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LIS1-Associated Lissencephaly/Subcortical Band Heterotopia

Synonyms: PAFAH1B1-Associated Lissencephaly/Subcortical Band Heterotopia. Includes: 17-Linked Subcortical Band Heterotopia, Isolated 17-Linked Lissencephaly, Miller-Dieker Syndrome

, MD and , PhD.

Author Information
, MD
Department of Human Genetics
University of Chicago
Chicago, Illinois
, PhD
Department of Human Genetics
University of Chicago
Chicago, Illinois

Initial Posting: .

Summary

Disease characteristics. LIS1-associated lissencephaly/subcortical band heterotopia (SBH) includes Miller-Dieker syndrome (MDS) and isolated lissencephaly sequence (ILS). Lissencephaly and SBH are cortical malformations caused by deficient neuronal migration during embryogenesis. Lissencephaly refers to a "smooth brain" with absent gyri (agyria) or abnormally wide gyri (pachygyria). SBH refers to a band of heterotopic gray matter located just beneath the cortex and separated from it by a thin zone of normal white matter. MDS is characterized by lissencephaly, typical facial features, and severe neurologic abnormalities. ILS is characterized by lissencephaly and its direct sequelae: developmental delay, intellectual disability, and seizures.

Diagnosis/testing. MDS is caused by either small cytogenetically visible deletions or FISH-detectable microdeletions of 17p13.3 that include LIS1 (also known as PAFAH1B1) and additional telomeric genes. ILS is caused by smaller submicroscopic deletions of LIS1; intragenic deletions or duplications of LIS1; or sequence variants of LIS1.

Management. Treatment of manifestations: Poor feeding may require nasogastric tube feedings in newborns and later placement of a gastrostomy. Seizures require prompt and aggressive management based on the specific seizure type and frequency; response to treatment is similar to that in children with seizures due to other causes.

Genetic counseling. Approximately 80% of individuals with MDS have a de novo deletion involving 17p13.3 and approximately 20% have inherited a deletion from a parent who carries a balanced chromosome rearrangement. If neither parent has a structural chromosome rearrangement detectable by high-resolution chromosome analysis, the risk to sibs is negligible. If a parent has a balanced structural chromosome rearrangement, the risk to sibs for MDS depends on the specific rearrangement. Although mosaicism in a parent could lead to familial recurrence of ILS, all LIS1 intragenic mutations reported to date have been de novo; thus, the risk to sibs for ILS is negligible if neither parent has mosaicism for the LIS1 mutation present in the proband. Prenatal testing for pregnancies at increased risk for MDS is possible if the familial chromosome rearrangement is known.

Diagnosis

Clinical Diagnosis

Together, lissencephaly and subcortical band heterotopia (SBH) comprise the "agyria-pachygyria-band" spectrum of cortical malformations that are caused by deficient neuronal migration during embryogenesis [Barkovich et al 1991, Norman et al 1995]. The term lissencephaly refers to a "smooth brain" with absent gyri (agyria) or abnormally wide gyri (pachygyria).

MRI Findings

Lissencephaly

  • Cerebral gyri are absent or abnormally broad.
  • The cerebral cortex is abnormally thick (12-20 mm; normal: 3-4 mm) [Barkovich et al 1991].
  • Associated findings in the most common ("classic") form of lissencephaly include:
    • Enlarged lateral ventricles, especially posteriorly
    • Mild hypoplasia of the corpus callosum (the anterior portion often appears flattened)
    • Cavum septi pellucidi et vergae
    • Normal brain stem and cerebellum except for mild vermis hypoplasia in some individuals

Subcortical band heterotopia (SBH)

  • A subcortical band of heterotopic gray matter, present just beneath the cortex, is separated from it by a thin zone of normal white matter [Barkovich et al 1994].
  • The subcortical bands are most often symmetric and diffuse, extending from the frontal to occipital regions; however, they may be asymmetric.
    • Subcortical bands restricted to the frontal lobes are more typically associated with mutations of DCX. (See DCX-Related Disorders.)
    • Subcortical bands restricted to the posterior lobes are more typically associated with LIS1 mutations.
  • The gyral pattern is normal or demonstrates mildly simplified shallow sulci; a normal cortical ribbon is present.

