Rare variants in PPFIA3 cause delayed development, intellectual disability, autism, and epilepsy.

PPFIA3 encodes the Protein-Tyrosine Phosphatase, Receptor-Type, F Polypeptide-Interacting Protein Alpha-3 (PPFIA3), which is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family involved in synaptic vesicle transport and presynaptic active zone assembly. The protein structure and function are well conserved in both invertebrates and vertebrates, but human diseases related to PPFIA3 dysfunction are not yet known. Here, we report 14 individuals with rare mono-allelic PPFIA3 variants presenting with features including developmental delay, intellectual disability, hypotonia, autism, and epilepsy. To determine the pathogenicity of PPFIA3 variants in vivo , we generated transgenic fruit flies expressing either human PPFIA3 wildtype (WT) or variant protein using GAL4-UAS targeted gene expression systems. Ubiquitous expression with Actin-GAL4 showed that the PPFIA3 variants had variable penetrance of pupal lethality, eclosion defects, and anatomical leg defects. Neuronal expression with elav-GAL4 showed that the PPFIA3 variants had seizure-like behaviors, motor defects, and bouton loss at the 3 rd instar larval neuromuscular junction (NMJ). Altogether, in the fly overexpression assays, we found that the PPFIA3 variants in the N-terminal coiled coil domain exhibited stronger phenotypes compared to those in the C-terminal region. In the loss-of-function fly assay, we show that the homozygous loss of fly Liprin- α leads to embryonic lethality. This lethality is partially rescued by the expression of human PPFIA3 WT, suggesting human PPFIA3 protein function is partially conserved in the fly. However, the PPFIA3 variants failed to rescue lethality. Altogether, the human and fruit fly data reveal that the rare PPFIA3 variants are dominant negative loss-of-function alleles that perturb multiple developmental processes and synapse formation.

Brown-Vialetto-Van Laere Syndrome as a Mimic of Neuroimmune Disorders: 3 Cases From the Clinic and Review of the Literature.

We present 3 patients identified at 2 different institutions with Brown-Vialetto-Van Laere syndrome. Each patient was initially diagnosed with a neuroimmune disorder for a period of a few weeks to a few months. In each case, genetic analysis revealed mutations in one of the riboflavin transporters, confirming Brown-Vialetto-Van Laere syndrome. It is likely that Brown-Vialetto-Van Laere syndrome is more common than previously reported, and because it mimics neuroimmune disorders, it may be misdiagnosed as such. It shares many features with diseases such as chronic inflammatory demyelinating neuropathy, may present with positive cerebrospinal fluid antibody titers, and may transiently respond to intravenous immunoglobulin. We review the literature on Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome, 2 riboflavin transporter disorders, looking for clinical presentations that may lead to confusion with neuroimmune disorders. We emphasize the importance of correctly diagnosing the disease, as its treatment is relatively benign and will stop progression of the disease and may even reverse it.