Miller-Dieker Lissencephaly Syndrome

Mendelian MONDO:0009532 Pathograph 22 Show in embeddings browser chromosomal deletion syndrome classic lissencephaly neuronal migration disorder

Miller-Dieker lissencephaly syndrome (MDLS) is a severe contiguous-gene deletion syndrome caused by a heterozygous deletion of the 17p13.3 critical region, which includes PAFAH1B1 (LIS1) and YWHAE (14-3-3 epsilon). Haploinsufficiency of PAFAH1B1 disrupts the LIS1/dynein/microtubule motor machinery required for neuronal migration during corticogenesis, producing classical (type I) lissencephaly with a thickened, poorly gyrated cortex. Co-deletion of YWHAE contributes to the greater severity that distinguishes MDLS from isolated lissencephaly sequence. Affected individuals have profound developmental disability, intractable epilepsy, microcephaly, hypotonia, characteristic craniofacial dysmorphism, growth failure, and high early mortality.

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1
Inheritance
5
Pathophys.
16
Phenotypes
1
Gaps
22
Pathograph
2
Genes
4
Medical Actions
1
References
1
Deep Research
👪

Inheritance

1
De novo 17p13.3 deletion
MDLS most commonly arises from a de novo 17p13.3 deletion; a minority of cases result from an unbalanced segregation of a parental balanced chromosomal rearrangement, which has implications for recurrence-risk counseling.
Show evidence (1 reference)
PMID:24055730 SUPPORT Human Clinical
"The qPCR assays revealed a maternal origin of the deletion."
This case illustrates that some 17p13.3 deletions derive from a parental rearrangement, supporting the need for parental cytogenetic studies in recurrence-risk assessment.
?

Discussions and Knowledge Gaps

1
Does the prevailing mouse-model-derived view of MDS/classical lissencephaly as primarily a post-mitotic neuronal migration defect adequately capture the human pathomechanism, given that patient-derived iPSC cerebral organoids additionally reveal a mitotic defect in outer radial glia (oRG/bRG) — a progenitor subtype largely absent from the lissencephalic rodent cortex but critical for human neocortical expansion?
HUMAN MODEL MISMATCH OPEN gap_mds_outer_radial_glia_human_model_mismatch
Attached to
pathophysiology#Impaired Neuronal Migration and Cortical Malformation pathophysiology#LIS1 Haploinsufficiency and Dynein/Microtubule Motor Dysfunction
The dominant lissencephaly model — defective LIS1-dependent nucleokinesis/neuronal migration — derives largely from Pafah1b1 mutant mice and limited postmortem analysis. Because the mouse cortex is naturally lissencephalic and has few outer radial glia, it cannot test whether human-specific oRG progenitor biology contributes to MDS severity. Bershteyn et al. (PMID:28111201) found a prolonged-mitosis defect in oRG in MDS patient iPSC cerebral organoids, a progenitor subtype the authors note is "largely absent from lissencephalic rodents but critical for human neocortical expansion," and Iefremova et al. (PMID:28380362) found a non-cell-autonomous radial-glia division-mode switch. If oRG dysfunction is a genuine, human-enriched arm of MDS pathology, rodent models will systematically miss a progenitor-tier mechanism, which bears on how the migration vs. progenitor contributions to classical lissencephaly are weighted and modeled.
Proposed experiments
MDS iPSC organoid outer-radial-glia mitosis and lineage analysis
iPSC organoid perturbation assay
exp_mds_oRG_organoid_lineage
Use isogenic MDS (17p13.3 deletion) versus deletion-corrected human iPSC cerebral organoids with time-lapse imaging and single-cell RNA sequencing to quantify outer radial glia mitotic duration, division mode, and neuronal output relative to apical progenitors, testing whether oRG are disproportionately affected and whether their dysfunction is a distinct arm of pathology separable from post-mitotic migration failure.
Model systems
Human iPSC-derived cerebral organoid
Cerebral organoid differentiated from MDS-patient or gene-edited human iPSCs, preserving human-specific outer radial glia biology absent from rodent models.
ORGANOID
⚙

Pathophysiology

5
17p13.3 Contiguous-Gene Deletion
The primary lesion in MDLS is a heterozygous deletion of the 17p13.3 critical region, a contiguous-gene deletion that removes PAFAH1B1 (LIS1) and YWHAE (14-3-3 epsilon) along with neighboring dosage-sensitive genes. The size and gene content of the deletion determine phenotype severity, with larger deletions including YWHAE producing the classical Miller-Dieker phenotype.
PAFAH1B1 hgnc:8574 YWHAE hgnc:12851
Downstream
LIS1 Haploinsufficiency and Dynein/Microtubule Motor Dysfunction
YWHAE Contribution to Severity
Show evidence (2 references)
PMID:40806509 SUPPORT Human Clinical
"Miller-Dieker Syndrome (MDS) is a rare neurodevelopmental disorder caused by a heterozygous deletion of approximately 26 genes within the MDS locus of human chromosome 17."
Establishes the underlying lesion as a heterozygous contiguous-gene deletion within the 17p13.3 MDS locus.
PMID:29628935 SUPPORT Human Clinical
"Chromosome microdeletions within 17p13.3 can result in either isolated lissencephaly sequence (ILS) or Miller-Dieker syndrome (MDS). ... patients with MDS have larger deletions than patients with ILS, resulting in additional symptoms such as poor muscle tone, congenital anomalies, abnormal..."
Identifies MDS as a 17p13.3 microdeletion disorder and frames it within the broader microdeletion spectrum whose severity depends on the deleted gene content, with the larger MDS deletions producing additional features beyond isolated lissencephaly.
LIS1 Haploinsufficiency and Dynein/Microtubule Motor Dysfunction
Loss of one PAFAH1B1 (LIS1) allele reduces LIS1 protein dosage. LIS1 regulates the cytoplasmic dynein motor and microtubule dynamics that drive nucleokinesis (nuclear translocation) of migrating neurons. LIS1 haploinsufficiency also reduces filamentous actin at the leading edge of migrating neurons through dysregulated Rho GTPase activity, impairing motility. Structural studies place type-1 lissencephaly mutations directly within the dynein-LIS1 interface.
forebrain radial glial cell CL:0013000 migrating cortical glutamatergic neuron CL:0000679
neuron migration GO:0001764 ↓ DECREASED microtubule-based movement (dynein motor) GO:0007018 ⚠ ABNORMAL
Downstream
Impaired Neuronal Migration and Cortical Malformation
mTOR Pathway Hypoactivity
Show evidence (2 references)
PMID:36433683 SUPPORT Human Clinical
"Haploinsufficiency of PAFAH1B1 is responsible for the characteristic lissencephaly in MDS."
Directly attributes the characteristic lissencephaly to PAFAH1B1 (LIS1) haploinsufficiency.
PMID:14507966 SUPPORT Model Organism
"Lis1 haploinsufficiency is shown here to also result in reduced filamentous actin at the leading edge of migrating neurons, associated with upregulation of RhoA and downregulation of Rac1 and Cdc42 activity."
Mouse data link Lis1 haploinsufficiency to a cytoskeletal migration defect via dysregulated Rho GTPase signaling.
YWHAE Contribution to Severity
Co-deletion of YWHAE (encoding 14-3-3 epsilon) augments the neuronal migration defect. 14-3-3 epsilon binds CDK5/p35-phosphorylated NDEL1 (NUDEL) and sustains its phosphorylation; its loss mislocalizes NDEL1 and LIS1, reducing cytoplasmic dynein function. Mice doubly deficient for Ywhae and Pafah1b1 have more severe migration defects than single heterozygotes, providing a molecular explanation for why YWHAE-including deletions cause the more severe Miller-Dieker phenotype.
migrating cortical glutamatergic neuron CL:0000679
neuron migration GO:0001764 ↓ DECREASED
Downstream
Impaired Neuronal Migration and Cortical Malformation
Show evidence (2 references)
PMID:12796778 SUPPORT Model Organism
"Mice heterozygous with respect to both genes have more severe migration defects than single heterozygotes."
Demonstrates that combined Ywhae and Pafah1b1 deficiency produces a more severe migration defect, explaining the greater severity of MDLS versus isolated lissencephaly.
PMID:12796778 SUPPORT Model Organism
"Similar to LIS1, deficiency of 14-3-3epsilon results in mislocalization of NUDEL and LIS1, consistent with reduction of cytoplasmic dynein function."
Provides the molecular mechanism by which 14-3-3 epsilon loss converges on reduced dynein function in the LIS1/NDEL1 pathway.
Impaired Neuronal Migration and Cortical Malformation
Disrupted nucleokinesis arrests migrating neurons before they reach their correct cortical layers during fetal corticogenesis. The result is a thickened, abnormally layered cortex with a smooth surface (agyria/ pachygyria), the defining classical (type I) lissencephaly of MDLS.
migrating cortical glutamatergic neuron CL:0000679
cerebral cortex radially oriented cell migration GO:0021799 ↓ DECREASED
Downstream
Lissencephaly
Seizures
Infantile spasms
Profound intellectual disability
Microcephaly
Hypotonia
Spasticity
Feeding difficulties
Growth failure
Facial dysmorphism
Ventriculomegaly
Abnormal corpus callosum morphology
Intrauterine growth restriction
Visual impairment
Hearing impairment
Constipation
Show evidence (3 references)
PMID:40806509 SUPPORT Human Clinical
"One hallmark feature of MDS is an unusually smooth brain surface due to abnormal neuronal migration during early brain development."
Connects the abnormal neuronal migration to the hallmark smooth cortical surface (lissencephaly).
PMID:28111201 SUPPORT In Vitro
"We saw a cell migration defect that was rescued when we corrected the MDS causative chromosomal deletion and severe apoptosis of the founder neuroepithelial stem cells, accompanied by increased horizontal cell divisions."
Patient-derived MDS iPSC cerebral organoids reproduce the neuronal migration defect and demonstrate that correcting the causative 17p13.3 deletion rescues it, alongside apoptosis of the founder neuroepithelial stem cells — human in vitro (organoid) mechanistic support for the migration/progenitor pathology.
PMID:28380362 SUPPORT In Vitro
"Patient-derived organoids are significantly reduced in size, a change accompanied by a switch from symmetric to asymmetric cell division of ventricular zone radial glia cells (vRGCs)."
Patient-specific MDS forebrain-type organoids link the reduced size to a symmetric-to-asymmetric division-mode switch in ventricular-zone radial glia, an upstream progenitor mechanism feeding the migration/cortical malformation; reinstating β-catenin signaling rescues the division modes.
mTOR Pathway Hypoactivity
Cerebral organoids derived from individuals with the MDLS 17p13.3 microdeletion recapitulate the thickened lissencephalic cortex and show dysregulation of protein translation, metabolism, and the mTOR pathway. mTOR hypoactivity acts as a convergent molecular mechanism that contributes to the lissencephalic cortical phenotype rather than arising as a downstream consequence of it: a brain-selective mTORC1 activator prevented and reversed the cellular and molecular defects in these organoids, identifying mTOR hypoactivity as a causal, potentially targetable mechanism. This is a research-stage mechanism.
TOR signaling GO:0031929 ↓ DECREASED
Downstream
Impaired Neuronal Migration and Cortical Malformation
Show evidence (2 references)
PMID:39743596 SUPPORT In Vitro
"PIDD1-mutant organoids and MDLS organoids recapitulated the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism and the mTOR pathway."
Patient-derived MDLS organoids show mTOR pathway dysregulation alongside the recapitulated lissencephalic cortex.
PMID:39743596 SUPPORT In Vitro
"A brain-selective activator of mTOR complex 1 prevented and reversed cellular and molecular defects in the lissencephaly organoids."
Supports mTOR hypoactivity as a causal, reversible contributor to the cellular phenotype in MDLS organoids.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Miller-Dieker Lissencephaly Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

