Case Report: An Adult Case of Poretti-Boltshauser Syndrome Diagnosed by Medical Checkup.

This report describes an adult case of Poretti-Boltshauser syndrome (PTBHS) and with novel variants of LAMA1. A 65-year-old Japanese woman with cerebellar malformation identified during a medical checkup was referred to our hospital. Subsequently, neurological examination, brain imaging, and genetic investigation via whole-exome sequencing were performed. The patient presented with mild cerebellar ataxia and intellectual disability. Magnetic resonance imaging revealed cerebellar dysplasia and cysts and an absence of molar tooth sign. Genetic analysis revealed a novel homozygous variant of c.1711_1712del in LAMA1 (NM_005559.4). Most cases with PTBHS are reported in pediatric patients; however, our patient expressed a mild phenotype and was undiagnosed until her 60 s. These findings suggest that PTBHS should be considered in not only pediatric cerebellar dysplasia but also adult cerebellar ataxia with mild presentation.

Phenotypic spectrum of patients with Poretti-Boltshauser syndrome: Patient report of antenatal ventriculomegaly and esophageal atresia.

Poretti-Boltshauser syndrome (PTBHS) is an autosomal recessive disorder characterized by cerebellar dysplasia with cysts and an abnormal shape of the fourth ventricle on neuroimaging, due to pathogenic variants in the LAMA1 gene. The clinical spectrum mainly consists of neurological and ophthalmological manifestations, including non-progressive cerebellar ataxia, oculomotor apraxia, language impairment, intellectual disability, high myopia, abnormal eye movements and retinal dystrophy. We report a patient presenting with ventriculomegaly on antenatal neuroimaging and a neonatal diagnosis of Type III esophageal atresia. She subsequently developed severe myopia and strabismus with retinal dystrophy, mild developmental delay, and cerebellar dysplasia. Genetic investigations confirmed PTBHS. This report confirms previous reports of antenatal ventriculomegaly in PTBHS patients and documents a so far unreported occurrence of esophageal atresia in PTBHS. We additionally gathered phenotype and genotype descriptions of published cases in an effort to better define the spectrum of PTBHS.

Variability of retinopathy consequent upon novel mutations in LAMA1.

PURPOSE: Bi-allelic mutations in LAMA1 (laminin 1) (OMIM # 150320) cause Poretti-Boltshauser Syndrome (PTBHS), a rare non-progressive cerebellar dysplasia disorder with ophthalmic manifestations including oculomotor apraxia, high myopia, and retinal dystrophy. Only 38 variants, nearly all loss of function have been reported. Here, we describe novel LAMA1 variants and detailed retinal manifestations in two unrelated families. METHODS: Whole-genome sequencing was conducted on three siblings of a consanguineous family with myopia and retinal dystrophy and on a child from an unrelated non-consanguineous couple. Clinical evaluation included full ophthalmic examination, detailed colour, autofluorescence retinal imaging, retinal optical coherence tomography (OCT), fluorescein angiography under anesthesia, and pattern and full-field electroretinography. RESULTS: Genetic analysis revealed a novel homozygous LAMA1 frameshift variant, c.1492del p.(Arg498Glyfs *25), in the affected siblings in family 1 and a novel frameshift c.3065del p.(Gly1022Valfs *2) and a deletion spanning exons 17-23 in an unrelated individual in family 2. Two of the three siblings and the unrelated child had oculomotor apraxia in childhood; none of the siblings had symptoms of other neurological dysfunction as adults. All four had myopia. The affected siblings had a qualitatively similar retinopathy of wide-ranging severity. The unrelated patient had a severe abnormality of retinal vascular development, which resulted in vitreous haemorrhage and neovascular glaucoma in the left eye and a rhegmatogenous retinal detachment in the right eye. CONCLUSIONS: This report describes the detailed retinal structural and functional consequences of LAMA1 deficiency in four patients from two families, and these exhibit significant variability with evidence of both retinal dystrophy and abnormal and incomplete retinal vascularisation.

Antenatal presentation and supratentorial brain abnormalities in a child with Poretti-Boltshauser syndrome.

Autosomal recessively inherited Poretti-Boltshauser syndrome (PBS) with loss-of-function variants in the LAMA1 gene are characterized by motor and speech developmental delay, high myopia, and cerebellar dysplasia with cysts without any supratentorial abnormalities on neuroimaging. There is no muscular involvement. We report an eight months child with genetically confirmed PBS who presented with antenatally detected ventriculomegaly and had global developmental delay, focal seizures, myopic degeneration of fundi. Neuroimaging showed asymmetric ventriculomegaly and lissencephaly in bilateral temporal horns along with cerebellar dysplasia and cysts. These supratentorial abnormalities and antenatal presentation as ventriculomegaly have not been reported earlier. Child also had a small subaortic ventricular septal defect.

Identification of LAMA1 mutations ends diagnostic odyssey and has prognostic implications for patients with presumed Joubert syndrome.

Paediatric neurology syndromes are a broad and complex group of conditions with a large spectrum of clinical phenotypes. Joubert syndrome is a genetically heterogeneous neurological ciliopathy syndrome with molar tooth sign as the neuroimaging hallmark. We reviewed the clinical, radiological and genetic data for several families with a clinical diagnosis of Joubert syndrome but negative genetic analysis. We detected biallelic pathogenic variants in LAMA1, including novel alleles, in each of the four cases we report, thereby establishing a firm diagnosis of Poretti-Boltshauser syndrome. Analysis of brain MRI revealed cerebellar dysplasia and cerebellar cysts, associated with Poretti-Boltshauser syndrome and the absence of typical molar tooth signs. Using large UK patient cohorts, the relative prevalence of Joubert syndrome as a cause of intellectual disability was 0.2% and of Poretti-Boltshauser syndrome was 0.02%. We conclude that children with congenital brain disorders that mimic Joubert syndrome may have a delayed diagnosis due to poor recognition of key features on brain imaging and the lack of inclusion of LAMA1 on molecular genetic gene panels. We advocate the inclusion of LAMA1 genetic analysis on all intellectual disability and Joubert syndrome gene panels and promote a wider awareness of the clinical and radiological features of these syndromes.