Lissencephaly and SBH are graded by anterior-posterior gradient and severity (Table 1 and Figure 1). When the lissencephaly or SBH is more severe posteriorly, it is referred to as a posterior to anterior (p>a) gradient. When more severe anteriorly, it is referred to as an anterior to posterior (a>p) gradient. LIS1 abnormalities generally give rise to a p>a gradient, whereas abnormalities of DCX generally give rise to an a>p gradient [Pilz et al 1998a, Dobyns et al 1999].

Figure 1

Figure

Figure 1. Brain MRIs of lissencephaly, ranging from grade 1 (the most severe) to grade 6 (subcortical band heterotopia, the least severe). (P) indicates posterior; (A) indicates anterior. Lissencephaly that is more severe posteriorly than anteriorly (best (more...)

Table 1. Grading System for Classic Lissencephaly and SBH

GradientGrade of Severity
1a=p 1Complete agyria
2p>a or 2a>pDiffuse agyria with a few undulations at the frontal or occipital poles
3p>a or 3a>pMixed agyria and pachygyria
4p>a or 4a>pDiffuse pachygyria, or mixed pachygyria and normal or simplified gyri
5a>p (the reverse 5p>a has not been observed)Mixed pachygyria and subcortical band heterotopia
6p>a or 6a>pSubcortical band heterotopia only

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

Histologic Findings

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

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

SBH. The architecture of the cortex is normal with readily distinguishable white matter including U-fibers, scattered neurons in the outer portion of the bands, a somewhat columnar arrangement of neurons in the inner part of the bands accentuated by radially oriented bundles of myelinated fibers, and scattered inverted neurons [Harding 1996].

Testing

Chromosome analysis

  • High-resolution chromosome studies at the 450-band level or higher identify cytogenetically visible deletions or other structural rearrangements of 17p13.3 in approximately 70% of individuals with Miller-Dieker syndrome (MDS), but not isolated lissencephaly sequence (ILS) or SBH [Dobyns et al 1991].
  • Rarely, individuals with isolated lissencephaly sequence (ILS) have a balanced reciprocal translocation disrupting LIS1.
  • Rarely, individuals with SBH have mosaic deletions of 17p13.3 visible on cytogenetic analysis.

Molecular Genetic Testing

Gene. Abnormalities of LIS1 cause isolated LIS1-associated lissencephaly/SBH [Pilz et al 1998b, Pilz et al 1999, Cardoso et al 2000, Cardoso et al 2002, Sicca et al 2003]. The official gene designation for LIS1 has been changed to PAFAH1B1 (see Tables in Molecular Genetics). However, in this GeneReview LIS1 designation is retained because of its common use in the medical genetics field.

Clinical testing

  • FISH testing is performed using a probe containing LIS1 (e.g., PAC95H6).
    • MDS. As currently defined, MDS is associated with deletions that include both LIS1 and YWHAE in 17p13.3 [Pilz et al 1998a, Cardoso et al 2003].
    • ILS. Approximately 54% of individuals with LIS1-related ILS have a deletion of LIS1 detectable by FISH. Partial LIS1 deletions may not be detectable by FISH. Almost all LIS1 deletions (partial and complete) can be detected by MLPA analysis (see MLPA analysis below).
    • SBH. Mosaic deletions of 17p13.3 involving LIS1 have been observed in two individuals with SBH [unpublished, reviewed by WB Dobyns].
  • Deletion/duplication analysis, testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA, can be accomplished with a variety of methods, such as quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridization (CGH).
    • Array comparative genomic hybridization (aCGH) analysis. Targeted and whole-genome aCGH analyses that contain probes to LIS1 can be used to detect whole-gene deletions of LIS1. However, partial-gene deletions, which appear to be common, may not be detected.
    • MLPA analysis. Intragenic deletions and duplications of LIS1 that range in size from a single exon to multiple exons to the entire gene are present in approximately 14% of individuals with LIS1-related ILS [Haverfield et al 2009, Mei et al 2008] and can be detected by MLPA analysis. This category of deletions/duplications is not detected by FISH or aCGH analysis.
  • Sequence analysis detects:

Table 2. Molecular Genetic Testing Used in LIS1-Related Lissencephaly/SBH

Gene SymbolTest Method Mutations Detected Frequency of Mutations 1 2
MDSILSSBH
LIS1FISH 3
aCGH 4, 5
MLPA 5
Deletions of LIS1 and adjacent genes/regions100%~54%0.3% 6
MLPA 5Exonic and multiexonic deletions and duplications0~68% (54%+14%)ND 8
Sequence analysis Sequence variants 80~32%0.7% 9

