WikiJournal of Medicine/Microlissencephaly: a narrative review
Author: Ahmed-Reda Maaty
Microlissencephaly (MLIS) is a rare congenital brain disorder that combines severe microcephaly (small head) with lissencephaly (smooth brain surface due to absent sulci and gyri) (Figure 1). MLIS is a heterogeneous disorder, having many different causes and a variable clinical course. It is a malformation of cortical development (MCD) that occurs due to the failure of neuronal migration between the third and fifth month of gestation as well as stem cell population abnormalities (either increased apoptosis or decreased production). Thus far, 15 genes have been found to be associated with MLIS. However, the pathophysiology is still not completely understood.
The combination of lissencephaly with severe congenital microcephaly is designated as MLIS only when the cortex is abnormally thick. If such combination exists with a normal cortical thickness (2.5 to 3 mm), it is known as "microcephaly with simplified gyral pattern" (MSGP). Both MLIS and MSGP have a much more severe clinical course than microcephaly alone. They are inherited in an autosomal recessive manner. Prior to the year 2000, the term “microlissencephaly” was used to designate both MLIS and MSGP. Both MLIS and MSGP result from either decreased stem cell proliferation or increased apoptosis in the germinal zone of the cerebral cortex.
Figure 2 | STRING protein-protein interaction networks of proteins associated with MLIS. No mutation in NDEL1, PAFAH1B1, CAPN1, CAPN2 (lower right corner) or KATNA1 (upper right) is detected in MLIS; they are only shown in this diagram since they interact with those proteins mutated in MLIS. Tubulin proteins are grouped together. No direct interaction among CIT, DMRTA2, WDR62, WDR81 (left side) and the rest is detected. RNU4ATAC protein, mutated in MOPD1, is not found in STRING.
The genetic basis and pathophysiology of MLIS are still not completely understood. Most cases of MLIS are described in consanguineous families suggesting an autosomal recessive inheritance. Numerous genes have been found to be associated with MLIS (Table 1). Mutations of the RELN or CIT genes could cause MLIS.Moreover, human NDE1 mutations and mouse Nde1 loss lead to cortical lamination deficits, which, together with reduced neuronal production cause MLIS. Homozygous frameshift mutations in NDE1 gene was found to cause MLIS with up to 90% reduction in brain mass and seizures starting early in life.
|Gene||Location||Protein encoded||OMIM number|
|DMRTA2 (DMRT5)||1p32.3||Doublesex- And Mab-3-Related Transcription Factor 5||614804|
|DYNC1H1||14q32.31||Cytoplasmic Dynein 1 Heavy Chain 1||600112|
|KATNB1||16q21||Katanin p80 subunit B1||602703|
|NDE1||16p13.11||NudE Neurodevelopment Protein 1||609449|
|RNU4ATAC||2q14.2||U4atac small nuclear RNA (snRNA)||601428|
|TUBA1A||12q13.12||Alpha Tubulin 1A||602529|
|TUBA3E||2q21.1||Alpha Tubulin 3E||N/A|
|TUBB2B||6p25.2||Beta Tubulin 2B||612850|
|TUBB3||16q24.3||Beta Tubulin 3||602661|
|TUBG1||17q21.2||Gamma Tubulin 1||191135|
|WDR62||19q13.12||WD Repeat-containing protein 62||613583|
|WDR81||17p13.3||WD Repeat-containing protein 81||614218|
Some other associated genes include KATNB1 (Katanin p80) and WDR62. Katanin, a microtubule-severing enzyme, is composed of a catalytic, p60 (KATNA1), and a regulatory, p80 (KATNB1), subunit. p80/KATNB1 binds to p60 and targets it to subcellular structures including the centrosome, further mediating its interactions with dynein, LIS1, and NDEL1. In developing neurons, Katanin localizes to microtubules and centrosomes and is essential for microtubule shortening and release. Katanin functions in cell division and neuronal morphogenesis. It is hypothesized that the KATNB1-associated MLIS is the result of a combined effect of reduced neural progenitor populations and impaired interaction between the Katanin P80 subunit (encoded by KATNB1) and LIS1 (also known as PAFAH1B1), a protein mutated in type 1 lissencephaly.
