Microlissencephaly: a comprehensive review

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This pre-print is undergoing public peer review

First submitted: 20 December 2017

Last updated: 12 January 2018

Reviewer comments
Last reviewed version


Licensing: Open Access logo PLoS white.svg Cc.logo.circle.svg This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction, provided the original author and source are credited.



This is an unpublished pre-print. It is undergoing peer review.

Author: Ahmed-Reda Maaty, et al.
Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
Author 1 ORCID: Orcid icon.png 0000-0002-8442-9511

Author correspondence: ahmed.reda.maaty@jupiter.uni-freiburg.de


Abstract

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). Microlissencephaly 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 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). Eight genes (RELN, CIT, NDE1, KATNB1, WDR62, WDR81, ACTG1, DMRTA2) are so far associated with microlissencephaly along with six tubulin genes; however, the pathophysiology is still not completely understood. In this review, the genetics of microlissencephaly, types, clinical manifestations and its diagnosis will be discussed.

Key words: Microlissencephaly (MLIS), Microcephaly with simplified gyral pattern (MSGP), Malformation of cortical development (MCD), Neuronal migration disorders (NMDs), Microcephaly, Lissencephaly

Introduction[edit]

MLIS TUBB2B (cropped).jpg

Figure 1 | Microlissencephaly in a 27 WG (week of gestation) foetus with TUBB2B mutation. Macroscopical view of the left hemisphere showing agyria, absent sylvian fissure and absent olfactory bulb.[1]
Cropped from a photo by Fallet-Bianco et al, CC-BY-SA 4.0

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.[2] It is a malformation of cortical development (MCD) that occurs due to 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).[3][4] Thus far, 14 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[5]), it is known as "microcephaly with simplified gyral pattern" (MSGP).[6] Both MLIS and MSGP have a much more severe clinical course than microcephaly alone.[7] They are inherited in an autosomal recessive manner.[8] Prior to the year 2000, the term “microlissencephaly” was used to designate both MLIS and MSGP.[9]

Epidemiology[edit]

MLIS is a rare disease.[10] There is not much information available about the epidemiology of microlissencepahly in literature. A PhD 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).[11]

Pathophysiology[edit]

Table 1 | Genes associated with MLIS with corresponding chromosomal location and proteins encoded
Gene Location Protein encoded OMIM number
RELN 7q22.1 Reelin 600514
CIT 12q24.23 Citron Kinase 605629
NDE1 16p13.11 NudE Neurodevelopment Protein 1 609449
KATNB1 16q21 Katanin p80 subunit B1 602703
WDR62 19q13.12 WD Repeat-containing protein 62 613583
WDR81 17p13.3 WD Repeat-containing protein 81 614218
DMRTA2 1p32.3 Doublesex- And Mab-3-Related Transcription Factor 5 614804
ACTG1 17q25.3 Gamma Actin 102560
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

The genetic basis and pathophysiology of MLIS are still not completely understood.[12] Most cases of MLIS are described in consanguineous families suggesting an autosomal recessive inheritance.[8][13][14] Numerous genes have been found to be associated with MLIS (Table 1). Mutations of the RELN or CIT genes could cause MLIS.[1][14][15]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.[16][17][18][19] Some other associated genes include: KATNB1 and WDR62. 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.[20] 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.[21] 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.[22] 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.[13]

Microlissencepahly is considered a tubulinopathy (tubulin gene defect)[23] i.e. it can be caused by mutations in tubulin genes, mainly TUBA1A[24] (Figure 2) and less commonly TUBB2B, TUBB3, TUBA3E and TUBG1.[25] Central pachygyria and polymicrogyria are more commonly seen in patients with defects in TUBB2B, TUBB3, and TUBB5.[26] This implies the critical role of the microtubule cytoskeleton in the pathophysiology of MLIS as well as other neuronal migration disorders.[13]

Congenital infections like cytomegalovirus may cause MLIS.[14]

Both MLIS and MSGP result from either decreased stem cell proliferation or increased apoptosis in the germinal zone of the cerebral cortex.[3]

Clinical Picture[edit]

Microlissencephaly (cropped).gif

Figure 2 | MRI of a patient with TUBA1A mutation shows MLIS with cerebellar hypoplasia. a. smooth brain surface (arrow) b. absent corpus callosum (arrow).[27]
Cropped from a photo by Yohei Bamba et al, CC-BY-SA 4.0

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).[9][10][14]

MLIS may arise as a part of Baraitser-Winter syndrome which comprises also ptosis, coloboma, hearing loss and learning disability.[28] Moreover, it is the distinct developmental brain abnormality in "microcephalic osteodysplastic primordial dwarfism" (MOPD1).[29] MLIS may be accompanied by micromelia (shortening of the limbs) as in Basel-Vanagaite-Sirota syndrome (also known as Microlissencephaly-Micromelia syndrome).

Types[edit]

MLIS is one of five subtypes of lissencephaly.[30] MLIS, in turn, can be subclassified based on imaging and clinical picture into 4 types:[8][31][32]

MLIS1[edit]

MLIS Type A or Norman-Roberts syndrome (NRS) is a 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.[33]

MLIS2[edit]

MLIS Type B or Barth microlissencephaly syndrome is a 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.[34] Barth described two siblings with this type as having a very low brainweight, wide ventricles, a very thin neopalliumabsent corpus callosum and absent olfactory nerve.[35]

MLIS3[edit]

MLIS with intermediate cortex and abrupt anteroposterior gradient.

MLIS4[edit]

MLIS with mildly to moderately thick (6–8 mm) cortex, callosal agenesis.

Dobyns-Barkovich classification[edit]

In 1999, Dobyns and Barkovich suggested a classification of patients with severe microcephaly combined with gyral abnormalities including: microcephaly with simplified gyral pattern (MSGP), MLIS and polymicrogyria (multiple small gyri). The classification divided those patients into ten groups in which MSGP represented the first four groups, MLIS referred to the groups from 5-8 and polymicrogyria in the last two groups.[36]

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).[36][37]

Diagnosis[edit]

MLIS can be diagnosed by prenatal MRI (Figure 2).[23] MRI is better than ultrasound when it comes to detecting MLIS or MSGP prenatally.[38] 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.[39]

At birth, lissencephaly with a head circumference of less than minus three standard deviations (< –3 SD) is considered MLIS.[40]

Although genetic diagnosis in patients with MLIS is challenging, exome sequencing has been suggested to be a powerful diagnostic tool.[21]

Differential Diagnosis[edit]

MLIS is considered a more severe form than microcephaly with simplified gyral pattern (Table 2). 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 normal cortical thickness (3 mm) and is usually an isolated anomaly.[3]

Table 2 | Microlissencephaly and Microcephaly with simplified gyral pattern
MLIS MSGP
Mode of inheritance (if genetic) Autosomal recessive
Cortical thickness thickened (>3 mm) normal (3 mm)
Cortical surface smooth too few sulci
Severity Severe form Mild form
Associated anomalies? usually present not present (MSGP is usually isolated)

Management[edit]

MLIS usually leads to an early fatal outcome during the neonatal period.[21]

History[edit]

In 1976, the first syndrome with MLIS was reported, now known as Norman–Roberts syndrome (MLIS type A).[41] The Barth type (MLIS type B) was for the first time described in 1982 in two siblings who died soon after birth.[35]

Acknowledgements[edit]

The author declares that there is no conflict of interest.

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