Data from Pilz et al [1998a], Pilz et al [1998b], Pilz et al [1999], D’Agostino et al [2002], Cardoso et al [2002], Cardoso et al [2003], Sicca et al [2003], Haverfield et al [2009], Mei et al [2008]

1. The ability of the test method used to detect a mutation that is present in the indicated gene

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

3. Using the PAC95H6 or Vysis® LIS1 probe

4. Array CGH that contains probes that correspond to LIS1; 3/5 cases

5. MLPA and aCGH are methods that identify deletions/duplications not detectable by sequence analysis of genomic DNA; other methods including quantitative PCR and real-time PCR may also be used.

6. Mosaic deletion or sequence variant; 2/6 cases

7. ND = not described

8. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

9. Mosaic deletion or sequence variant; 3/6 cases

Issues with interpretation of test results

  • Normal results of FISH analysis using a LIS1-derived probe such as 95H6 do not exclude the presence of the following:
    • A submicroscopic deletion of 17p13. Although the majority of LIS1 may be intact, small regions may be deleted but not detectable (e.g., the promoter, the 5' untranslated region [UTR], or an individual exon).
    • An intragenic mutation of LIS1
  • Normal results of aCGH analysis do not exclude the presence of LIS1 Intragenic deletions or duplications that affect single or multiple exons.
  • For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

The following testing strategies involve testing for deletions and mutations of LIS1 and mutations of DCX, an X-linked gene associated with ILS and SBH, and TUBA1A, an autosomal gene associated with ILS (see Differential Diagnosis). These testing strategies do not take into consideration the gradient or grade of lissencephaly.

Testing strategy for probands with isolated lissencephaly

  • Deletion/duplication analysis (e.g., MLPA) detects all large deletions involving LIS1 as well as small exonic deletions and duplications not detected by sequence analysis. Deletions may be detected by FISH or aCGH analysis rather than by MLPA, but the yield is only 54% compared to 68% for MLPA. Thus, MLPA would need to be performed in all individuals in whom FISH analysis or aCGH analysis were negative.
  • Sequence analysis of LIS1
  • Sequence analysis of DCX
    • Males. When the gradient of lissencephaly seen on brain imaging studies is more severe over the frontal lobes than over the posterior brain regions, DCX sequence analysis may be performed prior to MLPA analysis.
    • Females. The yield is expected to be <5%. DCX mutations were found in two of 50 such females [WB Dobyns, personal observation].
  • Sequence analysis of TUBA1A
  • Chromosome analysis. Only two individuals with balanced reciprocal translocations disrupting LIS1 have been observed (<1%).

Testing strategy for probands with SBH

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The phenotypes associated with mutations of LIS1 comprise a spectrum of severity that can be separated into Miller-Dieker syndrome (MDS), ILS (or isolated lissencephaly) and, on rare occasion, subcortical band heterotopia (SBH).

MDS consists of severe lissencephaly (grade 1-2) (see Table 1 and Figure 1), characteristic facial changes, other more variable malformations, and severe neurologic and developmental abnormalities [Dobyns et al 1991, Cardoso et al 2003]. The facial changes consist of high and prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip with downturned vermillion border, and small jaw (Figure 2). Other malformations seen on occasion include omphalocele and congenital heart defects.

Figure 2

Figure

Figure 2. Two children with Miller-Dieker syndrome showing typical facial features
Photographs have been obtained with consent of the families.

ILS consists of more variable lissencephaly (grades 2-4) (see Table 1 and Figure 1), minor facial changes, rare malformations outside of the brain, and similar neurologic and developmental handicaps as in MDS [Dobyns et al 1992].

In both MDS and ILS, the pregnancy may be complicated by polyhydramnios. Affected newborns may appear normal or may have mild to moderate hypotonia, poor feeding, and transient elevations in bilirubin likely related to feeding difficulties [Dobyns et al 1991, Dobyns et al 1992]. At birth, the occipitofrontal circumference (OFC) is typically normal (between the mean and 2 SD below the mean). However, postnatal head growth is slow; most children develop microcephaly by age one year. Prior to the onset of seizures, most infants have mild delay in development and mild hypotonia including poor head control. Some have difficulty with feeding.

