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, i.e. it has many different causes and a variable clinical course.[1] Microlissencephaly 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.[2][3] Numerous genes have been found to be associated with microlissencephaly, however, the pathophysiology is still not completely understood.
The combination of lissencephaly with severe congenital microcephaly is designated as microlissencephaly only when the
cortex is abnormally thick. If such combination exists with a normal cortical thickness (2.5 to 3 mm[4]), it is known as "
microcephaly with simplified gyral pattern" (MSGP).[5] Both MLIS and MSGP have a much more severe clinical course than microcephaly alone.[6] They are inherited in autosomal recessive manner.[7] Prior to 2000, the term "microlissencephaly" was used to designate both MLIS and MSGP.[8]
Types
Microlissencephaly is one of five subtypes of
lissencephaly.[9] Microlissencephaly, in turn, can be subclassified based on imaging and clinical picture into four types:[7][10][11]
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.[12]
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.[13] Barth described two siblings with this type as having a very low brainweight, wide
ventricles, a very thin
neopallium,
absent corpus callosum and absent olfactory nerve.[14]
MLIS3
Microlissencephaly with intermediate cortex and abrupt anteroposterior gradient[citation needed]
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.[8][15][16]
The genetic basis and pathophysiology of microlissencephaly are still not completely understood.[19]
Most cases of microlissencephaly are described in
consanguineous families suggesting an
autosomal recessive inheritance.[7][20][16] Mutation of RELN gene or CIT could cause MLIS.[21][16][22] Human NDE1 mutations and mouse Nde1 loss lead to cortical lamination deficits, which, together with reduced neuronal production cause microlissencephaly.
Homozygousframeshift mutations in NDE1 gene was found to cause microlissencephaly with up to 90% reduction in brain mass and seizures starting early in life.[23][24][25][26] Some other disease-causing genes include: KATNB1 and WDR62. It is hypothesized that the KATNB1-associated microlissencephaly 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 (
a.k.a. PAFAH1B1), a protein mutated in type 1
lissencephaly.[27]Missense mutation in ACTG1 gene was identified in three cases of microlissencephaly. ACTG1 is the same gene that, when mutated, causes Baraitser-Winter syndrome.[28] 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 microlissencephaly, implicating DMRTA2 as a critical regulator of cortical neural
progenitor cell dynamics.[29]
Microlissencephaly can be diagnosed by
prenatalMRI.[30] MRI is better than ultrasound when it comes to detecting microlissencephaly or MSGP prenatally.[34]
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 microlissencephaly cases, the primary sulci would be unusually wide and flat while secondary sulci would be missing.[35]
Although genetic diagnosis in patients with MLIS is challenging,
exome sequencing has been suggested to be a powerful diagnostic tool.[28]
Dobyns-Barkovich classification
In 1999, Dobyns and Barkovich suggested a classification of patients with severe microcephaly combined with gyral abnormalities including: microcephaly with simplified gyral pattern (MSGP), microlissencephaly and
polymicrogyria. The classification divided those patients into ten groups in which MSGP represented the first four groups, microlissencephaly referred to the groups from 5-8 and polymicrogyria in the last two groups.[37]
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).[37][38]
Differential diagnosis
Microlissencephaly is considered a more severe form than microcephaly with simplified gyral pattern. Microlissencephaly 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.[2]
Microlissencephaly and microcephaly with simplified gyral pattern
Microlissencephaly
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)
Prognosis
Many patients will die within the first 10 years of life.[39]
Epidemiology
Microlissencephaly is listed in
Orphanet database as a rare disease.[15] There is not much information available about the epidemiology of microlissencepahly in literature. A PhD thesis has estimated the
prevalence of microlissencepahly in southeastern
Hungary between July 1992 and June 2006 to be a case every 91,000 live births (0.11:10,000).[40]
History
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.[14]
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