A mosaic intragenic microduplication of LAMA1 and a constitutional 18p11.32 microduplication in a patient with keratosis pilaris and intellectual disability.

The application of array-based comparative genomic hybridization and next-generation sequencing has identified many chromosomal microdeletions and microduplications in patients with different pathological phenotypes. Different copy number variations are described within the short arm of chromosome 18 in patients with skin diseases. In particular, full or partial monosomy 18p has also been associated with keratosis pilaris. Here, for the first time, we report a young male patient with intellectual disability, diabetes mellitus (type I), and keratosis pilaris, who exhibited a de novo 45-kb microduplication of exons 4-22 of LAMA1, located at 18p11.31, and a 432-kb 18p11.32 microduplication of paternal origin containing the genes METTL4, NDC80, and CBX3P2 and exons 1-15 of the SMCHD1 gene. The microduplication of LAMA1 was identified in skin fibroblasts but not in lymphocytes, whereas the larger microduplication was present in both tissues. We propose LAMA1 as a novel candidate gene for keratosis pilaris. Although inherited from a healthy father, the 18p11.32 microduplication, which included relevant genes, could also contribute to phenotype manifestation.

TGFB1 and LAMA1 gene polymorphisms in children with high myopia.

OBJECTIVE: To investigate TGFB1 and LAMA1 gene polymorphisms in children with high myopia in order to determine the genetic basis of large myopic shifts causing severe visual impairment and complications. METHODS: Seventy-four children with high myopia (≥6 diopters [D]; study group) and 77 emmetropic children (±0.5D; control group) were included. Genetic and polymorphism analyses were performed in the Medical Genetics Laboratory using DNA purified from the patients' blood samples. RESULTS: Mean ages of the patients were 7.1±3 (3-13) and 9.6±1.8 (6-13) years in the study and control groups, respectively. Mean refraction in the high myopia group were -10.1±4.3D in the right and -8.9±3.6D in the left eye. LAMA1 gene analysis of the study group revealed heterozygous mutations in 34 patients (45.9%), homozygous mutations in 25 patients (33.8%), and no mutations in the remaining 15 patients (20.3%). In the control group, there were 31 subjects (40.3%) with heterozygous, 27 (35.1%) with homozygous LAMA1 mutations, and no mutations in 19 (24.7%) (p=0.73). TGFB1 gene analysis showed heterozygous mutations in 32 (43.2%) and homozygous mutations in 10 patients (13.5%) in the study group, while 32 patients (43.2%) had no mutations. In the control group, 35 subjects (45.5%) had heterozygous, 8 (10.4%) had homozygous, and 34 (44.1%) had no TGFB1 mutations (p=0.36). CONCLUSION: This is the first study to simultaneously examine two genes in high myopia in a Turkish population. However, we observed no significant differences in TGFB1 and LAMA1 gene polymorphisms in patients with high myopia compared to healthy subjects.

Effect of a Single Nucleotide Polymorphism in the LAMA1 Promoter Region on Transcriptional Activity: Implication for Pathological Myopia.

PURPOSE: To elucidate the role of the protein coding laminin α1 (LAMA1) gene in pathological myopia (PM) at the transcriptional level. To achieve this, the binding affinity of single nucleotide polymorphism (SNP) rs2089760-located on the LAMA1 promoter gene-to human fetal scleral fibroblast (HFSF) nucleoprotein was investigated and its effect on LAMA1 transcriptional initiation activity was analyzed. METHODS: Binding interactions of the HFSF nucleoprotein and biotin-labeled SNP rs2089760 probe were investigated by amplifying the LAMA1 promoter gene and performing overlap extension polymerase chain reaction (PCR) to obtain the G/A mutation of LAMA1 SNP rs2089760. Recombinant adenovirus vectors, Ad5f11p-pLAMA1SNPa-Luc2, Ad5f11p-pLAMA1SNPg-Luc2, and Ad5f11p-CMV-RLuc, were constructed. Fluorescence intensity ratios of firefly luciferase (FLuc) and renilla luciferase (RLuc) vectors were measured 48 h after HFSF infection. RESULTS: Both specific and mutant probes banded precisely with HFSF nucleoprotein. The intensity value of the mutant probe was significantly lower than that of the specific probe (p < 0.05). HFSFs were successfully infected by the recombinant adenoviruses. The FLuc/RLuc fluorescence intensity ratio of Ad5f11p-pLAMA1SNPa-Luc2 (0.0238 ± 0.0009) was significantly lower than that of Ad5f11p-pLAMA1SNPg-Luc2 (0.0281 ± 0.0015) (p < 0.05). CONCLUSIONS: It is highly likely that SNP rs2089760 in the LAMA1 promoter region is located at the transcription factor binding site. The SNP rs2089760 G > A mutation reduces transcription factor binding ability and transcriptional initiation activity, and negatively regulates gene transcription of LAMA1. We suggest that LAMA1 SNP rs2089760 plays an important role in the development of PM.