Children with lissencephaly have epileptic encephalopathies that typically evolve from infantile spasms (West syndrome) to Lennox-Gastaut syndrome of mixed epilepsy with a slow spike and wave pattern on EEG. Overall, seizures occur in more than 90% of children with lissencephaly with onset usually before age six months. Approximately 80% have infantile spasms, although the EEG does not always show the typical hypsarrhythmia pattern. The onset of infantile spasms is typically associated with a precipitous decline in function. After the first months of life, most children have mixed seizure disorders including persisting infantile spasms, focal motor and generalized tonic seizures [Guerrini 2005], complex partial seizures, atypical absences, and atonic and myoclonic seizures. Some children with lissencephaly have characteristic EEG changes, including diffuse high-amplitude fast rhythms that are considered to be highly specific for this malformation [Quirk et al 1993].

The developmental prognosis is poor for all children with MDS and for the majority with isolated lissencephaly. Even with good seizure control, the best developmental level achieved by children with MDS or isolated lissencephaly (excluding the few with partial lissencephaly) is the equivalent of about age three to five months. This may include brief visual tracking, rolling over, limited creeping, and very rarely, sitting. With poor seizure control, children with lissencephaly may function at or below the level of a newborn. A few individuals with less severe (grade 4) lissencephaly, especially partial posterior lissencephaly or pachygyria, have a better developmental outcome [Leventer et al 2001].

During the first years, neurologic examination typically demonstrates brief visual tracking and response to sounds, axial hypotonia, and mild distal spasticity. Infants often demonstrate abnormal arching (opisthotonus). Later, distal spasticity becomes more prominent although hypotonia remains. Rarely, affected individuals develop moderate spastic quadriplegia and scoliosis.

Feeding often improves during the first few months of life, but typically worsens again with seizure onset during the first year of life, and then again at several years of age for various reasons.

Children with lissencephaly have poor control of their airways, which predisposes to aspiration pneumonia, the most common terminal event.

The prognosis differs somewhat between MDS and isolated lissencephaly. In MDS, death occurs within the first two years in many children, and only a few reach age ten years. The oldest known individual with MDS died at age 17 years. In isolated lissencephaly, approximately 50% live to age ten years, and very few reach age 20 years. The oldest known individual lived to age 30 years. These estimates apply only to individuals with typical lissencephaly affecting the entire brain (the large majority of those with lissencephaly).

Only four individuals with SBH associated with LIS1 mutations have been reported, one with a germline mutation and three with mosaic mutations [Pilz et al 1999, D’Agostino et al 2002, Sicca et al 2003, Uyanik et al 2007]. Two other unreported individuals have had mosaic deletions of chromosome 17p13.3 [Author, personal observation].

SBH is characterized by normal facial appearance, epilepsy, and intellectual disability. Three of the four individuals with LIS1-related SBH had frequent seizures. One had an IQ of 107 at age seven years that declined to 60 by age 13 years, most likely as a result of severe seizures; one had an IQ of approximately 60; and one had severe intellectual disability. The fourth had attained normal developmental milestones and had language delay at age three years [Uyanik et al 2007].

In general individuals with SBH live into adult life. No reliable data regarding life span exist; it is likely to be shortened in those with severe intellectual disability, intractable epilepsy, or both.

Genotype-Phenotype Correlations

MDS. The most severely affected individuals with MDS have large cytogenetically visible deletions of 17p13.3 and unbalanced chromosome rearrangements associated with duplication of another chromosomal segment.

The next-most severe abnormality is deletion of 17p13.3 that includes both LIS1 and YWHAE [Cardoso et al 2003], the latter located telomeric to LIS1 in the MDS chromosome region.

ILS. Smaller deletions, including intragenic deletions and duplications of LIS1, cause ILS that is less severe than MDS and range in severity from grade 2 to 4.

  • Most individuals with a telomeric deletion including the 5’ end of LIS1 have grades 2-3 lissencephaly.
  • Most individuals with a deletion of the 3’ end of LIS1 only have grade 3 or 4 lissencephaly [Chong et al 1997; unpublished data].
  • The vast majority of individuals with intragenic deletions and duplications of LIS1 have grade 3 lissencephaly [Haverfield et al 2009].

