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Lissencephaly 6 with microcephaly(LIS6)

MedGen UID:
863962
Concept ID:
C4015525
Congenital Abnormality
Synonyms: LIS6; LISSENCEPHALY 6 WITH MICROCEPHALY
 
Gene (location): KATNB1 (16q21)
 
Monarch Initiative: MONDO:0014534
OMIM®: 616212

Definition

Lissencephaly-6 (LIS6) is an autosomal recessive neurodevelopmental disorder characterized by severe microcephaly and developmental delay. Brain imaging shows variable malformations of cortical development, including lissencephaly, pachygyria, and hypoplasia of the corpus callosum (summary by Mishra-Gorur et al., 2014). For a general description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432). [from OMIM]

Clinical features

From HPO
Single transverse palmar crease
MedGen UID:
96108
Concept ID:
C0424731
Finding
The distal and proximal transverse palmar creases are merged into a single transverse palmar crease.
Tapered finger
MedGen UID:
98098
Concept ID:
C0426886
Finding
The gradual reduction in girth of the finger from proximal to distal.
Limb hypertonia
MedGen UID:
333083
Concept ID:
C1838391
Finding
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Lissencephaly
MedGen UID:
78604
Concept ID:
C0266463
Finding
A spectrum of malformations of cortical development caused by insufficient neuronal migration that subsumes the terms agyria, pachygyria and subcortical band heterotopia. See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Polymicrogyria
MedGen UID:
78605
Concept ID:
C0266464
Congenital Abnormality
Polymicrogyria is a congenital malformation of the cerebral cortex characterized by abnormal cortical layering (lamination) and an excessive number of small gyri (folds).
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Partial agenesis of the corpus callosum
MedGen UID:
98127
Concept ID:
C0431368
Congenital Abnormality
A partial failure of the development of the corpus callosum.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Microlissencephaly
MedGen UID:
365439
Concept ID:
C1956147
Congenital Abnormality
Severe microcephaly and lissencephaly with granular surfaces with immature cortical plate, reduced in thickness, with focal polymicrogyria and immature small neurons with rare processes, intermingled with a considerable number of glial elements.
Simplified gyral pattern
MedGen UID:
413664
Concept ID:
C2749675
Finding
An abnormality of the cerebral cortex with fewer gyri but with normal cortical thickness. This pattern is usually often associated with congenital microcephaly.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Periventricular heterotopia
MedGen UID:
1766888
Concept ID:
C5399973
Disease or Syndrome
A form of gray matter heterotopia were the mislocalized gray matter is typically located periventricularly, also sometimes called subependymal heterotopia. Periventricular means beside the ventricles. This is by far the most common location for heterotopia. Subependymal heterotopia present in a wide array of variations. There can be a small single node or a large number of nodes, can exist on either or both sides of the brain at any point along the higher ventricle margins, can be small or large, single or multiple, and can form a small node or a large wavy or curved mass.
Pachygyria
MedGen UID:
504794
Concept ID:
CN001193
Finding
Pachygyria is a malformation of cortical development with abnormally wide gyri with sulci 1,5-3 cm apart and abnormally thick cortex measuring more than 5 mm (radiological definition). See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Enlarged cisterna magna
MedGen UID:
344031
Concept ID:
C1853377
Finding
Increase in size of the cisterna magna, one of three principal openings in the subarachnoid space between the arachnoid and pia mater, located between the cerebellum and the dorsal surface of the medulla oblongata.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Wide mouth
MedGen UID:
44238
Concept ID:
C0024433
Congenital Abnormality
Distance between the oral commissures more than 2 SD above the mean. Alternatively, an apparently increased width of the oral aperture (subjective).
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Widely spaced teeth
MedGen UID:
337093
Concept ID:
C1844813
Finding
Increased spaces (diastemata) between most of the teeth in the same dental arch.
Sloping forehead
MedGen UID:
346640
Concept ID:
C1857679
Finding
Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
Almond-shaped palpebral fissure
MedGen UID:
870336
Concept ID:
C4024780
Finding
A shape created by an acute downward arching of the upper eyelid and upward arching of the lower eyelid, toward the medial canthus, which gives the outline of the palpebral fissures the configuration of an almond. Thus, the maximum distance between the fissures is offset from, and medial to, the center point.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
Wide intermamillary distance
MedGen UID:
473489
Concept ID:
C1827524
Finding
A larger than usual distance between the left and right nipple.