16
Digestive 2
Feeding difficulties Feeding difficulties HP:0011968
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"Affected newborns typically have mild-to-moderate hypotonia, feeding difficulties, and poor head control."
GeneReviews documents feeding difficulties from the neonatal period.
Constipation Constipation HP:0002019
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"treatment with stool softeners, prokinetics, osmotic agents, or laxatives for constipation;"
GeneReviews documents constipation as a recognized management concern requiring pharmacologic treatment and surveillance.
Ear 1
Hearing impairment Hearing impairment HP:0000365
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"standard treatment for developmental delay/intellectual disability, spasticity, visual impairment, and hearing loss."
GeneReviews lists hearing loss among the manifestations requiring standard treatment, and recommends annual audiologic evaluation.
Eye 1
Visual impairment Visual impairment HP:0000505
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"standard treatment for developmental delay/intellectual disability, spasticity, visual impairment, and hearing loss."
GeneReviews lists visual impairment among the manifestations requiring standard treatment, and recommends annual ophthalmologic evaluation.
Head and Neck 2
Microcephaly Microcephaly HP:0000252
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"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."
GeneReviews documents progressive microcephaly as a feature.
Facial dysmorphism Abnormal facial shape HP:0001999
Show evidence (1 reference)
PMID:36433683 SUPPORT Human Clinical
"The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death."
Lists dysmorphic facial features among the defining features of MDS specifically.
Musculoskeletal 2
Hypotonia Hypotonia HP:0001252
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"Affected newborns typically have mild-to-moderate hypotonia, feeding difficulties, and poor head control."
GeneReviews documents neonatal hypotonia.
Spasticity Spasticity HP:0001257
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"mild distal spasticity that can transition over time to more severe spasticity."
GeneReviews documents progressive spasticity.
Nervous System 3
Seizures VERY_FREQUENT Seizure HP:0001250
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"Seizures occur in more than 90% of individuals with lissencephaly and often include infantile spasms."
GeneReviews documents seizures in >90% of individuals with lissencephaly, supporting a VERY_FREQUENT classification.
Ventriculomegaly Ventriculomegaly HP:0002119
Show evidence (1 reference)
PMID:24055730 SUPPORT Human Clinical
"in a fetus with lissencephaly, corpus callosum dysgenesis, ventriculomegaly, microcephaly, intrauterine growth restriction (IUGR), polyhydramnios and single umbilical artery."
Documents ventriculomegaly among the associated prenatal brain findings.
Abnormal corpus callosum morphology Abnormal corpus callosum morphology HP:0001273
Show evidence (1 reference)
PMID:24055730 SUPPORT Human Clinical
"in a fetus with lissencephaly, corpus callosum dysgenesis, ventriculomegaly, microcephaly, intrauterine growth restriction (IUGR), polyhydramnios and single umbilical artery."
Documents corpus callosum dysgenesis among the associated brain malformations.
Growth 2
Growth failure Growth delay HP:0001510
Show evidence (1 reference)
PMID:36433683 SUPPORT Human Clinical
"The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death."
Lists growth failure among the defining features of MDLS.
Intrauterine growth restriction Intrauterine growth retardation HP:0001511
Show evidence (1 reference)
PMID:24055730 SUPPORT Human Clinical
"in a fetus with lissencephaly, corpus callosum dysgenesis, ventriculomegaly, microcephaly, intrauterine growth restriction (IUGR), polyhydramnios and single umbilical artery."
Documents IUGR as an associated prenatal finding.
Other 3
Lissencephaly Lissencephaly HP:0001339
Show evidence (1 reference)
PMID:36433683 SUPPORT Human Clinical
"The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death."
Identifies lissencephaly as a core defining feature of MDLS.
Infantile spasms Infantile spasms HP:0012469
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"Seizures occur in more than 90% of individuals with lissencephaly and often include infantile spasms."
GeneReviews lists infantile spasms among the common seizure types.
Profound intellectual disability Profound intellectual disability HP:0002187
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"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."
Supports a profound degree of developmental/intellectual impairment.
🧬

Genetic Associations

2
17p13.3 deletion including PAFAH1B1 and YWHAE (Causal contiguous-gene deletion)
Gene: PAFAH1B1 hgnc:8574
Show evidence (2 references)
PMID:36433683 SUPPORT Human Clinical
"Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion."
Supports the genotype-phenotype relationship in which deletion size and gene content determine severity.
PMID:24055730 SUPPORT Human Clinical
"We report a molecular cytogenetic characterization of 17p13.3 deletion syndrome by array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH) and quantitative polymerase chain reaction (qPCR)"
Documents the molecular cytogenetic confirmation of a 17p13.3 deletion causing the syndrome.
YWHAE haploinsufficiency (Severity modifier within the deletion)
Gene: YWHAE hgnc:12851
Show evidence (2 references)
PMID:12796778 SUPPORT Human Clinical
"we show that the gene encoding 14-3-3epsilon (YWHAE), one of a family of ubiquitous phosphoserine/threonine-binding proteins, is always deleted in individuals with MDS."
Establishes that YWHAE is consistently deleted in Miller-Dieker syndrome.
PMID:36433683 SUPPORT Human Clinical
"We conclude that deletion of 17p13.3 excluding PAFAH1B1 but including YWHAE is associated with a consistent phenotype and should be considered a distinct condition from MDS."
Clarifies that YWHAE-only deletions form a distinct, non-MDLS condition, delineating the genotype-phenotype boundary.
💊

Medical Actions

4
Antiseizure Pharmacotherapy
Action: Pharmacotherapy NCIT:C15986
Agent: valproic acid CHEBI:39867 lamotrigine CHEBI:6367
Management is centered on controlling seizures with antiseizure medications selected by seizure type; polytherapy with valproic acid and lamotrigine appears most effective in reducing drug-resistant seizures.
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"polytherapy with valproic acid and lamotrigine appears most effective in reducing drug-resistant seizures"
GeneReviews documents the antiseizure regimen used in PAFAH1B1-related lissencephaly.
Gastrostomy Tube Placement
Action: gastrostomy MAXO:0001346
Placement of a gastrostomy tube is used for individuals with failure to thrive, dysphagia, and/or recurrent aspiration pneumonia.
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"placement of a gastrostomy tube for those with failure to thrive, dysphagia, and/or recurrent aspiration pneumonia"
GeneReviews documents gastrostomy tube placement for feeding and aspiration management.
Supportive and Rehabilitative Care
Action: supportive care MAXO:0000950
Standard supportive treatment for developmental delay/intellectual disability, spasticity, visual impairment, and hearing loss, with surveillance for nutrition, aspiration, and respiratory insufficiency.
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"standard treatment for developmental delay/intellectual disability, spasticity, visual impairment, and hearing loss."
GeneReviews documents standard supportive treatment across the multisystem manifestations.
Genetic Counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling addresses recurrence risk, including the possibility of parental balanced rearrangement or germline mosaicism, and reproductive options such as prenatal testing.
Show evidence (1 reference)
PMID:20301752 SUPPORT Human Clinical
"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."
GeneReviews documents the genetic counseling and prenatal testing considerations.
{ }

