EXPANDING PHENOTYPIC DIVERSITY OF PRUNE1 RELATED DISORDERS: AN EXPERIENCE OF FOUR CASES IN A TERTIARY CENTER

OBJECTIVES: PRUNE1(Prune exopolyphosphatase-1),a member of phosphodiesterase superfamily,is a gene responsible for normal cortical development.Biallelic loss-of-function variants of this gene lead to the disease NMIHBA(OMIM#617481;neurodevelopmental disorder with microcephaly,hypotonia,variable brain abnormalities).The main clinical symptoms are developmental delay,early onset hypotonia resulting in spastic/flask quadriparesis and epilepsy. Signs of spinal motor neuron involvement as a rare presentation also fortify the phenotypic heterogenity of the disease.In our case series, we aimed to emphasize the phenotypic diversity of PRUNE1 related disorders.

MATERIALS and METHODS: Whole exome(Case1/2/3) or genome(Case4) sequencing were performed.Karyotype analysis,microarray CGH and SMN gene analysis were among other genetic tests applied before.

RESULTS: Common features of our cases were profound developmental delay, generalized muscle weakness and epilepsy with progressive disease course as summarized in Table-1. All cases needed early respiratory and nutritional support.The most common seizure type was epileptic spasm.All cases had microcephaly(except case2) with mild facial dysmorphology(except Case1).Major brain abnormalities were diffuse brain atrophy ± ventriculomegaly and delayed myelination with thin corpus callosum.Early onset hypotonia with quadriparesis(spastic/flask) and skeletal deformities were pervasive neurological signs suggesting neuromuscular involvement.Electromyography of Case3 and 4 displayed neurogenic discharges with denervation.CK levels were in a range of 347-1940 IU/L.The most common variant in PRUNE1 gene was homozygous c.316 G > A(p.D106N) variant.

CONCLUSION: Although NMIHBA is the core phenotype of PRUNE1 related disorders, PRUNE1 mutations should also be considered in a patient with congenital hypotonia related to elevated CK levels and neurogenic EMG findings.Also c.316 G > A(p.D106N) may be common variant in Turkish population.