Intragenic mutations of LIS1 usually result in ILS grades 2-4. In general:

Note: These generalizations notwithstanding, severity of the phenotype does not always appear to correspond to location and type of mutation, as a more severe phenotype has been observed in some individuals with missense mutations and more severe grades (2 and 3) of lissencephaly have been observed in individuals with truncation/deletion mutations in the coiled-coil domain toward the 3’ end of LIS1 [Uyanik et al 2007].

SBH. Somatic mosaicism for LIS1 missense mutations and a LIS1 in-frame deletion have been identified in three individuals with a milder phenotype of SBH [Sicca et al 2003, Uyanik et al 2007].

Somatic mosaicism for a LIS1 deletion also results in the milder phenotype SBH [seen in two individuals; WB Dobyns, unpublished observation].

Prevalence

Classic lissencephaly is rare. Birth prevalence is estimated to range from 11.7 per million births to 40 per million births [personal communication with Metropolitan Atlanta Congenital Defects Program Personnel, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, 2002]. Even the latter is likely to be an underestimate as the CDC program ascertains only hospitalized children in the first several years of life.

Differential Diagnosis

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

Table 3. Types of Lissencephaly

TypeDescriptionGenesInheritance Pattern
Classic lissencephalyVery thick cortex (15-20 mm), normal corpus callosum, and cerebellar vermis (or mild hypoplasia)LIS1AD
DCXX-linked
TUBA1AAD
Cobblestone cortical malformation (lissencephaly)Pebbled brain surface, moderately thick 5-10 mm cortex (unless thinned by hydrocephalus), diffuse or patchy white matter abnormality, brain stem and cerebellar hypoplasiaFKTNAR
FKRP
LARGE
POMGnT1
POMT
POMT2
GPR56
Lissencephaly with agenesis of the corpus callosumLissencephaly with total or severe partial agenesis of the corpus callosumARXX-linked
Lissencephaly with cerebellar hypoplasiaLissencephaly with moderate to severe cerebellar hypoplasiaRELNAR
VLDLR
MicrolissencephalyBirth OFC -3 SD or small, thick cortexNANA

AD = Autosomal dominant

AR = Autosomal recessive

NA = Not applicable

OFC = Occipital frontal circumference

About half of individuals reported to have lissencephaly on a brain imaging study actually have another malformation, most often severe congenital microcephaly or polymicrogyria, frequently described as "pachygyria" [personal observation]. (See Polymicrogyria Overview.)

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

The differential diagnosis of classic lissencephaly includes the LIS1-related malformations, DCX-related malformations, TUBA1A-related malformations and the rare Baraitser-Winter syndrome (BWS) [Dobyns et al 1991, Dobyns et al 1992, Pilz et al 1998a, Pilz et al 1998b, Dobyns et al 1999, Matsumoto et al 2001, Ross et al 2001, Rossi et al 2003, Poirier et al 2007]. These disorders are distinguished by the mode of inheritance, grade and gradient of lissencephaly or SBH (Table 1), presence of other congenital anomalies, and results of molecular genetic testing.

  • Classic lissencephaly associated with deletions or intragenic mutations of LIS1 is more common than classic lissencephaly associated with mutations of DCX, located on the X chromosome [Pilz et al 1998b], and classic lissencephaly associated with mutations in TUBA1A.
  • SBH in females associated with mutations of DCX is far more common than SBH in females with LIS1 mutations [Pilz et al 1999, D’Agostino et al 2002, Sicca et al 2003].
  • LIS1-related malformations are characterized by a p>a gradient (see Table 1). DCX-related malformations are associated with an a>p gradient [Pilz et al 1998b, Dobyns et al 1999]. However, in severe classic lissencephaly or SBH the gradient may be difficult to discern.
  • TUBA1A-related malformations, like LIS-1 related malformations, are characterized by a p>a gradient similar. The lissencephaly phenotype associated with mutations in these two genes may be indistinguishable. The TUBA1A-related malformation generally appears to be more severe than the LIS1-related malformation [Poirier et al 2007].
  • Baraitser-Winter syndrome is characterized by: lissencephaly with an a>p gradient similar to that of DCX-related malformations; trigonocephaly; shallow orbits; ptosis; and colobomas of the iris, choroid, or both [Ramer et al 1995, Rossi et al 2003].

