Band-like calcification with simplified gyration and polymicrogyria: further delineation of phenotype and review of literature

Case Report: Microcephaly and abnormal neurological findings in newborns, together with intracranial calcification are indicative for intrauterine infection as well as for a subgroup of Aicardi-Goutières Syndrome. We report on a girl, born as the first child of nonconsanguineous Turkish parents. At birth, a microcephaly was noted and she developed nonresponsive seizures at the second day of life. A brain MRI showed hyperintense signals in the deep cortical gray matter and the thalami concordant with calcifications resulting from a congenital infection or intracerebral bleeding. Laboratory testing was normal despite for slightly elevated liver enzymes and a recurrent thrombocytopenia. A congenital infection was ruled out. Mutation analysis of genes associated with Aicardi-Goutières Syndrome was negative. A preliminary diagnose of an atypical Aicardi-Goutières Syndrome was made.

Over the course of the disease the girl developed severe intellectual disability and tetraspasticity. A brain MRI done at the age of 9 months indicated simplified gyration in addition to the known calcifications.

To elucidate the molecular basis of the disease we performed exome sequencing. We detected a homozygous 22 base pair deletion in OCLN predicting a frameshift and premature truncation of the protein. Only very recently, mutations in OCLN have been associated with an autosomal recessive neurodegenerative disorder characterized by band-like calcification and simplified gyration and polymicrogyria (BLC-PMG). So far, nine patients with BLC-PMG tested positive for OCLN mutations have been reported and seven with a suggestive BLC-PMG phenotype but unclear genetic status. This case highlights, that rare but clinically recognizable phenotypes predestined for single gene diagnostics often remain undiagnosed and are than picked up by systematic approaches such as exome sequencing. To increase awareness and provide diagnostic guidance we present a clinical description of all reported BLC-PMG cases highlighting the similarities and differences with respect to Aicardi-Goutières Syndrome.