Source YAML

click to show 
name: Miller-Dieker Lissencephaly Syndrome
creation_date: "2026-06-03T00:00:00Z"
synonyms:
- Miller-Dieker syndrome
- MDLS
- MDS
- Lissencephaly due to 17p13.3 deletion
- Monosomy 17p13.3
description: >-
  Miller-Dieker lissencephaly syndrome (MDLS) is a severe contiguous-gene
  deletion syndrome caused by a heterozygous deletion of the 17p13.3 critical
  region, which includes PAFAH1B1 (LIS1) and YWHAE (14-3-3 epsilon).
  Haploinsufficiency of PAFAH1B1 disrupts the LIS1/dynein/microtubule motor
  machinery required for neuronal migration during corticogenesis, producing
  classical (type I) lissencephaly with a thickened, poorly gyrated cortex.
  Co-deletion of YWHAE contributes to the greater severity that distinguishes
  MDLS from isolated lissencephaly sequence. Affected individuals have profound
  developmental disability, intractable epilepsy, microcephaly, hypotonia,
  characteristic craniofacial dysmorphism, growth failure, and high early
  mortality.
category: Mendelian
parents:
- chromosomal deletion syndrome
- classic lissencephaly
- neuronal migration disorder
disease_term:
  preferred_term: Miller-Dieker lissencephaly syndrome
  term:
    id: MONDO:0009532
    label: Miller-Dieker lissencephaly syndrome
references:
- reference: PMID:20301752
  title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
  tags:
  - GeneReviews
inheritance:
- name: De novo 17p13.3 deletion
  description: >-
    MDLS most commonly arises from a de novo 17p13.3 deletion; a minority of
    cases result from an unbalanced segregation of a parental balanced
    chromosomal rearrangement, which has implications for recurrence-risk
    counseling.
  evidence:
  - reference: PMID:24055730
    reference_title: "Chromosome 17p13.3 deletion syndrome: aCGH characterization, prenatal findings and diagnosis, and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The qPCR assays revealed a maternal origin of the deletion.
    explanation: >-
      This case illustrates that some 17p13.3 deletions derive from a parental
      rearrangement, supporting the need for parental cytogenetic studies in
      recurrence-risk assessment.
pathophysiology:
- name: 17p13.3 Contiguous-Gene Deletion
  description: >-
    The primary lesion in MDLS is a heterozygous deletion of the 17p13.3
    critical region, a contiguous-gene deletion that removes PAFAH1B1 (LIS1)
    and YWHAE (14-3-3 epsilon) along with neighboring dosage-sensitive genes.
    The size and gene content of the deletion determine phenotype severity,
    with larger deletions including YWHAE producing the classical Miller-Dieker
    phenotype.
  genes:
  - preferred_term: PAFAH1B1
    term:
      id: hgnc:8574
      label: PAFAH1B1
  - preferred_term: YWHAE
    term:
      id: hgnc:12851
      label: YWHAE
  evidence:
  - reference: PMID:40806509
    reference_title: "Understanding the Molecular Basis of Miller-Dieker Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Miller-Dieker Syndrome (MDS) is a rare neurodevelopmental disorder caused
      by a heterozygous deletion of approximately 26 genes within the MDS locus
      of human chromosome 17.
    explanation: >-
      Establishes the underlying lesion as a heterozygous contiguous-gene
      deletion within the 17p13.3 MDS locus.
  - reference: PMID:29628935
    reference_title: "Neurodevelopmental Genetic Diseases Associated With Microdeletions and Microduplications of Chromosome 17p13.3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosome microdeletions within 17p13.3 can result in either isolated
      lissencephaly sequence (ILS) or Miller-Dieker syndrome (MDS). ... patients
      with MDS have larger deletions than patients with ILS, resulting in
      additional symptoms such as poor muscle tone, congenital anomalies,
      abnormal spasticity, and craniofacial dysmorphisms.
    explanation: >-
      Identifies MDS as a 17p13.3 microdeletion disorder and frames it within
      the broader microdeletion spectrum whose severity depends on the deleted
      gene content, with the larger MDS deletions producing additional features
      beyond isolated lissencephaly.
  downstream:
  - target: LIS1 Haploinsufficiency and Dynein/Microtubule Motor Dysfunction
    causal_link_type: DIRECT
  - target: YWHAE Contribution to Severity
    causal_link_type: DIRECT
- name: LIS1 Haploinsufficiency and Dynein/Microtubule Motor Dysfunction
  conforms_to: "microtubule_dependent_neuronal_migration_failure#Microtubule-Based Neuronal Motility Failure"
  description: >-
    Loss of one PAFAH1B1 (LIS1) allele reduces LIS1 protein dosage. LIS1
    regulates the cytoplasmic dynein motor and microtubule dynamics that drive
    nucleokinesis (nuclear translocation) of migrating neurons. LIS1
    haploinsufficiency also reduces filamentous actin at the leading edge of
    migrating neurons through dysregulated Rho GTPase activity, impairing
    motility. Structural studies place type-1 lissencephaly mutations directly
    within the dynein-LIS1 interface.
  cell_types:
  - preferred_term: forebrain radial glial cell
    term:
      id: CL:0013000
      label: forebrain radial glial cell
  - preferred_term: migrating cortical glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  - preferred_term: microtubule-based movement (dynein motor)
    term:
      id: GO:0007018
      label: microtubule-based movement
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36433683
    reference_title: "Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Haploinsufficiency of PAFAH1B1 is responsible for the characteristic
      lissencephaly in MDS.
    explanation: >-
      Directly attributes the characteristic lissencephaly to PAFAH1B1 (LIS1)
      haploinsufficiency.
  - reference: PMID:14507966
    reference_title: "Disregulated RhoGTPases and actin cytoskeleton contribute to the migration defect in Lis1-deficient neurons."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Lis1 haploinsufficiency is shown here to also result in reduced
      filamentous actin at the leading edge of migrating neurons, associated
      with upregulation of RhoA and downregulation of Rac1 and Cdc42 activity.
    explanation: >-
      Mouse data link Lis1 haploinsufficiency to a cytoskeletal migration
      defect via dysregulated Rho GTPase signaling.
  downstream:
  - target: Impaired Neuronal Migration and Cortical Malformation
    causal_link_type: DIRECT
  - target: mTOR Pathway Hypoactivity
    causal_link_type: UNKNOWN
- name: YWHAE Contribution to Severity
  description: >-
    Co-deletion of YWHAE (encoding 14-3-3 epsilon) augments the neuronal
    migration defect. 14-3-3 epsilon binds CDK5/p35-phosphorylated NDEL1
    (NUDEL) and sustains its phosphorylation; its loss mislocalizes NDEL1 and
    LIS1, reducing cytoplasmic dynein function. Mice doubly deficient for Ywhae
    and Pafah1b1 have more severe migration defects than single heterozygotes,
    providing a molecular explanation for why YWHAE-including deletions cause
    the more severe Miller-Dieker phenotype.
  cell_types:
  - preferred_term: migrating cortical glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: DECREASED
  evidence:
  - reference: PMID:12796778
    reference_title: "14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice heterozygous with respect to both genes have more severe migration
      defects than single heterozygotes.
    explanation: >-
      Demonstrates that combined Ywhae and Pafah1b1 deficiency produces a more
      severe migration defect, explaining the greater severity of MDLS versus
      isolated lissencephaly.
  - reference: PMID:12796778
    reference_title: "14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Similar to LIS1, deficiency of 14-3-3epsilon results in mislocalization
      of NUDEL and LIS1, consistent with reduction of cytoplasmic dynein
      function.
    explanation: >-
      Provides the molecular mechanism by which 14-3-3 epsilon loss converges on
      reduced dynein function in the LIS1/NDEL1 pathway.
  downstream:
  - target: Impaired Neuronal Migration and Cortical Malformation
    causal_link_type: DIRECT
- name: Impaired Neuronal Migration and Cortical Malformation
  description: >-
    Disrupted nucleokinesis arrests migrating neurons before they reach their
    correct cortical layers during fetal corticogenesis. The result is a
    thickened, abnormally layered cortex with a smooth surface (agyria/
    pachygyria), the defining classical (type I) lissencephaly of MDLS.
  cell_types:
  - preferred_term: migrating cortical glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: cerebral cortex radially oriented cell migration
    term:
      id: GO:0021799
      label: cerebral cortex radially oriented cell migration
    modifier: DECREASED
  evidence:
  - reference: PMID:40806509
    reference_title: "Understanding the Molecular Basis of Miller-Dieker Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One hallmark feature of MDS is an unusually smooth brain surface due to
      abnormal neuronal migration during early brain development.
    explanation: >-
      Connects the abnormal neuronal migration to the hallmark smooth cortical
      surface (lissencephaly).
  - reference: PMID:28111201
    reference_title: "Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We saw a cell migration defect that was rescued when we corrected the MDS
      causative chromosomal deletion and severe apoptosis of the founder
      neuroepithelial stem cells, accompanied by increased horizontal cell
      divisions.
    explanation: >-
      Patient-derived MDS iPSC cerebral organoids reproduce the neuronal
      migration defect and demonstrate that correcting the causative 17p13.3
      deletion rescues it, alongside apoptosis of the founder neuroepithelial
      stem cells — human in vitro (organoid) mechanistic support for the
      migration/progenitor pathology.
  - reference: PMID:28380362
    reference_title: "An Organoid-Based Model of Cortical Development Identifies Non-Cell-Autonomous Defects in Wnt Signaling Contributing to Miller-Dieker Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient-derived organoids are significantly reduced in size, a change
      accompanied by a switch from symmetric to asymmetric cell division of
      ventricular zone radial glia cells (vRGCs).
    explanation: >-
      Patient-specific MDS forebrain-type organoids link the reduced size to a
      symmetric-to-asymmetric division-mode switch in ventricular-zone radial
      glia, an upstream progenitor mechanism feeding the migration/cortical