Lissencephaly with agenesis of the corpus callosum is typically associated with mutations in ARX. The XLAG (X-linked lissencephaly with abnormal genitalia) phenotype in severely affected individuals with a 46,XY karyotype differs significantly from the phenotype associated with mutations of either LIS1 or DCX. XLAG is characterized by congenital or postnatal microcephaly, neonatal-onset intractable epilepsy, poor temperature regulation, chronic diarrhea, and abnormal genitalia [Kato & Dobyns 2003, Kato et al 2004].

The cobblestone cortical malformation (lissencephaly) syndromes (Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy) have many clinical differences including frequent hydrocephalus and cerebellar hypoplasia, many different eye anomalies, and congenital muscular dystrophy (see Congenital Muscular Dystrophy Overview), and manifest by hypotonia and elevated serum creatine kinase concentrations.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with LIS1-associated lissencephaly/ subcortical band heterotopia (SBH), the following evaluations are recommended:

  • Growth
  • Feeding and nutrition
  • Respiratory status
  • Development
  • Seizures. Whenever any unusual spells or any developmental regression is noted, an EEG should be performed.

MRI should be interpreted carefully to provide as much prognostic information as possible. Note: Although most affected individuals have severe to profound intellectual disability, a minority have less extensive lissencephaly that results in only moderate intellectual disability, and a few have limited malformations that allow near-normal development. In the latter, the lissencephaly or SBH is typically less severe and less extensive on MRI. The resolution of brain CT scan is not usually sufficient to allow this.

Treatment of Manifestations

Parents seem best able to deal with this severe disorder when accurate information regarding the prognosis is given as soon as possible after the diagnosis is recognized. For those with severe lissencephaly, it is usually appropriate to discuss limitations of care, such as "do not resuscitate" (DNR) orders, in the event of severe illnesses.

Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life. But they often worsen again with intercurrent illnesses and with advancing age and size. At least half of children with LIS1-related lissencephaly (but not SBH) eventually have a gastrostomy tube placed for feeding.

Management of seizures in children with ILS or SBH is based on the specific seizure type and frequency. In general, seizures should be treated promptly and aggressively by specialists, as poor seizure control frequently results in decline in function and health. The response to treatment is typically similar to that in children with seizures due to other causes.

Therapies Under Investigation

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

Genetic Counseling

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

Mode of Inheritance

LIS1-associated lissencephaly/subcortical band heterotopia (SBH) is inherited in an autosomal dominant manner although most deletions and all intragenic mutations reported to date have been de novo.

Risk to Family Members

Parents of a proband

  • Approximately 80% of probands with Miller-Dieker syndrome (MDS) have a de novo deletion involving 17p13.3.
  • Approximately 20% of probands with MDS have inherited a deletion from a parent who carries a balanced chromosome rearrangement [Dobyns, unpublished data].
    • Parents of a proband with a structural unbalanced chromosome constitution (e.g., deletion or duplication) are at increased risk for balanced chromosome rearrangements and should be offered chromosome analysis.
  • Most LIS1 intragenic mutations are de novo.
    • Parental studies are recommended to exclude mosaicism in one parent.

Sibs of a proband

  • Proband with a cytogenetic deletion
    • If neither parent has a structural chromosome rearrangement detectable by high-resolution chromosome analysis, the risk to sibs is negligible.
    • If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific rearrangement, and possibly other variables.
  • Proband with an intragenic mutation in LIS1

Offspring of a proband. Individuals with LIS1-associated lissencephaly/SBH do not reproduce.

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

Related Genetic Counseling Issues

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

Family planning

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

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

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for an unbalanced chromosome rearrangement or LIS1 variants is possible. Fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation are analyzed by chromosome analysis. If a LIS1 variant is identified in the proband, DNA extracted from fetal cells is analyzed. The chromosome rearrangement or disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

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

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

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

  • Lissencephaly Network, Inc (Canada)
    1549 Regent Street
    Regina Saskatchewan S4N 1S1
    Canada
    Phone: 306-569-0146
    Fax: 306-522-1153
  • Lissencephaly Network, Inc. (USA)
    10408 Bitterroot Court
    Fort Wayne IN 46804
    Fax: 260-432-4310
    Email: lissnet@lissencephaly.org; LissencephalyOne@aol.com
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • American Epilepsy Society (AES)
    342 North Main Street
    West Hartford CT 06117-2507
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Molecular Genetics

