DOI: 10.1038/s41431-023-01461-2, https://doi.org/10.1038/s41431-023-01461-2 2024-10 (uctepe2024biallelictruncatingvariants pages 1-2)
Spectrum subtypes / pathology Classic lissencephaly is linked to cortical dyslamination genes such as PAFAH1B1, DCX, ARX; cobblestone lissencephaly shows distinct neuropathology associated with glycosylation pathway genes such as POMGNT1, POMT1, POMT2. Brock et al., systematic review; summarized neuropathology of genetically defined MCDs n/a (brockUnknownyearneuropathologyofgenetically pages 13-13)
Standardized disease concept MONDO includes lissencephaly spectrum disorders = MONDO:0018838; Open Targets links high-confidence associated targets including DCX, PAFAH1B1, TUBA1A, ARX, RELN, CEP85L, LAMB1, MACF1. Open Targets disease-target association, https://platform.opentargets.org current platform query (OpenTargets Search: lissencephaly)
Key genes / common established causes The most common established genes across classic lissencephaly are PAFAH1B1 (LIS1) and DCX; major additional genes include TUBA1A, DYNC1H1, TUBG1, ARX, RELN, CEP85L, LAMB1, MACF1, KATNB1. Open Targets; Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z 2026-05; platform current (OpenTargets Search: lissencephaly, proepper2026genespecificlongtermcourse pages 6-11)
Inheritance pattern: AD / de novo Many lissencephaly-spectrum disorders are autosomal dominant, often de novo, especially tubulinopathies. TUBA1A is reported as the most commonly mutated tubulin gene; “most cases” show de novo autosomal dominant inheritance. Ren et al., Front Pediatr 2024, DOI: 10.3389/fped.2024.1367305, https://doi.org/10.3389/fped.2024.1367305 2024-05 (ren2024lissencephalycausedby pages 1-2)
Inheritance pattern: X-linked DCX is an X-linked cause: males often show classic lissencephaly, while females may show SBH/double cortex; mosaic/non-coding variation can yield milder phenotypes. Gao et al., Heliyon 2023, DOI: 10.1016/j.heliyon.2023.e22323, https://doi.org/10.1016/j.heliyon.2023.e22323; Open Targets 2023-11 (OpenTargets Search: lissencephaly)
Inheritance pattern: AR Recessive forms are increasingly recognized, including CASP2, CLASP1, TUBGCP2, and earlier CRADD/PIDD1-related anterior-predominant LIS. Uctepe et al. 2024; Alsafh et al. 2024; Yu et al. 2025 2024-10; 2024-08; 2025-02 (uctepe2024biallelictruncatingvariants pages 1-2, alsafh2024multiplexconsanguineousfamily pages 1-2, yu2025tubgcp2variantscause pages 1-2)
Inheritance pattern: somatic mosaic NDEL1 p.Arg105Pro was identified as a de novo somatic mosaic cause of pachygyria with or without SBH, establishing mosaic dynein-pathway disease within the lissencephaly spectrum. Tsai et al., Acta Neuropathol 2024, DOI: 10.1007/s00401-023-02665-y, https://doi.org/10.1007/s00401-023-02665-y 2024-01 (tsai2024novellissencephalyassociatedndel1 pages 1-2)
Quantitative stat: exome diagnostic yield In 102 children with brain malformations, singleton clinical exome had 36% diagnostic yield, increasing to 43% after research follow-up/reanalysis; one additional diagnosis came from trio exome. Lissencephaly represented 10% of the cohort, and the highest phenotype-based yields were for cobblestone malformation, tubulinopathy, and lissencephaly. Kooshavar et al., Brain Communications 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056 2024-02-28 (kooshavar2024diagnosticutilityof pages 1-3)
Quantitative stat: malformation subtype mix Among the Kooshavar cohort, commonest subtypes were polymicrogyria 36%, pontocerebellar hypoplasia 14%, periventricular nodular heterotopia 11%, tubulinopathy 10%, lissencephaly 10%, cortical dysplasia 9%. Kooshavar et al., Brain Communications 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056 2024-02-28 (kooshavar2024diagnosticutilityof pages 1-3, kooshavar2024diagnosticutilityof pages 3-4)
Quantitative stat: recurrent gene in diagnostics In the Kooshavar series, the most frequent genetic diagnosis was TUBA1A. Kooshavar et al., Brain Communications 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056 2024-02-28 (kooshavar2024diagnosticutilityof pages 1-3)
Quantitative stat: prenatal genetics In prenatal MCD literature synthesized by Hu et al., de novo mutations accounted for 50.6% of pathogenic alterations, and up to 75.1% of pathogenic mutations were not detectable by routine prenatal screening; proliferation-phase abnormalities were 62.9% of prenatal MCD phenotypes. Hu et al., Biomedicines 2026, DOI: 10.3390/biomedicines14010107, https://doi.org/10.3390/biomedicines14010107 2026-01 (hu2026prenataldiagnosisof pages 1-2)