A missense mutation in the ACTG1 gene was identified in three cases of MLIS. ACTG1 is the same gene that, when mutated, causes Baraitser-Winter syndrome. A loss-of-function mutation in the Doublesex- and Mab-3–Related Transcription factor A2 (DMRTA2, also known as DMRT5) gene has been reported in a case of MLIS, implicating DMRTA2 as a critical regulator of cortical neural progenitor cell dynamics. Another gene that could be involved in the pathogenesis of MLIS is WDR81. Compound heterozygous mutations in WDR81 were found in seven cases from five non-consanguineous families with microcephaly and extremely reduced gyration including agyria (no gyri). WDR81 is suggested to play a role in normal cell proliferation. In a family of two cases with microlissencephaly and arthrogryposis with consequent pregnancy termination, a common variant in DYNC1H1 gene on chromosome 14 was identified.
Microlissencepahly is considered a tubulinopathy (tubulin gene defect) i.e. it can be caused by mutations in tubulin genes, mainly TUBA1A (Figure 3) and less commonly TUBB2B, TUBB3, TUBA3E, and TUBG1. Central pachygyria (unusually thick convolutions of the cerebral cortex) and polymicrogyria (multiple small gyri) are more commonly seen in patients with defects in TUBB2B, TUBB3, and TUBB5. This implies the critical role of the microtubule cytoskeleton in the pathophysiology of MLIS as well as other neuronal migration disorders.
RNU4ATAC is a gene on chromosome 2 which encodes for a small nuclear RNA (snRNA) called U4atac. U4atac is a part of the U12-dependent minor spliceosome complex. Mutation in this protein is associated with "microcephalic osteodysplastic primordial dwarfism" (MOPD1) which can involve MLIS.
Microlissencephalic patients suffer from spasticity, seizures, severe developmental delay and intellectual disabilities with survival varying from days to years. Patients may also have dysmorphic craniofacial features, abnormal genitalia, and arthrogryposis (congenital joint contracture in two or more areas of the body).
MLIS is a classic finding of holoprosencephaly, where the forebrain of the embryo fails to develop into two cerebral hemispheres. MLIS may arise as a part of Baraitser-Winter syndrome which comprises also ptosis, coloboma, hearing loss and learning disability. Moreover, it is the distinct developmental brain abnormality in "microcephalic osteodysplastic primordial dwarfism" (MOPD1). MLIS may be accompanied by micromelia (shortening of the limbs) as in Basel-Vanagaite-Sirota syndrome (also known as Microlissencephaly-Micromelia syndrome).
MLIS is one of five subtypes of lissencephaly  and a distinct subtype of autosomal recessive primary microcephaly (MCPH). MLIS, in turn, can be subclassified based on imaging and clinical picture into four types as illustrated in (Table 2).
|MLIS 1||MLIS Type A or Norman-Roberts syndrome (NRS) is an MLIS with thick cortex without infratentorial anomalies.
Other clinical features may include a bitemporal narrowing, a broad nasal root. There is postnatal growth retardation, severe mental retardation associated with pyramidal spasticity and epilepsy. This entity could be identical to "lissencephaly with cerebellar hypoplasia type B" (LCHb), and therefore linked to mutations in RELN gene.
|MLIS 2||MLIS Type B or Barth microlissencephaly syndrome is an MLIS with thick cortex with infratentorial anomalies i.e. severe cerebellar and brainstem hypoplasia. The Barth-type of MLIS is the most severe of all the known lissencephaly syndromes.
This phenotype consists of polyhydramnios (probably due to poor fetal swallowing), severe congenital microcephaly, weak respiratory effort, and survival for only a few hours or days. Barth, after whom the subtype is named, described two siblings with this type as having a very low brain weight, wide ventricles, a very thin neopallium, absent corpus callosum and absent olfactory nerve.
|MLIS 3||an MLIS with intermediate cortex and abrupt anteroposterior gradient.|
|MLIS 4||an MLIS with mildly to moderately thick (6–8 mm) cortex, callosal agenesis.|
In 1999, Dobyns and Barkovich classified patients with severe microcephaly and gyral abnormalities (including microcephaly with simplified gyral pattern (MSGP), MLIS and polymicrogyria (multiple small gyri)) into ten groups. MSGP represented the first four groups, MLIS referred to the groups from 5-8 and polymicrogyria in the last two groups.
In Dobyns-Barkovich classification, Dobyns-Barkovich type 6 is equivalent to Norman-Roberts syndrome (MLIS1) while Dobyns-Barkovich type 8 corresponds to Barth microlissencephaly syndrome (MLIS2).