      malformation; reinstating β-catenin signaling rescues the division modes.
  downstream:
  - target: Lissencephaly
    causal_link_type: DIRECT
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Infantile spasms
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Profound intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Growth failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Facial dysmorphism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventriculomegaly
    causal_link_type: DIRECT
  - target: Abnormal corpus callosum morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intrauterine growth restriction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Visual impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Constipation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: mTOR Pathway Hypoactivity
  description: >-
    Cerebral organoids derived from individuals with the MDLS 17p13.3
    microdeletion recapitulate the thickened lissencephalic cortex and show
    dysregulation of protein translation, metabolism, and the mTOR pathway.
    mTOR hypoactivity acts as a convergent molecular mechanism that contributes
    to the lissencephalic cortical phenotype rather than arising as a downstream
    consequence of it: a brain-selective mTORC1 activator prevented and reversed
    the cellular and molecular defects in these organoids, identifying mTOR
    hypoactivity as a causal, potentially targetable mechanism. This is a
    research-stage mechanism.
  biological_processes:
  - preferred_term: TOR signaling
    term:
      id: GO:0031929
      label: TOR signaling
    modifier: DECREASED
  evidence:
  - reference: PMID:39743596
    reference_title: "Dysregulation of mTOR signalling is a converging mechanism in lissencephaly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PIDD1-mutant organoids and MDLS organoids recapitulated the thickened
      cortex typical of human lissencephaly and demonstrated dysregulation of
      protein translation, metabolism and the mTOR pathway.
    explanation: >-
      Patient-derived MDLS organoids show mTOR pathway dysregulation alongside
      the recapitulated lissencephalic cortex.
  - reference: PMID:39743596
    reference_title: "Dysregulation of mTOR signalling is a converging mechanism in lissencephaly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A brain-selective activator of mTOR complex 1 prevented and reversed
      cellular and molecular defects in the lissencephaly organoids.
    explanation: >-
      Supports mTOR hypoactivity as a causal, reversible contributor to the
      cellular phenotype in MDLS organoids.
  downstream:
  - target: Impaired Neuronal Migration and Cortical Malformation
    causal_link_type: UNKNOWN
phenotypes:
- name: Lissencephaly
  description: >-
    Classical (type I) lissencephaly with agyria/pachygyria and an abnormally
    thick, smooth cortex.
  phenotype_term:
    preferred_term: Lissencephaly
    term:
      id: HP:0001339
      label: Lissencephaly
  evidence:
  - reference: PMID:36433683
    reference_title: "Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most severe phenotype is Miller-Dieker syndrome (MDS) which is
      characterized by lissencephaly, dysmorphic facial features, growth
      failure, developmental disability, and often early death.
    explanation: >-
      Identifies lissencephaly as a core defining feature of MDLS.
- name: Seizures
  description: >-
    Epilepsy is highly frequent, often with onset in infancy and frequently
    including infantile spasms; seizures are often drug resistant.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures occur in more than 90% of individuals with lissencephaly and
      often include infantile spasms.
    explanation: >-
      GeneReviews documents seizures in >90% of individuals with lissencephaly,
      supporting a VERY_FREQUENT classification.
- name: Infantile spasms
  description: >-
    A characteristic early seizure type in PAFAH1B1-related lissencephaly.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures occur in more than 90% of individuals with lissencephaly and
      often include infantile spasms.
    explanation: >-
      GeneReviews lists infantile spasms among the common seizure types.
- name: Profound intellectual disability
  description: >-
    Even with good seizure control, the best developmental level achieved is
    typically equivalent to age three to five months.
  phenotype_term:
    preferred_term: Profound intellectual disability
    term:
      id: HP:0002187
      label: Profound intellectual disability
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Supports a profound degree of developmental/intellectual impairment.
- name: Microcephaly
  description: >-
    Progressive microcephaly is a documented feature of PAFAH1B1-related
    lissencephaly/SBH.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      GeneReviews documents progressive microcephaly as a feature.
- name: Hypotonia
  description: >-
    Affected newborns typically have mild-to-moderate hypotonia; axial
    hypotonia is common and may coexist with distal spasticity.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected newborns typically have mild-to-moderate hypotonia, feeding
      difficulties, and poor head control.
    explanation: >-
      GeneReviews documents neonatal hypotonia.
- name: Spasticity
  description: >-
    Mild distal spasticity early in life can transition over time to more
    severe spasticity.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild distal spasticity that can transition over time to more severe
      spasticity.
    explanation: >-
      GeneReviews documents progressive spasticity.
- name: Feeding difficulties
  description: >-
    Feeding difficulties and aspiration are common and may necessitate
    gastrostomy tube placement.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected newborns typically have mild-to-moderate hypotonia, feeding
      difficulties, and poor head control.
    explanation: >-
      GeneReviews documents feeding difficulties from the neonatal period.
- name: Growth failure
  description: >-
    Growth failure is a recognized feature of the severe Miller-Dieker
    phenotype.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:36433683
    reference_title: "Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most severe phenotype is Miller-Dieker syndrome (MDS) which is
      characterized by lissencephaly, dysmorphic facial features, growth
      failure, developmental disability, and often early death.
    explanation: >-
      Lists growth failure among the defining features of MDLS.
- name: Facial dysmorphism
  description: >-
    Characteristic craniofacial dysmorphism is a defining feature of
    Miller-Dieker syndrome, classically including a prominent forehead,
    midface hypoplasia, small upturned nose, and thick upper lip (per the
    MONDO definition, NCIT:C124852).
  phenotype_term:
    preferred_term: Dysmorphic facial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:36433683
    reference_title: "Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most severe phenotype is Miller-Dieker syndrome (MDS) which is
      characterized by lissencephaly, dysmorphic facial features, growth
      failure, developmental disability, and often early death.
    explanation: >-
      Lists dysmorphic facial features among the defining features of MDS
      specifically.
- name: Ventriculomegaly
  description: >-
    Cerebral ventriculomegaly is a frequently associated brain finding,
    often detectable prenatally.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:24055730
    reference_title: "Chromosome 17p13.3 deletion syndrome: aCGH characterization, prenatal findings and diagnosis, and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in a fetus with lissencephaly, corpus callosum dysgenesis,
      ventriculomegaly, microcephaly, intrauterine growth restriction (IUGR),
      polyhydramnios and single umbilical artery.
    explanation: >-
      Documents ventriculomegaly among the associated prenatal brain findings.
- name: Abnormal corpus callosum morphology
  description: >-
    Corpus callosum dysgenesis/agenesis can co-occur with the cortical
    malformation.
  phenotype_term:
    preferred_term: Corpus callosum dysgenesis
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:24055730
    reference_title: "Chromosome 17p13.3 deletion syndrome: aCGH characterization, prenatal findings and diagnosis, and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in a fetus with lissencephaly, corpus callosum dysgenesis,
      ventriculomegaly, microcephaly, intrauterine growth restriction (IUGR),
      polyhydramnios and single umbilical artery.
    explanation: >-
      Documents corpus callosum dysgenesis among the associated brain
      malformations.
- name: Intrauterine growth restriction
  description: >-
    Prenatal growth restriction is commonly associated with the 17p13.3
    deletion phenotype.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:24055730
    reference_title: "Chromosome 17p13.3 deletion syndrome: aCGH characterization, prenatal findings and diagnosis, and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in a fetus with lissencephaly, corpus callosum dysgenesis,
      ventriculomegaly, microcephaly, intrauterine growth restriction (IUGR),
      polyhydramnios and single umbilical artery.
    explanation: >-
      Documents IUGR as an associated prenatal finding.
- name: Visual impairment
  description: >-
    Affected individuals show poor visual tracking in the first years of life,
    and GeneReviews recommends standard treatment and annual ophthalmologic
    evaluation for visual impairment.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      standard treatment for developmental delay/intellectual disability,
      spasticity, visual impairment, and hearing loss.
    explanation: >-
      GeneReviews lists visual impairment among the manifestations requiring
      standard treatment, and recommends annual ophthalmologic evaluation.
- name: Hearing impairment
  description: >-
    Reduced response to sounds is noted on early neurologic examination, and
    GeneReviews recommends standard treatment and annual audiologic evaluation
    for hearing loss.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      standard treatment for developmental delay/intellectual disability,
      spasticity, visual impairment, and hearing loss.
    explanation: >-
      GeneReviews lists hearing loss among the manifestations requiring standard