Quantitative stat: incidence / mortality A recent long-term cohort summary cites classic lissencephaly incidence of 11.7–40 per million births, infantile epileptic spasms syndrome in 57%, and approximately 50% mortality by age 10 years. Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z 2026-05 (proepper2026genespecificlongtermcourse pages 6-11)
Quantitative stat: prenatal abnormalities and age at recognition In the Proepper cohort, prenatal abnormalities were seen in 14/37 (38%) of PAFAH1B1/LIS1 and 2/5 (40%) of DCX cases; median age at suspected diagnosis was 5 months for LIS1-related and 9 months for DCX-related disease. Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z 2026-05 (proepper2026genespecificlongtermcourse pages 6-11, proepper2026genespecificlongtermcourse pages 11-16)
Quantitative stat: complications / feeding / respiratory In the Proepper cohort, frequent complications included recurrent respiratory infections 14/38 (37%) in LIS1 and 1/4 (25%) in DCX; dysphagia/vomiting 23/37 (62%) in LIS1 and 2/4 (50%) in DCX; tube feeding required in 15/38 (40%) in LIS1 and 1/5 (20%) in DCX. Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z 2026-05 (proepper2026genespecificlongtermcourse pages 6-11)
Quantitative stat: supportive care burden / QoL Families reported a median of 8 supportive therapies per patient (range 1–17); physiotherapy and respiratory therapy were rated most effective. Parental HRQL mean was 61.23 (SD 16.79), indicating substantial caregiver burden. Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z 2026-05 (proepper2026genespecificlongtermcourse pages 6-11)
Recent expansion: NDEL1 First lissencephaly-associated NDEL1 variant: two unrelated patients with pachygyria ± SBH carried the same de novo somatic mosaic p.Arg105Pro; mechanism implicated failure of nucleokinesis via disrupted NDEL1–LIS1 interaction. Tsai et al., Acta Neuropathol 2024, DOI: 10.1007/s00401-023-02665-y, https://doi.org/10.1007/s00401-023-02665-y 2024-01 (tsai2024novellissencephalyassociatedndel1 pages 1-2)
Recent expansion: CASP2 CASP2 added to the PIDDosome-related lissencephaly genes: 7 patients from 5 families with biallelic truncating/splice variants had anterior/frontotemporal LIS and pachygyria resembling CRADD/PIDD1 disease. Uctepe et al., Eur J Hum Genet 2024, DOI: 10.1038/s41431-023-01461-2, https://doi.org/10.1038/s41431-023-01461-2 2024-10 (uctepe2024biallelictruncatingvariants pages 1-2)
Recent expansion: CLASP1 CLASP1 emerged as a candidate recessive lissencephaly gene in a multiplex consanguineous family; 3 siblings had homozygous c.4442G>A p.Arg1481His with classic lissencephaly, microcephaly, severe developmental delay, and early refractory epilepsy. Alsafh et al., Neurology Genetics 2024, DOI: 10.1212/NXG.0000000000200172, https://doi.org/10.1212/NXG.0000000000200172 2024-08 (alsafh2024multiplexconsanguineousfamily pages 1-2)
Diagnostic approach: imaging Brain MRI remains the core diagnostic modality for defining the malformation pattern and guiding gene prioritization. Recognizable signatures include anterior/frontotemporal LIS in CASP2/CRADD/PIDD1, posterior>anterior classic LIS plus thin splenium/pontine hypoplasia in CLASP1, and pachygyria ± SBH in mosaic NDEL1. Uctepe et al. 2024; Alsafh et al. 2024; Tsai et al. 2024 2024 (uctepe2024biallelictruncatingvariants pages 1-2, alsafh2024multiplexconsanguineousfamily pages 1-2, tsai2024novellissencephalyassociatedndel1 pages 1-2)
Diagnostic approach: genetics Recommended workflow supported by recent evidence: CMA first to detect CNVs; then exome sequencing; then periodic reanalysis because reanalysis contributed more to added diagnoses than trio expansion in a real-world MCD cohort. Kooshavar et al., Brain Communications 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056 2024-02-28 (kooshavar2024diagnosticutilityof pages 1-3, kooshavar2024diagnosticutilityof pages 3-4)
Diagnostic approach: prenatal For suspected fetal cortical malformations, fetal neurosonography + fetal MRI + NGS/WES are increasingly emphasized; routine prenatal screens miss many pathogenic variants. Hu et al., Biomedicines 2026, DOI: 10.3390/biomedicines14010107, https://doi.org/10.3390/biomedicines14010107 2026-01 (hu2026prenataldiagnosisof pages 1-2)
Management / supportive therapies No disease-modifying therapy is established; current care is multidisciplinary and supportive: antiepileptic therapy, feeding support including tube feeding/PEG when needed, physiotherapy, respiratory therapy, developmental therapies, and caregiver support. Physiotherapy and respiratory therapy were reported as most effective in family surveys. Proepper et al., Orphanet J Rare Dis 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z; Ren et al. 2024 2026-05; 2024-05 (proepper2026genespecificlongtermcourse pages 6-11, ren2024lissencephalycausedby pages 1-2)

