Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti–Boltshauser syndrome)

Abstract

Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise nonprogressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS.

Genotype-Phenotype Analysis, Neuropsychological Assessment, and Growth Hormone Response in a Patient with 18p Deletion Syndrome

“…LAMA1 , encoding laminin alpha 1 subunit, plays a role in the development of retina, kidney, and cerebellum by negatively regulating the TGF-β pathway [Ning et al, 2014;Bryan et al, 2016]. LAMA1 biallelic mutations were identified in Poretti-Boltshauser syndrome patients characterized by cerebellar ataxia, intellectual disability, motor delay, language impairment, myopia, and retinal abnormalities [Bryan et al, 2016;Micalizzi et al, 2016;Vilboux et al, 2016]. Neuroimaging of these patients showed cerebellar dysplasia with cysts, an enlarged 4th ventricle, and hypoplasia of the cerebellar vermis [Aldinger et al, 2014;Micalizzi et al, 2016].…”

“…LAMA1 biallelic mutations were identified in Poretti-Boltshauser syndrome patients characterized by cerebellar ataxia, intellectual disability, motor delay, language impairment, myopia, and retinal abnormalities [Bryan et al, 2016;Micalizzi et al, 2016;Vilboux et al, 2016]. Neuroimaging of these patients showed cerebellar dysplasia with cysts, an enlarged 4th ventricle, and hypoplasia of the cerebellar vermis [Aldinger et al, 2014;Micalizzi et al, 2016]. Some of the clinical features in our patient, such as hypoplasia of cerebellar vermis, DandyWalker malformations, cognitive impairment, language and motor delay, may be caused by LAMA1 deletions [Hasi-Zogaj et al, 2015;Abdel Razek and Castillo, 2016;Giordano et al, 2016].…”

Prenatal detection of interstitial 18p11.31‐p11.22 microduplications: Phenotypic diversity and literature review

“…Eleven morbid genes exist in the 18p11 region ( 20,21 According to the literature review and database searching, there is no available pathogenic evidence for triplosensitivity associated with LAMA1. All fetuses in our report shared partial duplications of the LAMA1 locus.…”

The Cerebellum and Its Wrapping Meninge: Developmental Interplay between Two Major Structures

“…In this syndrome, the cerebellar cysts are not associated with supratentorial abnormalities 60 or with various inconstant abnormalities. 61,62 Ophthalmological problems could be associated. 61,63 This syndrome has been found to be related to mutations of LAMA1, [61][62][63] the gene that encodes the a 1 chain of laminin.…”

“…61,62 Ophthalmological problems could be associated. 61,63 This syndrome has been found to be related to mutations of LAMA1, [61][62][63] the gene that encodes the a 1 chain of laminin. Homozygous mice for which Lama1 gene has been invalidated die very early during development due to a lack of differentiation of Reichert membrane.…”