      treatment, and recommends annual audiologic evaluation.
- name: Constipation
  description: >-
    Constipation is a recognized management concern, with GeneReviews
    recommending stool softeners, prokinetics, osmotic agents, or laxatives and
    surveillance for signs and symptoms of constipation.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment with stool softeners, prokinetics, osmotic agents, or laxatives
      for constipation;
    explanation: >-
      GeneReviews documents constipation as a recognized management concern
      requiring pharmacologic treatment and surveillance.
genetic:
- name: 17p13.3 deletion including PAFAH1B1 and YWHAE
  association: Causal contiguous-gene deletion
  gene_term:
    preferred_term: PAFAH1B1
    term:
      id: hgnc:8574
      label: PAFAH1B1
  notes: >-
    The classical Miller-Dieker phenotype results from a 17p13.3 deletion that
    removes both PAFAH1B1 (LIS1) and YWHAE. PAFAH1B1 haploinsufficiency drives
    the lissencephaly, while co-deletion of YWHAE increases severity. Smaller
    deletions or intragenic PAFAH1B1 variants sparing YWHAE produce the milder
    isolated lissencephaly sequence.
  evidence:
  - reference: PMID:36433683
    reference_title: "Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deletion of 17p13.3 has varying degrees of severity on brain development
      based on precise location and size of the deletion.
    explanation: >-
      Supports the genotype-phenotype relationship in which deletion size and
      gene content determine severity.
  - reference: PMID:24055730
    reference_title: "Chromosome 17p13.3 deletion syndrome: aCGH characterization, prenatal findings and diagnosis, and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a molecular cytogenetic characterization of 17p13.3 deletion
      syndrome by array comparative genomic hybridization (aCGH), fluorescence
      in situ hybridization (FISH) and quantitative polymerase chain reaction
      (qPCR)
    explanation: >-
      Documents the molecular cytogenetic confirmation of a 17p13.3 deletion
      causing the syndrome.
- name: YWHAE haploinsufficiency
  association: Severity modifier within the deletion
  gene_term:
    preferred_term: YWHAE
    term:
      id: hgnc:12851
      label: YWHAE
  notes: >-
    YWHAE encodes 14-3-3 epsilon. Its deletion is consistently present in
    Miller-Dieker syndrome and increases the severity of the migration defect
    relative to PAFAH1B1 loss alone. Deletions involving YWHAE but sparing
    PAFAH1B1 produce a distinct, milder condition rather than classical MDLS.
  evidence:
  - reference: PMID:12796778
    reference_title: "14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we show that the gene encoding 14-3-3epsilon (YWHAE), one of a family of
      ubiquitous phosphoserine/threonine-binding proteins, is always deleted in
      individuals with MDS.
    explanation: >-
      Establishes that YWHAE is consistently deleted in Miller-Dieker syndrome.
  - reference: PMID:36433683
    reference_title: "Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that deletion of 17p13.3 excluding PAFAH1B1 but including
      YWHAE is associated with a consistent phenotype and should be considered
      a distinct condition from MDS.
    explanation: >-
      Clarifies that YWHAE-only deletions form a distinct, non-MDLS condition,
      delineating the genotype-phenotype boundary.
prevalence:
- notes: >-
    MDS is a rare disorder, with a reported prevalence of approximately 1 in
    100,000 births.
  evidence:
  - reference: PMID:40806509
    reference_title: "Understanding the Molecular Basis of Miller-Dieker Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MDS, which affects 1 in 100,000 babies, can lead to a range of
      phenotypes, including lissencephaly, severe neurological defects,
      distinctive facial abnormalities, cognitive impairments, seizures, growth
      retardation, and congenital heart and liver abnormalities.
    explanation: >-
      Provides a prevalence estimate of approximately 1 in 100,000 births.
progression:
- phase: Prenatal and neonatal presentation
  age_range: Fetal life through neonatal period
  notes: >-
    Lissencephaly and associated brain malformations may be detected
    prenatally; newborns present with hypotonia, feeding difficulties, and poor
    head control.
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected newborns typically have mild-to-moderate hypotonia, feeding
      difficulties, and poor head control.
    explanation: >-
      Describes the neonatal presentation.
- phase: Infancy and childhood with intractable epilepsy and high mortality
  age_range: Infancy through childhood
  notes: >-
    Severe drug-resistant epilepsy, profound developmental disability, and
    recurrent aspiration drive morbidity; most affected children die early,
    often from aspiration pneumonia.
  evidence:
  - reference: PMID:39508990
    reference_title: "Multi-Omics Approach Reveals Genes and Pathways Affected in Miller-Dieker Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MDS patients often die in utero and only 10% of those who are born reach
      10 years of age.
    explanation: >-
      Documents the high early mortality characteristic of MDS.
treatments:
- name: Antiseizure Pharmacotherapy
  description: >-
    Management is centered on controlling seizures with antiseizure medications
    selected by seizure type; polytherapy with valproic acid and lamotrigine
    appears most effective in reducing drug-resistant seizures.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
    - preferred_term: lamotrigine
      term:
        id: CHEBI:6367
        label: lamotrigine
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      polytherapy with valproic acid and lamotrigine appears most effective in
      reducing drug-resistant seizures
    explanation: >-
      GeneReviews documents the antiseizure regimen used in PAFAH1B1-related
      lissencephaly.
- name: Gastrostomy Tube Placement
  description: >-
    Placement of a gastrostomy tube is used for individuals with failure to
    thrive, dysphagia, and/or recurrent aspiration pneumonia.
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: MAXO:0001346
      label: gastrostomy
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      placement of a gastrostomy tube for those with failure to thrive,
      dysphagia, and/or recurrent aspiration pneumonia
    explanation: >-
      GeneReviews documents gastrostomy tube placement for feeding and
      aspiration management.
- name: Supportive and Rehabilitative Care
  description: >-
    Standard supportive treatment for developmental delay/intellectual
    disability, spasticity, visual impairment, and hearing loss, with
    surveillance for nutrition, aspiration, and respiratory insufficiency.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      standard treatment for developmental delay/intellectual disability,
      spasticity, visual impairment, and hearing loss.
    explanation: >-
      GeneReviews documents standard supportive treatment across the
      multisystem manifestations.
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses recurrence risk, including the possibility of
    parental balanced rearrangement or germline mosaicism, and reproductive
    options such as prenatal testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301752
    reference_title: "PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      GeneReviews documents the genetic counseling and prenatal testing
      considerations.
notes: >-
  Emerging research-stage mechanisms include convergent mTOR pathway
  hypoactivity (rescued by an mTORC1 activator in patient-derived organoids)
  and a role for METTL16 in restoring protein translation and cell migration in
  MDS patient cells. These are preclinical findings and not established
  clinical care.
discussions:
- discussion_id: gap_mds_outer_radial_glia_human_model_mismatch
  prompt: >-
    Does the prevailing mouse-model-derived view of MDS/classical lissencephaly
    as primarily a post-mitotic neuronal migration defect adequately capture the
    human pathomechanism, given that patient-derived iPSC cerebral organoids
    additionally reveal a mitotic defect in outer radial glia (oRG/bRG) — a
    progenitor subtype largely absent from the lissencephalic rodent cortex but
    critical for human neocortical expansion?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Neuronal Migration and Cortical Malformation
  - pathophysiology#LIS1 Haploinsufficiency and Dynein/Microtubule Motor Dysfunction
  rationale: >-
    The dominant lissencephaly model — defective LIS1-dependent
    nucleokinesis/neuronal migration — derives largely from Pafah1b1 mutant mice
    and limited postmortem analysis. Because the mouse cortex is naturally
    lissencephalic and has few outer radial glia, it cannot test whether
    human-specific oRG progenitor biology contributes to MDS severity. Bershteyn
    et al. (PMID:28111201) found a prolonged-mitosis defect in oRG in MDS
    patient iPSC cerebral organoids, a progenitor subtype the authors note is
    "largely absent from lissencephalic rodents but critical for human
    neocortical expansion," and Iefremova et al. (PMID:28380362) found a
    non-cell-autonomous radial-glia division-mode switch. If oRG dysfunction is
    a genuine, human-enriched arm of MDS pathology, rodent models will
    systematically miss a progenitor-tier mechanism, which bears on how the
    migration vs. progenitor contributions to classical lissencephaly are
    weighted and modeled.
  proposed_experiments:
  - experiment_id: exp_mds_oRG_organoid_lineage
    name: MDS iPSC organoid outer-radial-glia mitosis and lineage analysis
    description: >-
      Use isogenic MDS (17p13.3 deletion) versus deletion-corrected human iPSC
      cerebral organoids with time-lapse imaging and single-cell RNA sequencing
      to quantify outer radial glia mitotic duration, division mode, and
      neuronal output relative to apical progenitors, testing whether oRG are
      disproportionately affected and whether their dysfunction is a distinct
      arm of pathology separable from post-mitotic migration failure.
    experiment_type:
      preferred_term: iPSC organoid perturbation assay
    model_systems:
    - name: Human iPSC-derived cerebral organoid
      description: >-
        Cerebral organoid differentiated from MDS-patient or gene-edited human
        iPSCs, preserving human-specific outer radial glia biology absent from
        rodent models.
      experimental_model_type: ORGANOID
📚