Table: This table condenses high-yield definitions, genetics, quantitative clinical statistics, recent gene discoveries, and current diagnostic/management points for lissencephaly spectrum disorders. It is useful as a structured reference for building a disease knowledge-base entry with linked evidence.

Key recent developments (2023–2024 emphasis)

1) Diagnostic genomics evidence in real-world cohorts (2024): singleton exome yield 36% rising to 43% with reanalysis; reanalysis is a major contributor to additional diagnoses, and TUBA1A is a frequent diagnosis. (kooshavar2024diagnosticutilityof pages 1-3) 2) New mechanistic gene association with modern multi-omics (2024): somatic mosaic NDEL1 p.Arg105Pro linked to nucleokinesis failure via disrupted LIS1 binding, with scRNA-seq/spatial transcriptomics and functional migration assays. (tsai2024novellissencephalyassociatedndel1 pages 1-2) 3) Expansion of AR lissencephaly genes (2024): CASP2 biallelic truncating variants implicate the PIDDosome/caspase-2 axis in cortical development; CLASP1 is a candidate AR lissencephaly gene in a consanguineous family, supporting microtubule minus-end stabilization biology in disease. (uctepe2024biallelictruncatingvariants pages 1-2, alsafh2024multiplexconsanguineousfamily pages 1-2)

URLs and publication dates (selected high-authority recent sources)

References

  1. (OpenTargets Search: lissencephaly): Open Targets Query (lissencephaly, 25 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (uctepe2024biallelictruncatingvariants pages 1-2): Eyyup Uctepe, Barbara Vona, Fatma Nisa Esen, F. Mujgan Sonmez, Thomas Smol, Sait Tümer, Hanifenur Mancılar, Dilan Ece Geylan Durgun, Odile Boute, Meysam Moghbeli, Ehsan Ghayoor Karimiani, Narges Hashemi, Behnoosh Bakhshoodeh, Hyung Goo Kim, Reza Maroofian, and Ahmet Yesilyurt. Bi-allelic truncating variants in casp2 underlie a neurodevelopmental disorder with lissencephaly. European Journal of Human Genetics, 32:52-60, Oct 2024. URL: https://doi.org/10.1038/s41431-023-01461-2, doi:10.1038/s41431-023-01461-2. This article has 13 citations and is from a domain leading peer-reviewed journal.