Recent clinical studies

Etiology

Almeida IMLM, Ramos CV, Rodrigues DC, Sousa AC, Nascimento MLCAPCD, Silva MVBD, Batista FMA, Santos JPD, Oliveira RS, Soares FAF, Xavier SCDC, Carvalho-Costa FA
J Pediatr (Rio J) 2019 Jul-Aug;95(4):466-474. Epub 2018 Jun 29 doi: 10.1016/j.jped.2018.04.013. PMID: 29963988
Melo AS, Aguiar RS, Amorim MM, Arruda MB, Melo FO, Ribeiro ST, Batista AG, Ferreira T, Dos Santos MP, Sampaio VV, Moura SR, Rabello LP, Gonzaga CE, Malinger G, Ximenes R, de Oliveira-Szejnfeld PS, Tovar-Moll F, Chimelli L, Silveira PP, Delvechio R, Higa L, Campanati L, Nogueira RM, Filippis AM, Szejnfeld J, Voloch CM, Ferreira OC Jr, Brindeiro RM, Tanuri A
JAMA Neurol 2016 Dec 1;73(12):1407-1416. doi: 10.1001/jamaneurol.2016.3720. PMID: 27695855
Cavalheiro S, Lopez A, Serra S, Da Cunha A, da Costa MD, Moron A, Lederman HM
Childs Nerv Syst 2016 Jun;32(6):1057-60. Epub 2016 Apr 14 doi: 10.1007/s00381-016-3074-6. PMID: 27080092Free PMC Article
Bahi-Buisson N, Poirier K, Fourniol F, Saillour Y, Valence S, Lebrun N, Hully M, Bianco CF, Boddaert N, Elie C, Lascelles K, Souville I; LIS-Tubulinopathies Consortium, Beldjord C, Chelly J
Brain 2014 Jun;137(Pt 6):1676-700. doi: 10.1093/brain/awu082. PMID: 24860126
Güngör S, Yalnizoğlu D, Turanli G, Saatçi I, Erdoğan-Bakar E, Topçu M
Turk J Pediatr 2007 Apr-Jun;49(2):120-30. PMID: 17907510

Diagnosis

Jauhari P, Farmania R, Chakrabarty B, Kumar A, Gulati S
Seizure 2020 Dec;83:175-180. Epub 2020 Oct 31 doi: 10.1016/j.seizure.2020.10.020. PMID: 33161247
Almeida IMLM, Ramos CV, Rodrigues DC, Sousa AC, Nascimento MLCAPCD, Silva MVBD, Batista FMA, Santos JPD, Oliveira RS, Soares FAF, Xavier SCDC, Carvalho-Costa FA
J Pediatr (Rio J) 2019 Jul-Aug;95(4):466-474. Epub 2018 Jun 29 doi: 10.1016/j.jped.2018.04.013. PMID: 29963988
Lin PY, Tseng MH, Zenker M, Rao J, Hildebrandt F, Lin SH, Lin CC, Chang JH, Hsu CH, Lee MD, Lin SP, Tsai JD
Orphanet J Rare Dis 2018 Dec 17;13(1):226. doi: 10.1186/s13023-018-0961-9. PMID: 30558655Free PMC Article
Bahi-Buisson N, Poirier K, Fourniol F, Saillour Y, Valence S, Lebrun N, Hully M, Bianco CF, Boddaert N, Elie C, Lascelles K, Souville I; LIS-Tubulinopathies Consortium, Beldjord C, Chelly J
Brain 2014 Jun;137(Pt 6):1676-700. doi: 10.1093/brain/awu082. PMID: 24860126
Güngör S, Yalnizoğlu D, Turanli G, Saatçi I, Erdoğan-Bakar E, Topçu M
Turk J Pediatr 2007 Apr-Jun;49(2):120-30. PMID: 17907510

