Rare Saposin A deficiency: Novel variant and psychosine analysis.

Saposin A is a post-translation product of the prosaposin (PSAP) gene that serves as an activator protein of the galactocerebrosidase (GALC) enzyme, and is necessary for the degradation of certain glycosphingolipids. Deficiency of saposin A leads to a clinical picture identical to that of early-infantile Krabbe disease caused by GALC enzyme deficiency. Galactosylsphingosine, also known as psychosine, is a substrate of the GALC enzyme that is known to be elevated in classic Krabbe disease. We present the case of an 18-month-old male with clinical and radiological findings concerning for Krabbe disease who had preserved GALC enzyme activity and negative GALC gene sequencing, but was found to have a homozygous variant, c.257 T > A (p.I86N), in the saposin A peptide of PSAP. Psychosine determination on dried blood spot at 18 months of age was elevated to 12 nmol/L (normal <3 nmol/L). We present this case to add to the literature on the rare diagnosis of atypical Krabbe disease due to saposin A deficiency, to report a novel presumed pathogenic variant within PSAP, and to suggest that individuals with saposin A deficiency may have elevated levels of psychosine, similar to children with classic Krabbe disease due to GALC deficiency.

Mutation in the sixth immunoglobulin domain of L1CAM is associated with migrational brain anomalies.

OBJECTIVE: To describe the phenotype of a patient with classical features of X-linked L1 syndrome associated with novel brain malformations. METHODS: Diagnostic analysis included physical and dysmorphology examinations, MRI of the brain, and exome sequencing of the family trio. RESULTS: We report a 2.5-year-old boy with developmental delay, dysmorphic facies, and adducted thumbs. MRI of the brain showed a truncated corpus callosum and periventricular heterotopias associated with polymicrogyria (PMG). Variant segregation analysis with exome sequencing discovered a novel maternally derived hemizygous variant in exon 14 of the L1CAM gene (c.1759 G>C; p.G587R). CONCLUSIONS: This novel L1CAM mutation was located in the protein's sixth immunoglobin domain and involved glycine-587, a key residue in the structure of L1CAM because of its interactions with lysine-606, which indicates that any mutation at this site would likely affect the secondary structure and function of the protein. The replacement of the small nonpolar glycine residue with a large basic arginine would have an even more dramatic result. The presentation of periventricular nodular heterotopias with overlying PMG is very uncommon, and its association with L1CAM may provide insight into other similar cases. Furthermore, this presentation indicates the important role that L1CAM plays in neuronal migration and brain development and extends the phenotype associated with L1CAM-associated disorders.

Intrauterine exposure to mycophenolate mofetil and multiple congenital anomalies in a newborn: possible teratogenic effect.

There is very little data linking the use of immunomodulating agents following solid organ transplantation in pregnant women with specific congenital anomalies in the offspring. Here we report on a late preterm infant with multiple, nonsyndromic, congenital anomalies including microtia/anotia, cleft lip and palate, micrognathia, ocular hypertelorism, microphthalmia and cataracts, complex congenital heart disease, rib anomalies, and intestinal malrotation. The similarity of the complex anomalies in our case to other reported cases suggests that the abnormalities are likely due to mycophenolate mofetil alone or in combination with other immunosuppressive medications taken by the mother during pregnancy.