  3. (alsafh2024multiplexconsanguineousfamily pages 1-2): Rawan Alsafh, Amal Alhashem, Aly Elsyed, Zafer Yüksel, Kalthoum Graiess-Tlili, Khalid Hundallah, Farah Thabet, and Brahim Tabarki. Multiplex consanguineous family highlights clasp1 as a candidate gene for lissencephaly. Aug 2024. URL: https://doi.org/10.1212/nxg.0000000000200172, doi:10.1212/nxg.0000000000200172. This article has 6 citations.

  4. (tsai2024novellissencephalyassociatedndel1 pages 1-2): Meng-Han Tsai, Hao-Chen Ke, Wan-Cian Lin, Fang-Shin Nian, Chia-Wei Huang, Haw-Yuan Cheng, Chi-Sin Hsu, Tiziana Granata, Chien-Hui Chang, Barbara Castellotti, Shin-Yi Lin, Fabio M. Doniselli, Cheng-Ju Lu, Silvana Franceschetti, Francesca Ragona, Pei-Shan Hou, Laura Canafoglia, Chien-Yi Tung, Mei-Hsuan Lee, Won-Jing Wang, and Jin-Wu Tsai. Novel lissencephaly-associated ndel1 variant reveals distinct roles of nde1 and ndel1 in nucleokinesis and human cortical malformations. Acta Neuropathologica, Jan 2024. URL: https://doi.org/10.1007/s00401-023-02665-y, doi:10.1007/s00401-023-02665-y. This article has 11 citations and is from a highest quality peer-reviewed journal.

  5. (kooshavar2024diagnosticutilityof pages 1-3): Daniz Kooshavar, David J Amor, Kirsten Boggs, Naomi Baker, Christopher Barnett, Michelle G de Silva, Samantha Edwards, Michael C Fahey, Justine E Marum, Penny Snell, Kiymet Bozaoglu, Kate Pope, Shekeeb S Mohammad, Kate Riney, Rani Sachdev, Ingrid E Scheffer, Sarah Schenscher, John Silberstein, Nicholas Smith, Melanie Tom, Tyson L Ware, Paul J Lockhart, and Richard J Leventer. Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations. Brain Communications, Feb 2024. URL: https://doi.org/10.1093/braincomms/fcae056, doi:10.1093/braincomms/fcae056. This article has 6 citations and is from a peer-reviewed journal.

  6. (pavone2023casereportstructural pages 1-2): Piero Pavone, Pasquale Striano, Giovanni Cacciaguerra, Simona Domenica Marino, Enrico Parano, Xena Giada Pappalardo, Raffaele Falsaperla, and Martino Ruggieri. Case report: structural brain abnormalities in tuba1a-tubulinopathies: a narrative review. Frontiers in Pediatrics, Sep 2023. URL: https://doi.org/10.3389/fped.2023.1210272, doi:10.3389/fped.2023.1210272. This article has 7 citations.

  7. (ren2024lissencephalycausedby pages 1-2): Sijing Ren, Yu Kong, Ruihan Liu, Qiu-bo Li, Xuehua Shen, and Qing-xia Kong. Lissencephaly caused by a de novo mutation in tubulin tuba1a: a case report and literature review. Frontiers in Pediatrics, May 2024. URL: https://doi.org/10.3389/fped.2024.1367305, doi:10.3389/fped.2024.1367305. This article has 5 citations.