MLIS can be diagnosed by prenatal MRI (Figure 3). MRI is better than ultrasound when it comes to detecting MLIS or MSGP prenatally. The ideal time for proper prenatal diagnosis is between the 34th and 35th gestational week which is the time when the secondary gyration normally terminates. In MLIS cases, the primary sulci would be unusually wide and flat while secondary sulci would be missing.
MLIS is considered a more severe form than microcephaly with simplified gyral pattern. MLIS is characterized by a smooth cortical surface (absent sulci and gyri) with a thickened cortex (>3 mm) and is usually associated with other congenital anomalies. Microcephaly with a simplified gyral pattern has too few sulci and a normal cortical thickness (3 mm) and is usually an isolated anomaly. A comparison between MLIS and MSGP is summarized in (Table 3).
|Mode of inheritance (if genetic)||Autosomal recessive|
|Cortical thickness||thickened (>3 mm)||normal (3 mm)|
|Cortical surface||smooth (no sulci)||too few sulci|
|Severity||Severe form||Mild form|
|Associated anomalies?||usually present||not present (MSGP is usually isolated)|
Depending on the underlying pathogenesis, survival in MLIS varies from days to years. It can lead to an early fatal outcome during the neonatal period. Genetic counseling of family members is important in all cases of malformation of cortical developments (MCDs) and should include the type of mutation, the mutated genes as well as an explanation of the resultant clinical picture, particularly for subsequent pregnancies. In families with known molecular etiology, prenatal testing in the form of chorionic villus sampling or amniocentesis can be offered to guide subsequent pregnancies. Preimplantation genetic diagnosis (PGD) would be an option as well for those families.
The treatment of microlissencephaly and other malformations of cortical development is mostly symptomatic. Developmental delay is managed with neurorehabilitation, including physical and occupational therapy, and speech and feeding therapy. The management of epilepsy in microlissencephalic cases is complicated and depends on the underlying basis of the epileptiform activity. There are two aspects of neuronal functions that could generally contribute to epilepsy, either the epileptic intrinsic properties of neurons or the abnormally epileptic circuits of groups of neurons. In each case, the therapeutic approach differs. If the reason is abnormal epileptogenic circuits, then the neurosurgical resection of such zones would be beneficial. On the other side, if the abnormality arises from abnormal channels or receptors then the pharmacological approach could control epilepsy. However, it is still difficult to make a clear distinction between both mechanisms. Animal model studies are encouraged to further investigate how MLIS mutations in the aforementioned genes can lead to epilepsy which can help improve the understanding and management of epilepsy in those cases.
Figure 4 | The cytoplamic dynein complex and its regulators: the dynactin complex (green) and LIS1/NDE1/NDEL1 (orange-red).
Lissencephaly can result from a mutated LIS1 gene. LIS1 is a protein, normally essential for targeting of cytoplasmic dynein to the plus-end of microtubules. It was demonstrated that LIS1 (PAFAH1B1) is substantially degraded by calpain protein (encoded by CAPN1 and CAPN2) after reaching the plus-end of microtubule (protein interactions in the lower right corner of Figure 2). In an animal experiment, a calpain inhibitor called ALLN (Acetyl-Leucyl-Leucyl-Norleucinal) was applied to mice with LIS1 mutation. This has restored LIS1 to normal levels in neurons and consequently, improved neuronal migration and rescued apoptotic neuronal cell death. This provides a proof-of-principle for a potential therapeutic intervention for lissencephaly in the future.
Although LIS1 is not specifically mutated in MLIS, it is a part of a complex involving NDE1 and dynein DYNC1H1 gene, which both can be mutated in MLIS. This LIS1/NDE1/NDEL1/cytoplasmic dynein complex (Figure 4) plays a role in the regulation of neuron proliferation, migration, and intracellular transport. Targeting this complex in utero and throughout development could theoretically and potentially improve the outcome of microlissencephaly. Experimental animal studies are recommended to investigate the effect of calpain inhibitors in microlissencephaly.
MLIS is a rare disease. There is not much information available about the epidemiology of microlissencepahly in the literature. A Ph.D. thesis has estimated the prevalence of microlissencepahly in South-Eastern Hungary between July 1992 and June 2006 to be one case in every 91,000 live births (incidence of 1.1 per 100,000 newborns).
In 1976, the first syndrome with MLIS was reported, now known as Norman–Roberts syndrome (MLIS type A). The Barth type (MLIS type B) was for the first time described in 1982 in two siblings who died soon after birth.
The author declares no conflict of interest. The author is grateful to Prof. Andrew Copp (University College London) for reviewing the article and giving helpful comments.
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