References & Deep Research

References

1
PMID:20301752
PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Miller–Dieker Lissencephaly Syndrome (MDLS): Disease Characteristics Research Report
Edison Scientific Literature 22 citations 2026-06-03T16:50:06.265551

Miller–Dieker Lissencephaly Syndrome (MDLS): Disease Characteristics Research Report

1. Disease information

Overview / definition (current understanding)

Miller–Dieker lissencephaly syndrome (MDLS), also called Miller–Dieker syndrome (MDS), is a severe neuronal migration disorder caused by a chromosome 17p13.3 deletion involving multiple genes in the “Miller–Dieker critical region,” leading to classical (type I) lissencephaly (smooth cerebral surface) with profound neurodevelopmental impairment, seizures, characteristic craniofacial features, growth failure, and high early mortality. (baker2023furtherexpansionand pages 1-2, blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2, chen2013chromosome17p13.3deletion pages 1-2)

Key identifiers (from retrieved primary/review literature)

  • OMIM: 247200 (mahendran2025understandingthemolecular pages 1-2)
  • Chromosomal locus: 17p13.3 deletion (chen2013chromosome17p13.3deletion pages 1-2, mahendran2025understandingthemolecular pages 1-2)
  • MONDO / Orphanet / ICD-10/ICD-11 / MeSH: not explicitly retrievable from the gathered full texts in this run; requires dedicated ontology lookup beyond the current evidence set.

Synonyms / alternative names

  • Miller–Dieker syndrome (MDS) (mahendran2025understandingthemolecular pages 1-2)
  • Miller–Dieker lissencephaly syndrome (MDLS) (chen2013chromosome17p13.3deletion pages 1-2)
  • 17p13.3 deletion syndrome (used in some clinical genetics literature; nomenclature overlaps with adjacent 17p13.3 CNV syndromes) (liang2022clinicalfindingsand pages 1-2)

Evidence source type

The retrieved information is primarily from aggregated disease-level resources (peer-reviewed reviews and cohort descriptions) and case-based clinical genetics literature using cytogenetics/microarray testing and imaging (blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2, chen2013chromosome17p13.3deletion pages 1-2, liang2022clinicalfindingsand pages 1-2).

Disease name Key synonyms / alternative names OMIM ID Chromosomal region / core lesion Key genes implicated Prevalence estimates reported Key supporting source(s) / URL
Miller–Dieker lissencephaly syndrome Miller–Dieker syndrome; MDS; Miller–Dieker lissencephaly syndrome (MDLS); 17p13.3 deletion syndrome 247200 17p13.3 microdeletion / deletion syndrome; described as a heterozygous deletion in the MDS locus on chromosome 17 (chen2013chromosome17p13.3deletion pages 1-2, mahendran2025understandingthemolecular pages 1-2, liang2022clinicalfindingsand pages 1-2) PAFAH1B1 (LIS1), YWHAE; also commonly cited in the MDS region: CRK, METTL16 (mahendran2025understandingthemolecular pages 1-2, blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2) ~1 in 100,000 births/babies (mahendran2025understandingthemolecular pages 1-2); one 2022 single-center review reported ~1 in 13,000–20,000 newborns (liang2022clinicalfindingsand pages 1-2) IJMS review (2025): https://doi.org/10.3390/ijms26157375 ; BMC Med Genomics (2022): https://doi.org/10.1186/s12920-022-01423-5
Miller–Dieker syndrome (canonical severe 17p13.3 deletion phenotype) Severe form of lissencephaly / grade 1 lissencephaly; classical/type I lissencephaly in context of 17p13.3 deletion literature 247200 Larger 17p13.3 deletions including the Miller–Dieker critical region from PAFAH1B1 to YWHAE; cytogenetically visible deletions or submicroscopic microdeletions reported (blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2, chen2013chromosome17p13.3deletion pages 1-2) PAFAH1B1 (LIS1) haploinsufficiency is responsible for the characteristic lissencephaly; deletion including YWHAE is associated with the more severe Miller–Dieker phenotype (baker2023furtherexpansionand pages 1-2, blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2, chen2013chromosome17p13.3deletion pages 1-2) Rare; prevalence estimates above apply to MDS/MDLS nomenclature in retrieved evidence (mahendran2025understandingthemolecular pages 1-2, liang2022clinicalfindingsand pages 1-2) Gene (2013): https://doi.org/10.1016/j.gene.2013.09.044 ; Front Genet (2018): https://doi.org/10.3389/fgene.2018.00080 ; AJMG A (2023): https://doi.org/10.1002/ajmg.a.63057

Table: This table summarizes the core nomenclature and identifiers for Miller–Dieker lissencephaly syndrome, including accepted synonyms, OMIM ID, core 17p13.3 deletion region, major genes, and prevalence estimates reported in the gathered evidence. It is useful as a concise disease-knowledge-base normalization reference.

2. Etiology

Disease causal factors

Primary cause (genetic): contiguous gene deletion at 17p13.3. - A 2013 prenatal diagnostic report describes MDLS (OMIM 247200) as caused by deletions/microdeletions at 17p13.3 with haploinsufficiency of PAFAH1B1 (LIS1), and documents a representative deletion (“arr [hg19] 17p13.3 (0–3,165,530)×1”) with confirmatory FISH and karyotype. (chen2013chromosome17p13.3deletion pages 1-2) - A 2018 review describes MDLS/MDS as resulting from larger 17p13.3 microdeletions compared with isolated lissencephaly, with the MDS critical region spanning PAFAH1B1 to YWHAE. (blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2)

Key causal gene(s): - PAFAH1B1 (LIS1) haploinsufficiency is emphasized as responsible for the characteristic lissencephaly in MDS. (baker2023furtherexpansionand pages 1-2, chen2013chromosome17p13.3deletion pages 1-2) - Deletion of YWHAE (14-3-3ε) is frequently co-involved in the classical MDLS region, and literature distinguishes phenotypes when YWHAE is deleted without PAFAH1B1 (distinct condition). (baker2023furtherexpansionand pages 1-2, blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2)

Risk factors

For MDLS specifically, the dominant “risk factor” is a pathogenic de novo or inherited structural variant affecting 17p13.3. The gathered evidence set does not provide robust population-level risk-factor quantification (e.g., parental age effect) beyond the genetic mechanism.

Protective factors / gene–environment interactions

No protective variants or gene–environment interactions were identified in the retrieved evidence set; this is expected for a primarily contiguous gene deletion syndrome.

3. Phenotypes

Core phenotype spectrum (human clinical)

A 2023 cohort/literature synthesis states that the most severe 17p13.3 deletion phenotype is MDS, “characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death.” (baker2023furtherexpansionand pages 1-2)

A 2025 multi-omics paper summarizes commonly reported MDS features including lissencephaly/agyria, microcephaly and craniofacial anomalies, ventriculomegaly, hypotonia, epilepsy/seizures, and congenital anomalies; it also notes aspiration pneumonia as a leading cause of death and highlights that severity of lissencephaly correlates with life expectancy. (mahendran2025multiomicsapproachreveals pages 1-3)

Phenotype types and suggested HPO terms (examples): - Lissencephaly / agyria-pachygyria spectrum (clinical sign; congenital) → HP:0001339 (Lissencephaly) - Epilepsy / seizures (symptom/sign; infantile onset common) → HP:0001250 (Seizures), HP:0001251 (Ataxia) if present - Global developmental delay / severe intellectual disability → HP:0001263 (Global developmental delay), HP:0001249 (Intellectual disability) - Hypotonia → HP:0001252 - Microcephaly → HP:0000252 - Growth failure / growth retardation → HP:0001508 - Craniofacial dysmorphism (e.g., prominent forehead, broad nasal root, epicanthal folds noted across 17p13.3 CNV spectrum) → HP:0011220 (Prominent forehead), HP:0000286 (Epicanthus), HP:0000431 (Broad nasal bridge)

Frequency / statistics: robust phenotype frequency percentages for MDLS were not available in the gathered full texts; one table retrieved (below) summarizes frequencies for a related but distinct 17p13.3 deletion subtype (YWHAE deleted while PAFAH1B1 spared), included here to clarify genotype–phenotype boundaries. (baker2023furtherexpansionand media c19cbb92, baker2023furtherexpansionand media 4e57cd55)

Quality of life impact

Given severe neurodevelopmental impairment, epilepsy, feeding/respiratory complications, and hypotonia, MDLS has profound impacts on daily functioning. Direct validated QoL instrument results (e.g., EQ-5D, PedsQL) were not found in the retrieved evidence.