  8. (proepper2026genespecificlongtermcourse pages 6-11): Christiane R. Proepper, Lisa-Maria Schwarz, Sofia M. Schuetz, Katja von Au, Thomas Bast, Nathalie Beaud, Ingo Borggraefe, Friedrich Bosch, Melanie Busse, Jena Chung, Otfried Debus, Katharina Diepold, Thomas Fries, Gero von Gersdorff, Martin Haeussler, Andreas Hahn, Till Hartlieb, Ralf Heiming, Peter Herkenrath, Gerhard Kluger, Jonas H. Kreth, Gerhard Kurlemann, Peter Moeller, Deborah J. Morris-Rosendahl, Axel Panzer, Heike Philippi, Sophia Ruegner, Carolina Toepfer, Silvia Vieker, Adelheid Wiemer-Kruel, Anika Winter, Gerhard Schuierer, Ute Hehr, and Tobias Geis. Gene-specific long-term course, neurodevelopmental outcome and quality of life in patients with lis1/pafah1b1-, dcx-, dync1h1-, tuba1a- and tubg1-related lissencephaly. Orphanet Journal of Rare Diseases, May 2026. URL: https://doi.org/10.1186/s13023-026-04398-z, doi:10.1186/s13023-026-04398-z. This article has 0 citations and is from a peer-reviewed journal.

  9. (hu2026prenataldiagnosisof pages 1-2): Jinhua Hu, Xiaogang Xu, Ping Jiang, Ruibin Huang, Jiani Yuan, Long Lu, and Jin Han. Prenatal diagnosis of malformations of cortical development: a review of genetic and imaging advances. Biomedicines, 14:107, Jan 2026. URL: https://doi.org/10.3390/biomedicines14010107, doi:10.3390/biomedicines14010107. This article has 1 citations.

  10. (brockUnknownyearneuropathologyofgenetically pages 13-13): S Brock, F Cools, and AC Jansen. Neuropathology of genetically defined malformations of cortical development-a systematic. Unknown journal, Unknown year.

  11. (yu2025tubgcp2variantscause pages 1-2): Tao Yu, Miao Yu, Xueyan Liu, and Hua Wang. Tubgcp2 variants cause lissencephaly spectrum disorders: a case report and literature review. Frontiers in Pediatrics, Feb 2025. URL: https://doi.org/10.3389/fped.2025.1476390, doi:10.3389/fped.2025.1476390. This article has 1 citations.

  12. (kooshavar2024diagnosticutilityof pages 3-4): Daniz Kooshavar, David J Amor, Kirsten Boggs, Naomi Baker, Christopher Barnett, Michelle G de Silva, Samantha Edwards, Michael C Fahey, Justine E Marum, Penny Snell, Kiymet Bozaoglu, Kate Pope, Shekeeb S Mohammad, Kate Riney, Rani Sachdev, Ingrid E Scheffer, Sarah Schenscher, John Silberstein, Nicholas Smith, Melanie Tom, Tyson L Ware, Paul J Lockhart, and Richard J Leventer. Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations. Brain Communications, Feb 2024. URL: https://doi.org/10.1093/braincomms/fcae056, doi:10.1093/braincomms/fcae056. This article has 6 citations and is from a peer-reviewed journal.

  13. (proepper2026genespecificlongtermcourse pages 11-16): Christiane R. Proepper, Lisa-Maria Schwarz, Sofia M. Schuetz, Katja von Au, Thomas Bast, Nathalie Beaud, Ingo Borggraefe, Friedrich Bosch, Melanie Busse, Jena Chung, Otfried Debus, Katharina Diepold, Thomas Fries, Gero von Gersdorff, Martin Haeussler, Andreas Hahn, Till Hartlieb, Ralf Heiming, Peter Herkenrath, Gerhard Kluger, Jonas H. Kreth, Gerhard Kurlemann, Peter Moeller, Deborah J. Morris-Rosendahl, Axel Panzer, Heike Philippi, Sophia Ruegner, Carolina Toepfer, Silvia Vieker, Adelheid Wiemer-Kruel, Anika Winter, Gerhard Schuierer, Ute Hehr, and Tobias Geis. Gene-specific long-term course, neurodevelopmental outcome and quality of life in patients with lis1/pafah1b1-, dcx-, dync1h1-, tuba1a- and tubg1-related lissencephaly. Orphanet Journal of Rare Diseases, May 2026. URL: https://doi.org/10.1186/s13023-026-04398-z, doi:10.1186/s13023-026-04398-z. This article has 0 citations and is from a peer-reviewed journal.

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