Lissencephaly

Last update: December 3, 2018

Recommended Breda Genetics panel for this condition:

Lissencephaly (ARX, CDK5, DCX, NDE1, KATNB1, LAMB1, PAFAH1B1, POMT1, POMT2, RELN, TUBA1A)

possibly plus

Array-CGH

lyssencephalySummary

Lissencephaly, which means ‘smooth brain’, is a rare disorder which affects the formation of the brain between the 12th and the 24th week of gestation. It is a congenital cephalic disorder that stems from damaged or abnormal development of the nervous system in fetuses and prevents the formation of gyri (folds) and sulci (grooves) in the cerebrum. It is associated with developmental problems in children, shorting their lifespan.

Abnormal neuronal migration

The process of the development of the cerebral cortex of the fetus is split into three overlapping stages: cell proliferation, neuronal migration, and cortical organization. Lissencephaly is basically caused by abnormal neuronal migration.

Lissencephaly can be caused by viral infections during the first trimester of pregnancy or due to insufficient supply of blood to the fetus. There are also genetic causes (see below). Genetic testing can be done to calculate the reproductive risk in the following pregnancies.

Detailed clinical description

Infants born with lissencephaly are subject to significant delays in various aspects of mental and physical development. These delays further vary from individual to individual and are contingent upon the degree of damage to the brain structure. Generalized signs and symptoms include respiratory problems, shortened life expectancy, severe psychomotor retardation, seizures and muscle spasticity or hypotonia. Further sings may include facial dysmorphia, anomalous digits on hands and feet as well as difficulty with swallowing.

Summarizing, the following stigmata may be seen:

  • Deteriorated psychomotor skills
  • Shortened lifespan
  • Seizures
  • Muscle spasms
  • Microcephaly
  • Facial dysmorphisms
  • Uncontrolled or strange facial expressions
  • Swallowing difficulties
  • Malformation of the toes, hands and fingers.
  • Axial hypotonia
  • Autism
  • Sleep disorders

Mental and motor skills of children suffering from this disorder are usually slow. Their ability to perceive, process and act on information is significantly retarded. Slow emotional and physical reactions such as speech impairment or the ability to empathize are visible. The general IQ and EQ are significantly low.

Postnatal diagnosis

Postnatal diagnosis of lissencephaly is possible utilizing a number of methods such as ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). Caution is however required while dealing with the results as misdiagnosis is possible due to the similarity of the signs displayed by polymicogyria and lissencephaly.

Prenatal diagnosis

Ultrasounds (US) during pregnancy may reveal the presence of cerebral abnormality in fetuses. Genetic testing may compliment US if the disease-causing mutation in the previous affected child is known (see below for lissencephaly genes).

Familiarity with the normal ultrasonographic (US) and MRI appearances of the fetal cerebral cortex at different stages of gestation is required for the early successful detection of abnormal sulcal development. This means that the possibility of detecting fetal lissencephaly as soon as possible is strongly operator-dependent.

A certain degree of fetal development is required before it is possible to observe for any abnormality in the fetus. Around the 20th week of gestation fetal lissencephaly may start to be visible. Diagnosis before this time is not possible as the fetal brain is typically smooth before this time period. Upon the discovery of suspicious signs of lissencephaly, chorionic villus sampling may be utilized to test for some lissencephaly variants is the familial mutation is known.

While the prognosis is often poor and options fairly limited, the diagnosis of the disorder before birth offers solutions such as parental counseling and optimization of obstetric management.

Molecular genetics

Lissencephaly 1 (LIS1),  also known as classic lissencephaly, is caused by mutation in the PAFAH1B1 gene.  Classic lissencephaly is associated with an abnormally thick cortex, reduced or abnormal lamination, and diffuse neuronal heterotopia. The phenotype is dominant, meaning that a single heterozygous mutation in the PAFAH1B1 gene can cause the disorder.

Lissencephaly 2 (LIS2), also known as lissencephaly Norman-Roberts type, is caused by mutations in the RELN gene and shows autosomal recessive inheritance. In respect to LIS1, LIS2 presents distinctive associated features such as low sloping forehead and a prominent nasal bridge.

Lissencephaly 3 (LIS3) is caused by heterozygous mutation in the TUBA1A gene. Clinics may vary from patient to patient and include profound mental retardation, spastic tetraplegia, and intractable tonic-clonic seizures.

Lissencephaly 4 (LIS4) is caused by mutation in the NDE1 gene and shows autosomal recessive inheritance. Severe brain atrophy, extreme microcephaly and profound mental retardation are typical. This particular form of lissencephaly is sometimes referred to as microlissencephaly.