Genotype–phenotype boundary within the 17p13.3 region

A 2023 study explicitly distinguishes deletions including YWHAE but not PAFAH1B1 as “a distinct condition from MDS,” associated with developmental delay, dysmorphism, leukoencephalopathy, and high frequency of epilepsy and intellectual disability, but not the classical PAFAH1B1-driven lissencephaly. (baker2023furtherexpansionand pages 1-2, baker2023furtherexpansionand media c19cbb92, baker2023furtherexpansionand media 4e57cd55)

4. Genetic / molecular information

Causal genes and chromosomal abnormalities

Primary lesion: heterozygous 17p13.3 microdeletion spanning the MDLS critical region (blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2, chen2013chromosome17p13.3deletion pages 1-2).

Key genes in the MDLS/MDS region emphasized in recent reviews: - PAFAH1B1 (LIS1) (neuronal migration / dynein regulation) (baker2023furtherexpansionand pages 1-2, chen2013chromosome17p13.3deletion pages 1-2) - YWHAE (14-3-3ε; neuronal migration; NDEL1/LIS1 pathway context) (blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2) - CRK (often included in region; discussed in CNV spectrum reviews) (blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2) - Additional genes in the broader deleted region have been proposed to contribute to non-core features; recent reviews also highlight METTL16 in locus-focused mechanistic work. (mahendran2025multiomicsapproachreveals pages 1-3, mahendran2025understandingthemolecular pages 1-2)

Variant classes

  • Copy-number loss / deletion (structural variant): canonical MDLS. (blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2, chen2013chromosome17p13.3deletion pages 1-2)
  • MDLS may also arise via complex chromosomal rearrangements; the gathered evidence includes examples of cytogenetically visible deletions (karyotype del(17)(p13.3)) plus submicroscopic microdeletions resolved by aCGH/CMA and confirmed by FISH. (chen2013chromosome17p13.3deletion pages 1-2)

Inheritance

The retrieved evidence set does not provide a consolidated, quantified inheritance breakdown (e.g., % de novo vs inherited translocation) for MDLS. However, the diagnostic literature emphasizes evaluating for cryptic/unbalanced rearrangements using FISH/karyotype when arrays detect deletions. (chen2013chromosome17p13.3deletion pages 1-2)

Allele frequency / population databases

Not applicable for most MDLS cases because pathogenic events are typically large, rare, highly penetrant deletions not represented at meaningful frequency in population databases; no gnomAD-style allele frequencies were found in the retrieved texts.

5. Environmental information

MDLS is primarily genetic; no specific toxins, lifestyle factors, or infectious triggers were identified in the retrieved evidence.

6. Mechanism / pathophysiology

Canonical mechanism (causal chain)

17p13.3 deletion → haploinsufficiency of PAFAH1B1 (LIS1) ± YWHAE and other genes → disrupted neuronal migration during fetal corticogenesis → thickened, poorly gyrated cortex (type I lissencephaly) → severe developmental delay/intellectual disability, hypotonia, epilepsy, feeding/respiratory complications and high mortality. This causal framing is consistent across 17p13.3 CNV reviews and molecular diagnostic reports. (baker2023furtherexpansionand pages 1-2, blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2, chen2013chromosome17p13.3deletion pages 1-2)

Recent mechanistic developments (prioritize 2023–2024)

Dynein–dynactin–LIS1 molecular assembly (structural biology, 2024): A 2024 Science paper resolved cryo-EM structures of dynein–dynactin on microtubules with LIS1 and proposes that “LIS1 and p150 constrain dynein-dynactin to ensure efficient complex formation,” clarifying how LIS1 orchestrates assembly of active dynein complexes. This is directly relevant because LIS1 is the key dosage-sensitive gene in MDLS. URL: https://doi.org/10.1126/science.adk8544 (Mar 2024). (Note: full text evidence for this paper was retrieved in this run, but mechanistic claims should be interpreted as foundational cell biology rather than MDLS-patient specific.)

Human dynein–LIS1 complex structures (2023): A 2023 eLife study reports “cryo-EM structures of human dynein-LIS1 complexes” and states that these structures “map type-1 lissencephaly disease mutations… in the context of the dynein-LIS1 complex,” supporting structural interpretation of disease mutations in the LIS1–dynein axis. URL: https://doi.org/10.7554/eLife.84302 (Jan 2023). (mahendran2025understandingthemolecular pages 1-2)

Translational / systems-level mechanisms (organoids, multi-omics; 2024–2025 literature with 2024 DOI)

Convergent mTOR hypoactivity in lissencephaly including MDLS (organoids): A Nature article (published Jan 2025; DOI indicates 2024) reports that cerebral organoids derived from individuals with “a heterozygous chromosome 17p13.3 microdeletion leading to Miller–Dieker lissencephaly syndrome (MDLS)” show “dysregulation of protein translation, metabolism and the mTOR pathway,” and that “a brain-selective activator of mTOR complex 1 prevented and reversed cellular and molecular defects” in organoids. URL: https://doi.org/10.1038/s41586-024-08341-9. (mahendran2025multiomicsapproachreveals pages 1-3)

Multi-omics in MDS patient-derived cells (2025): RNA-seq and proteomics comparing control vs MDS patient cells found differential expression in genes linked to neuronal phenotypes and validated “enhanced calcium signaling, downregulated protein translation, and cell migration defects in MDS.” The authors report that METTL16 overexpression “restored defects in protein translation… and cell migration,” and note that intracellular SAM/SAH ratio was “eightfold lower in MDS cells,” connecting the deletion locus to translation/mTOR and methyl-donor biology. URL: https://doi.org/10.1007/s12035-024-04532-7 (Nov 2025). (mahendran2025multiomicsapproachreveals pages 1-3)

Suggested ontology terms for mechanisms

  • GO biological process: neuronal migration (GO:0001764); microtubule-based movement (GO:0007018); regulation of protein translation (GO:0006417); mTOR signaling (GO:0031929)
  • CL cell types (examples): cortical glutamatergic neuron (CL:0000540); radial glial cell / neural progenitor (CL:0000741)

7. Anatomical structures affected

Organ/system level

  • Central nervous system (primary): cerebral cortex malformation (lissencephaly), often with ventriculomegaly; prenatal imaging correlations are emphasized in MDLS diagnostic literature. (chen2013chromosome17p13.3deletion pages 1-2)

Tissue/cell level

  • Developing cerebral cortical plate / migrating neurons are implicated by the neuronal migration etiology and LIS1/dynein mechanism. (blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2)

Suggested anatomical ontology terms

  • UBERON: cerebral cortex (UBERON:0000956); telencephalon (UBERON:0001893)

8. Temporal development

Onset

Congenital/neurodevelopmental: neuronal migration defects occur during fetal development; lissencephaly is detectable by prenatal imaging in some cases and is present at birth. (chen2013chromosome17p13.3deletion pages 1-2)

Progression

A major component of morbidity is early-life severe epilepsy, feeding and respiratory complications, and profound developmental disability; longitudinal staging systems were not identified in the retrieved evidence.

9. Inheritance and population

Epidemiology (reported prevalence)

Prevalence estimates in the retrieved sources are inconsistent, likely reflecting differing definitions (MDS/MDLS strict vs broader 17p13.3 deletion categories) and ascertainment. - A 2025 review reports “MDS, which affects 1 in 100,000 babies.” (mahendran2025understandingthemolecular pages 1-2) - A 2022 single-center CNV series describes MDS as having a population frequency of “approximately one in 13,000–20,000 newborns.” (liang2022clinicalfindingsand pages 1-2)

Inheritance pattern

MDLS is caused by a heterozygous 17p13.3 deletion. The retrieved evidence did not provide a definitive quantitative statement for inheritance (e.g., % de novo). Diagnostic recommendations to perform karyotyping/FISH in addition to microarray imply that inherited balanced rearrangements can be relevant in some families. (chen2013chromosome17p13.3deletion pages 1-2)

10. Diagnostics

Clinical tests

  • Neuroimaging: Prenatal ultrasound and fetal MRI may suggest lissencephaly and associated brain findings, prompting targeted genetic testing for 17p13.3 deletions. (chen2013chromosome17p13.3deletion pages 1-2, liang2022clinicalfindingsand pages 1-2)

Genetic testing (current practice evidenced in retrieved literature)

A 2013 report describes a molecular cytogenetic workflow for 17p13.3 deletion syndrome using multiple complementary assays: - Abstract quote: “We report a molecular cytogenetic characterization of 17p13.3 deletion syndrome by array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH) and quantitative polymerase chain reaction (qPCR).” (chen2013chromosome17p13.3deletion pages 1-2) - Example result reporting: “aCGH analysis revealed a 3.17-Mb deletion at 17p13.3, or arr [hg19] 17p13.3 (0–3,165,530)×1,” and karyotype “46,XX,del(17)(p13.3)” with FISH loss of LIS1 probe. (chen2013chromosome17p13.3deletion pages 1-2)

A 2022 CNV cohort supports routine genome-wide CNV detection using SNP array (chromosomal microarray–class testing) plus karyotyping and parental studies in prenatal and postnatal contexts. (liang2022clinicalfindingsand pages 1-2)

Differential diagnosis

Not systematically retrievable from the current evidence set. In practice, differential diagnosis includes other malformations of cortical development and other genetic causes of classical lissencephaly, but robust differential tables/guidelines were not in the retrieved texts.

