Paganini-Miozzo Syndrome

A number sign (#) is used with this entry because of evidence that Paganini-Miozzo syndrome (MRXSPM) is caused by hemizygous mutation in the HS6ST2 gene (300545) on chromosome Xq26. One such family has been reported.

Description

Paganini-Miozzo syndrome (MRXSPM) is a neurodevelopmental disorder characterized by global developmental delay, impaired intellectual development, high myopia, and mild dysmorphic facial features (summary by Paganini et al., 2019)

Clinical Features

Paganini et al. (2019) reported 2 monozygotic Italian twin brothers with a syndromic neurodevelopmental disorder. The 2 boys and their unaffected brother, who were part of a triplet dichorionic-triamniotic pregnancy resulting from in vitro fertilization, were born at 30 weeks' gestation due to fetal distress. The 2 affected boys showed severely delayed psychomotor development, with walking at age 2 years and poor speech at age 5. Both had high myopia at -6 diopters, compared to -0.75 diopters for their unaffected brother, as well as chorioretinopathy. The affected boys also had febrile seizures in the first year of life that later resolved; brain imaging showed mildly enlarged lateral ventricles. Mild dysmorphic features included triangular face, large forehead, deep-set eyes, downslanting palpebral fissures and eyebrows, thin lips with downturned corners of the mouth, slight prognathism, pointed chin, and small, low-set, malrotated ears. At age 10 years, the patients had feeding difficulties and urinary incontinence. Laboratory studies showed mildly increased serum lactate and low glycemic scores.

Inheritance

The transmission pattern of MRXSPM in the family reported by Paganini et al. (2019) was consistent with X-linked recessive inheritance.

Molecular Genetics

In 2 Italian monozygotic twin brothers with MRXSPM, Paganini et al. (2019) identified a hemizygous missense mutation in the HS6ST2 gene (G306R; 300545.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother and was not present in the unaffected brother. The variant was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. Molecular modeling predicted that the mutation could change the structure of the enzyme, causing both a modification of enzyme activity as well as intracellular mislocalization of the protein. In vitro functional expression studies in HEK293 cells showed that the mutant protein was expressed normally, but had significantly reduced enzymatic activity (about 40% compared to wildtype). Paganini et al. (2019) noted that low heparan sulfate sulfation levels have been implicated in defective development of the mammalian visual system.