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Am J Med Genet C Semin Med Genet
2019 Dec 01;1814:627-637. doi: 10.1002/ajmg.c.31751.
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EML1-associated brain overgrowth syndrome with ribbon-like heterotopia.
Le Moing AG
van Haaften G
EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon-like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like cortical malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease-causing variants cause a highly specific pattern of congenital brain malformations, severe developmental delay, seizures and visual impairment.
Figure 1. (a) Partial homozygous EML1 deletion of Individual 1, screen shot of the SNP microarray IlluminaHumanOmni 2.5‐8v1.2; 2,500 K result. (b) Facial photograph of Individual 1, depicting macrocephaly, high forehead, downslanting and narrow palpebral fissures, esotropia, a low‐set left ear, long upper lip and a small chin. (c) Photograph of Individual 5. Note macrocephaly and prominent forehead, low‐set ear, chest deformity, and abnormal posturing. (d) Facial photograph of Individual 7. Note macrocephaly, narrow palpebral fissure, esotropia and small mouth. This picture was previously published by Shaheen et al. [Reprinted with permission from John Wiley and Sons under license number 4562451107943]
Figure 2. Brain MR imaging of Individuals 1, 5, 7, and 8. Individual 1 a‐b: Sagittal and axial T2 scans at 39 days of life demonstrates thin cortex with shallow polygyria; symmetrical undulating ribbon‐like heterotopia is also noted in the subcortical region. (c, d) Axial and sagittal T1 weighted scans at age 13 months demonstrate myelinated white matter on both sides of the ribbon‐like heterotopia in the periventricular regions and the subcortical regions. The sagittal T1 midline image (a) at 13 months shows further head growth with bossing of forehead. The corpus callosum is hypoplastic. There is progression of myelination and development of macrocerebellum with large vermis and ectopic cerebellar tonsils. The pons is flat and the midbrain is short. Individual 5 a‐d: Sagittal and axial T2 (a, b) and T1 (c, d) weighted images obtained at 4 months of age show the same typical ribbon‐like heterotopia with overlying polymicrogyric cortex. There is frontal bossing and an enlarged right occipital horn. Note the medial fusion of small and rotated thalami (b, d). On the sagittal T1 (c) high signal areas are visible, which are low on T2. Individual 7 A‐D: Sagittal and axial T2 (a, b) and T1 (c, d) weighted images at age 11 months show macrocephaly with extreme enlargement of the occipital horns, right more than left with compression on the tentorium and posterior fossa with tonsillar herniation through foramen magnum. The ribbon‐like heterotopia and abnormal dysgyric overlying cortex are seen in all lobes. Note also the medial fusion of the dysmorphic thalami (d). Partial callosal agenesis with presence of a very thin rostrum and genu was noted. Individual 8 a‐d: Sagittal T1 (a, c) and axial T2 (b, d) weighted images at age 5 days (a, b) and 8 years (c, d). Note the large interhemispheric cyst communicating with the occipital horn of the right lateral ventricle (a, b), partial agenesis of the corpus callosum (a, c). Postnatally, the thin dysplastic cortex with shallow sulci and the ribbon‐like heterotopia is easily noted (b). The basal ganglia are severely hypoplastic and the thalami are fused (d). Note also the patchy white matter changes especially in the frontal lobes (d)
Figure 3. Imaging pattern at different ages. Prenatal ultrasound at 17 weeks of gestational age (a), prenatal MRI at 22 weeks gestational age (b), postnatal MRI at birth (c), at 3 months (d) and at 3 years and 9 months (e) of affected individual 5. Fetal ultrasound at 17 weeks shows a posterior interhemispheric cyst communicating with an enlarged right occipital horn (a). On follow‐up ultrasound, not shown, the dilation of the lateral ventricles increased. Even on the earliest ultrasound the ribbon‐like band heterotopia is visible at the ventricular border, though not fully recognized at that time. Also the overlaying cortex seems abnormal. Fetal MRI at 22 weeks (b): The T2 weighted image is in line with the previous ultrasound findings. The macrocephaly with the colpocephaly of the right occipital horn with extention into the posterior part of the interhemispheric space can be delineated. The periventricular migration disturbance is visible in both cerebral hemispheres, which already shows its ribbon‐like appearance. Postnatal MRI at the day of birth at 33 weeks and 3 days (c): This axial T2 weighted image shows the ribbon‐like heterotopia similar to the fetal MRI. The abnormal cortex is better visualized here. Periventricular T1 high signal areasare noted. MRI at 4 months of age (d) shows a clearer picture of the ribbon‐like band heterotopia. The heterotopia is thicker compared to the MRI at birth (c) and the overlying cortex shows a more clear “lumpy bumpy” appearance. The right occipital horn is slightly decreased in size after ventriculo‐peritoneal drain placement visible on this axial T2 weighted image. At 3 years and 9 months a follow‐up MRI (e) shows further thickening of the heterotopia which occupies a large part of white matter space. Note the unchanged abnormal appearance of the thalami and basal ganglia