11. Outcome / prognosis

Survival and mortality statistics

A 2025 multi-omics paper summarizes a striking survival statistic (likely compiled from prior clinical literature): - Abstract quote: “MDS patients often die in utero and only 10% of those who are born reach 10 years of age.” (mahendran2025multiomicsapproachreveals pages 1-3) The same source notes that aspiration pneumonia is a leading cause of death and that life expectancy correlates with lissencephaly severity. (mahendran2025multiomicsapproachreveals pages 1-3)

Morbidity and complications

Common severe morbidity includes refractory epilepsy, hypotonia, profound developmental disability, and recurrent aspiration/pneumonia. (mahendran2025multiomicsapproachreveals pages 1-3)

12. Treatment

Current applications / real-world implementations

There is no established cure in the retrieved evidence; management is supportive and complication-focused. - A 2025 review states: “Currently, there is no cure for MDS, with management primarily focused on controlling seizures,” and recommends early genetic testing (“chromosomal microarray or DNA sequencing”) for suspected abnormalities in/near 17p13.3. (mahendran2025understandingthemolecular pages 15-17) - A 2025 multi-omics paper similarly states current treatments “mostly prevent complications and control seizures.” (mahendran2025multiomicsapproachreveals pages 1-3)

Supportive care domains (examples; evidence-supported at high level): - Antiseizure medications and epilepsy management (mahendran2025multiomicsapproachreveals pages 1-3) - Management of feeding/aspiration risk and recurrent respiratory infections (mahendran2025multiomicsapproachreveals pages 1-3)

Experimental / emerging therapeutic directions (research-stage)

  • Organoid-based work suggests mTOR pathway modulation could reverse cellular/molecular defects in lissencephaly organoids including MDLS. This is preclinical and not established clinical care. (mahendran2025multiomicsapproachreveals pages 1-3)
  • Locus-focused multi-omics suggests METTL16 restoration can rescue defects in patient-derived cells (in vitro), linking methyl-donor homeostasis and mTOR regulators to the phenotype. (mahendran2025multiomicsapproachreveals pages 1-3)

Suggested MAXO terms (examples)

  • Antiseizure therapy → MAXO:0000748 (antiepileptic therapy) (exact MAXO ID may require ontology validation)
  • Genetic counseling → MAXO:0000079
  • Supportive/palliative care → MAXO:0001298

13. Prevention

Primary prevention is not applicable in the usual sense for a genetic deletion syndrome; prevention focuses on reproductive options.

Secondary prevention / early detection

  • Prenatal identification of fetal brain findings (ultrasound/MRI) can prompt genetic testing for 17p13.3 deletions. (chen2013chromosome17p13.3deletion pages 1-2, liang2022clinicalfindingsand pages 1-2)

Genetic counseling / reproductive prevention

The diagnostic literature supports confirming CNVs and determining mechanism (e.g., deletion vs unbalanced rearrangement) using FISH/karyotype and parental studies, which is directly relevant for recurrence-risk counseling. (chen2013chromosome17p13.3deletion pages 1-2)

14. Other species / natural disease

The gathered evidence does not provide direct documentation of naturally occurring MDLS analogs in non-human species.

15. Model organisms

A 2018 review emphasizes the utility of mouse knockout models for genes in the 17p13.3 region (including single/double knockouts) due to conservation of the region and the need to study cortical development mechanistically; it also notes the usefulness of CRISPR/Cas9 and next-generation sequencing in studying these disorders. (blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2)

Expert opinion / analysis (from authoritative sources in retrieved set)

  • 17p13.3 deletion severity depends on deletion size and gene content; the distinction between MDS (PAFAH1B1-driven lissencephaly) versus other 17p13.3 CNV phenotypes (e.g., YWHAE-only deletions with leukoencephalopathy) is emphasized in contemporary clinical genetics synthesis. (baker2023furtherexpansionand pages 1-2, baker2023furtherexpansionand media c19cbb92)
  • Mechanistic convergence on translation/mTOR and dynein regulation is emerging from organoids, structural biology, and multi-omics. This supports a view that MDLS pathogenesis is not only “neuronal migration failure” but also involves broader dysregulation of protein translation and metabolic pathways (research-stage). (mahendran2025multiomicsapproachreveals pages 1-3)

Key abstract quotes (verbatim) supporting major claims

  • “Miller–Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death. Haploinsufficiency of PAFAH1B1 is responsible for the characteristic lissencephaly in MDS.” (AJMG A, Nov 2023; https://doi.org/10.1002/ajmg.a.63057) (baker2023furtherexpansionand pages 1-2)
  • “We report a molecular cytogenetic characterization of 17p13.3 deletion syndrome by array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH) and quantitative polymerase chain reaction (qPCR).” (Gene, Dec 2013; https://doi.org/10.1016/j.gene.2013.09.044) (chen2013chromosome17p13.3deletion pages 1-2)
  • “MDS patients often die in utero and only 10% of those who are born reach 10 years of age. Current treatments mostly prevent complications and control seizures.” (Molecular Neurobiology, Nov 2025; https://doi.org/10.1007/s12035-024-04532-7) (mahendran2025multiomicsapproachreveals pages 1-3)

Notes on evidence gaps

Within the retrieved full texts, explicit identifiers for MONDO, Orphanet, ICD-10/ICD-11, and MeSH were not found, and phenotype-frequency statistics specific to MDLS (beyond survival statements) were limited. A follow-up retrieval focused on GeneReviews/OMIM/Orphanet ontology pages and large clinical cohorts would be required to fully populate those fields with primary citations.

References

  1. (baker2023furtherexpansionand pages 1-2): Elizabeth K. Baker, Casey J. Brewer, Leonardo Ferreira, Mark Schapiro, Jeffrey Tenney, Heather M. Wied, Beth M. Kline‐Fath, Teresa A. Smolarek, K. Nicole Weaver, and Robert J. Hopkin. Further expansion and confirmation of phenotype in rare loss of ywhae gene distinct from miller–dieker syndrome. Nov 2023. URL: https://doi.org/10.1002/ajmg.a.63057, doi:10.1002/ajmg.a.63057. This article has 14 citations.

  2. (blazejewski2018neurodevelopmentalgeneticdiseases pages 1-2): Sara M. Blazejewski, Sarah A. Bennison, Trevor H. Smith, and Kazuhito Toyo-oka. Neurodevelopmental genetic diseases associated with microdeletions and microduplications of chromosome 17p13.3. Frontiers in Genetics, Mar 2018. URL: https://doi.org/10.3389/fgene.2018.00080, doi:10.3389/fgene.2018.00080. This article has 94 citations and is from a peer-reviewed journal.

  3. (chen2013chromosome17p13.3deletion pages 1-2): Chih-Ping Chen, Tung-Yao Chang, Wan-Yuo Guo, Pei-Chen Wu, Liang-Kai Wang, Schu-Rern Chern, Peih-Shan Wu, Jun-Wei Su, Yu-Ting Chen, Li-Feng Chen, and Wayseen Wang. Chromosome 17p13.3 deletion syndrome: acgh characterization, prenatal findings and diagnosis, and literature review. Gene, 532(1):152-159, Dec 2013. URL: https://doi.org/10.1016/j.gene.2013.09.044, doi:10.1016/j.gene.2013.09.044. This article has 40 citations and is from a peer-reviewed journal.

  4. (mahendran2025understandingthemolecular pages 1-2): Gowthami Mahendran and Jessica A. Brown. Understanding the molecular basis of miller–dieker syndrome. International Journal of Molecular Sciences, 26:7375, Jul 2025. URL: https://doi.org/10.3390/ijms26157375, doi:10.3390/ijms26157375. This article has 1 citations.

  5. (liang2022clinicalfindingsand pages 1-2): Bin Liang, Donghong Yu, Wantong Zhao, Yan Wang, Xiaoqing Wu, Lingji Chen, Na Lin, Hailong Huang, and Liangpu Xu. Clinical findings and genetic analysis of patients with copy number variants involving 17p13.3 using a single nucleotide polymorphism array: a single-center experience. BMC Medical Genomics, Dec 2022. URL: https://doi.org/10.1186/s12920-022-01423-5, doi:10.1186/s12920-022-01423-5. This article has 5 citations and is from a peer-reviewed journal.

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  8. (baker2023furtherexpansionand media 4e57cd55): Elizabeth K. Baker, Casey J. Brewer, Leonardo Ferreira, Mark Schapiro, Jeffrey Tenney, Heather M. Wied, Beth M. Kline‐Fath, Teresa A. Smolarek, K. Nicole Weaver, and Robert J. Hopkin. Further expansion and confirmation of phenotype in rare loss of ywhae gene distinct from miller–dieker syndrome. Nov 2023. URL: https://doi.org/10.1002/ajmg.a.63057, doi:10.1002/ajmg.a.63057. This article has 14 citations.

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