Therapy

Breuss M, Heng JI, Poirier K, Tian G, Jaglin XH, Qu Z, Braun A, Gstrein T, Ngo L, Haas M, Bahi-Buisson N, Moutard ML, Passemard S, Verloes A, Gressens P, Xie Y, Robson KJ, Rani DS, Thangaraj K, Clausen T, Chelly J, Cowan NJ, Keays DA
Cell Rep 2012 Dec 27;2(6):1554-62. Epub 2012 Dec 13 doi: 10.1016/j.celrep.2012.11.017. PMID: 23246003Free PMC Article

Prognosis

Naim A, Accogli A, Amadori E, D'Onofrio G, Madia F, Tortora D, Zara F, Striano P, Salpietro V, Severino M
Eur J Med Genet 2022 Nov;65(11):104622. Epub 2022 Sep 16 doi: 10.1016/j.ejmg.2022.104622. PMID: 36122673
Hebebrand M, Hüffmeier U, Trollmann R, Hehr U, Uebe S, Ekici AB, Kraus C, Krumbiegel M, Reis A, Thiel CT, Popp B
Orphanet J Rare Dis 2019 Feb 11;14(1):38. doi: 10.1186/s13023-019-1020-x. PMID: 30744660Free PMC Article
Almeida IMLM, Ramos CV, Rodrigues DC, Sousa AC, Nascimento MLCAPCD, Silva MVBD, Batista FMA, Santos JPD, Oliveira RS, Soares FAF, Xavier SCDC, Carvalho-Costa FA
J Pediatr (Rio J) 2019 Jul-Aug;95(4):466-474. Epub 2018 Jun 29 doi: 10.1016/j.jped.2018.04.013. PMID: 29963988
Bahi-Buisson N, Poirier K, Fourniol F, Saillour Y, Valence S, Lebrun N, Hully M, Bianco CF, Boddaert N, Elie C, Lascelles K, Souville I; LIS-Tubulinopathies Consortium, Beldjord C, Chelly J
Brain 2014 Jun;137(Pt 6):1676-700. doi: 10.1093/brain/awu082. PMID: 24860126
Güngör S, Yalnizoğlu D, Turanli G, Saatçi I, Erdoğan-Bakar E, Topçu M
Turk J Pediatr 2007 Apr-Jun;49(2):120-30. PMID: 17907510

Clinical prediction guides

Jauhari P, Farmania R, Chakrabarty B, Kumar A, Gulati S
Seizure 2020 Dec;83:175-180. Epub 2020 Oct 31 doi: 10.1016/j.seizure.2020.10.020. PMID: 33161247
Hebebrand M, Hüffmeier U, Trollmann R, Hehr U, Uebe S, Ekici AB, Kraus C, Krumbiegel M, Reis A, Thiel CT, Popp B
Orphanet J Rare Dis 2019 Feb 11;14(1):38. doi: 10.1186/s13023-019-1020-x. PMID: 30744660Free PMC Article
Almeida IMLM, Ramos CV, Rodrigues DC, Sousa AC, Nascimento MLCAPCD, Silva MVBD, Batista FMA, Santos JPD, Oliveira RS, Soares FAF, Xavier SCDC, Carvalho-Costa FA
J Pediatr (Rio J) 2019 Jul-Aug;95(4):466-474. Epub 2018 Jun 29 doi: 10.1016/j.jped.2018.04.013. PMID: 29963988
Cavalheiro S, Lopez A, Serra S, Da Cunha A, da Costa MD, Moron A, Lederman HM
Childs Nerv Syst 2016 Jun;32(6):1057-60. Epub 2016 Apr 14 doi: 10.1007/s00381-016-3074-6. PMID: 27080092Free PMC Article
Bahi-Buisson N, Poirier K, Fourniol F, Saillour Y, Valence S, Lebrun N, Hully M, Bianco CF, Boddaert N, Elie C, Lascelles K, Souville I; LIS-Tubulinopathies Consortium, Beldjord C, Chelly J
Brain 2014 Jun;137(Pt 6):1676-700. doi: 10.1093/brain/awu082. PMID: 24860126

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