Lissencephaly 5 (LIS5) is caused by mutation in the LAMB1 gene and shows autosomal recessive inheritance. LIS5 is characterized by cobblestone changes in the cortex, more severe in the posterior region, and subcortical band heterotopia (SBH). Patients show hydrocephalus, seizures, and severely delayed psychomotor development.

Lissencephaly 6 (LIS6), also known as lissencephaly with microcephaly, is caused by mutation in the KATNB1 and is autosomal recessive. It is characterized by severe microcephaly. At brain MRI pachygyria and hypoplasia of the corpus callosum can also be seen.

Lissencephaly 7 (LIS7), also known as lissencephaly with cerebellar hypoplasia, is caused by mutation in the CDK5 gene and show autosomal recessive inheritance. Facial dysmorphism, arthrogryposis, and early-onset intractable seizures resulting in death in infancy have been observed.

X-linked lissencephaly 1 (LISX1) occurs due to a genetic mutation in the DCX gene. Affected males generally have a more severe phenotype compared to females (the milder phenotype usually seen in females is known as subcortical band heterotopia – SBH).

X-linked lissencephaly 2 (LISX2) – also known as X-linked lissencephaly with ambiguous genitalia (XLAG) – is caused by mutation in the ARX gene. Proud syndrome is an allelic disorder with a phenotype overlapping with LISX2. Early infantile epileptic encephalopathy-1 (EIEE1) and two other forms of X-linked mental retardation (Partington syndrome and MRXARX) are also allelic disorders, but they don’t show brain malformations. Males with LISX2 are severely affected and often die within the first days or months of life, whereas females may be unaffected or have a milder phenotype. The ARX gene disorder spectrum comprises a nearly continuous series of developmental disorders which also includes hydranencephaly.

Lissencephaly is also be seen in muscular dystrophy-dystroglycanopathy type A, 1 (MDDGA1) and type A, 2 (MDDGA2), caused by mutations in the POMT1 or POMT2 gene respectively.

Miller-Dieker lissencephaly syndrome is a contiguous gene syndrome caused by the deletion (loss) of a group of adjacent genes on the short arm of chromsome 17 in the region 17p13.3. Features of the Miller-Dieker syndrome include classic lissencephaly, microcephaly, wrinkled skin over the glabella and frontal suture, prominent occiput, narrow forehead, downward slanting palpebral fissures, small nose and chin, cardiac malformations, hypoplastic male extrenal genitalia, growth retardation, and mental deficiency with seizures and EEG abnormalities. Life expectancy is grossly reduced, with death most often occurring during early childhood.

Recommended testing workflow

In case lissencephaly is diagnosed by US and/or MRI, genetic testing based on an extended panel of genes is recommended. Exome and non-exome based panels are available at Breda Genetics to test for this condition. Array-CGH or MLPA may be also considered to screen for Miller-Dieker lissencephaly syndrome.

Recommended Breda Genetics panel for this condition:

Lissencephaly (ARX, CDK5, DCX, NDE1, KATNB1, LAMB1, PAFAH1B1, POMT1, POMT2, RELN, TUBA1A)

possibly plus

Array-CGH

References

PAFAH1B1-Associated Lissencephaly/Subcortical Band Heterotopia. Dobyns WB, Das S. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2009 Mar 3 [updated 2014 Aug 14]. PMID: 20301752

DCX-Related Disorders. Hehr U, Uyanik G, Aigner L, Couillard-Despres S, Winkler J. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2007 Oct 19 [updated 2011 Mar 24]. PMID: 20301364

The genetics of lissencephaly. Fry AE, Cushion TD, Pilz DT. Am J Med Genet C Semin Med Genet. 2014 Jun;166C(2):198-210. PMID: 24862549

TUBA1A mutation-associated lissencephaly: case report and review of the literature. Sohal AP, Montgomery T, Mitra D, Ramesh V. Pediatr Neurol. 2012 Feb;46(2):127-31. PMID: 22264709

ARX spectrum disorders: making inroads into the molecular pathology. Shoubridge C, Fullston T, Gécz J. Hum Mutat. 2010 Aug;31(8):889-900. PMID: 20506206

Lissencephalic syndromes: brain and beyond. Pavone L, Corsello G, Pavone P, Iannetti P. Front Biosci (Schol Ed). 2010 Jan 1;2:85-95. PMID: 20036930

Lissencephaly: Expanded imaging and clinical classification. Di Donato N, Chiari S, Mirzaa GM, Aldinger K, Parrini E, Olds C, Barkovich AJ, Guerrini R, Dobyns WB. PMID: 28440899

OMIM: 607432

 

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