LAMA1 – Poretti-Boltshauser Syndrome

Autosomal recessive Poretti-Boltshauser syndrome (PBS; MONDO:0014419) is characterized by non-progressive cerebellar dysplasia with cysts, ataxia, intellectual disability and oculomotor apraxia due to biallelic pathogenic variants in LAMA1 (HGNC:6481). Initial multi-family studies identified loss-of-function variants in 14 of 15 unrelated families (18 probands) with PBS, with a recurrent founder frameshift allele, and no LAMA1 variants in 27 other cerebellar dysplasia cases, establishing a specific gene-disease link ([PMID:26932191]).

Genetic evidence supports autosomal recessive inheritance with segregation of biallelic LAMA1 alleles in consanguineous and non-consanguineous pedigrees. Across published reports, over 30 unrelated probands harbor homozygous or compound heterozygous LoF changes, including frameshift, nonsense, canonical splice-site, and exon-level deletions. The recurrent c.2935del (p.Arg979fsTer) variant arose independently in six families on a shared haplotype, consistent with a founder effect ([PMID:26932191]).

The phenotypic spectrum of PBS includes cerebellar dysplasia with cysts, ventriculomegaly, global developmental delay, focal seizures, high myopia, retinal dystrophy, oculomotor apraxia and variable supratentorial anomalies. Intrafamilial variability has been noted: some patients lack cerebellar cysts or present antenatally with ventriculomegaly, while others exhibit esophageal atresia or late-onset mild ataxia ([PMID:34666927], [PMID:36592689]).

Functional studies demonstrate that LAMA1 deficiency disrupts basement membrane integrity and neuronal migration. Conditional Lama1 knockout mice display cerebellar hypoplasia, glial disorganization and reduced granule-cell proliferation, recapitulating human PBS features ([PMID:21983115]). Patient-derived fibroblasts and neuronal cells show impaired adhesion, cytoskeletal dynamics and increased apoptosis, linking LAMA1 loss to defective cell migration in human lamininopathies ([PMID:27095636]).

No significant conflicting evidence has been reported; one atypical PBS-like case lacked LAMA1 mutations but displayed divergent imaging features, underscoring diagnostic specificity rather than refuting the association ([PMID:26932191]).

Together, genetic and experimental data support a Strong ClinGen classification for LAMA1-associated PBS. The identification of biallelic LoF variants and concordant animal and cellular models reinforces diagnostic testing for LAMA1 in patients with cerebellar dysplasia and oculomotor apraxia. Key take-home: targeted genetic analysis of LAMA1 enables definitive diagnosis and informs genetic counseling for PBS.

References

• European Journal of Human Genetics • 2016 • Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome) PMID:26932191
• Matrix Biology • 2012 • Laminin α1 is essential for mouse cerebellar development PMID:21983115
• Journal of Medical Genetics • 2016 • Cystic cerebellar dysplasia and biallelic LAMA1 mutations: a lamininopathy associated with tics, obsessive compulsive traits and myopia due to cell adhesion and migration defects PMID:27095636

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