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

Table A. LIS1-Associated Lissencephaly/Subcortical Band Heterotopia: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for LIS1-Associated Lissencephaly/Subcortical Band Heterotopia (View All in OMIM)

247200MILLER-DIEKER LISSENCEPHALY SYNDROME; MDLS
601545PLATELET-ACTIVATING FACTOR ACETYLHYDROLASE, ISOFORM 1B, ALPHA SUBUNIT; PAFAH1B1
607432LISSENCEPHALY 1; LIS1

Normal allelic variants. LIS1 (officially designated as PAFAH1B1, but referred to here as LIS1 because of its common use in the medical genetics field) is approximately 92 kb in size and consists of 11 exons. The coding region is 1230 bp, with the AUG start codon located in exon 2, and it encodes a protein of 410 amino acids called PAFAH1B1 (platelet-activating factor acetylhydrolase IB alpha subunit, also known as brain isoform 1b) [Reiner et al 1993]. There are two alternative transcripts (5.5 kb and 7.5 kb) that differ in the length at their respective 3’ UTR regions; both transcripts are expressed ubiquitously [Hattori et al 1994, Lo Nigro et al 1997].

To date, approximately 12 different polymorphisms have been identified in LIS1 (not all have been published). The polymorphic changes that have been identified are thought not to be disease causing, as they have either been found in individuals in whom a clearly deleterious mutation is also present or in individuals without the disease. Most of the polymorphic changes represent rare variants, with the exception of two polymorphisms in the 3’ UTR (c.X3T>G and c.X17C>T; see Table 4) that occur at frequencies of approximately 10% and 40% respectively [Koch et al 1996, Cardoso et al 2000].

Pathologic allelic variants. More than 78 different disease-causing LIS1 (PAFAH1B1) mutations have been described [Cardoso et al 2002; Uyanik et al 2007; Author, unpublished].

Most are private mutations; however, a few recurrent mutations have been described, including c.162delA and c.162dupA, which occur in a small stretch of adenine residues, and c.1050delG and c.1050dupG, which occur in a small stretch of guanine residues. Mutations appear to be evenly distributed throughout the gene. No predominant common mutation has been identified in any population.

Intragenic deletions and duplications of LIS1 that range from single-exon deletions or duplications to deletions of the entire coding region have been described; to date, 27 partial deletions and seven partial duplications of LIS1 have been identified [Mei et al 2008, Haverfield et al 2009]. These partial deletions and duplications appear to be spread throughout the gene. Microdeletions of the 17p13.3 region that delete all of LIS1 have been described in approximately 40% of individuals with ILS and differ with regard to size and break points. 17p13.3 microdeletions have been identified in affected individuals of different ethnic groups.

Table 4. Selected PAFAH1B1 (LIS1) Recurrent Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Normalc.X3T>C
(1233*3T>G)
--NM_000430​.3
NP_000421​.1
c.X17C>T
(1233*17C>T)
--
Pathologicc.162delAp.Lys54Asnfs*15
c.162dupA
(c.162_163insA)
p.Trp55Metfs*6
c.1050delGp.Lys351Serfs*4
c.1050dupG
(c.1050_1051insG)
p.Lys351Glufs*8
c.569-10T>C
(IVS6-10T>C)
--
c.1002+1G>A
(IVS9+1G>A)
--

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

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

1. Variant designation that does not conform to current naming conventions

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

Abnormal gene product. Mutations in LIS1 result in a reduction in the amount of correctly folded PAFAH1B1 protein [Sapir et al 1999]. Modeling studies of LIS1 mutations have shown that they abolish the binding of its protein, PAFAH1B1, with protein partners such as PAFAH1B2, PAFAH1B3, NUDE, or NUDEL [Sapir et al 1999, Feng et al 2000, Sasaki et al 2000, Sweeney et al 2000]. This in turn interferes with functions such as neuroblast proliferation and migration. LIS1 RNA interference studies indicate that an abnormal LIS1 gene product disrupts the production of neurons in the developing brain as well as their migration [Tsai et al 2005]. Both non-radial cell migration (inhibitory interneurons) and radial migration (excitatory projection neurons) appear to be affected [Fleck et al 2000, Pancoast et al 2005].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Suggested Reading

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

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