DeCure for Microphthalmia

Microphthalmia is a clinically and genetically heterogeneous disorder of eye development. A 1994 study of colobomatous microphthalmia in five families found the disorder to be an autosomal recessive trait in those pedigrees, with a relatively high incidence of that recessive allele reported in the Iranian Jewish community. A 2008 case report describes a one-week-old full-term female neonate with bilateral congenital microphthalmia as the only congenital anomaly present; the authors note the condition is uncommon and its management very challenging.

Genetic linkage studies have identified several loci but no causative mutations. A 2011 study of a Chinese family with autosomal-dominant congenital simple microphthalmia performed a whole-genome scan and found the most statistically significant linkage at marker D17S1824 (maximum LOD score 4.97), mapping the disease-causing gene to a 21.57-cM interval on chromosome 17p12-q12. However, no mutation or copy number variation was identified to be responsible for the phenotype in that pedigree. A 2013 study of a large autosomal-dominant simple microphthalmia pedigree from China, after excluding reported candidate loci, mapped the disorder to a new locus on chromosome 2q, with a maximum two-point LOD score of 3.290 at marker D2S2265, confining the gene to a 15-cM interval between D2S1890 and D2S347 on 2q11-14. The authors concluded that no mutation was found in either study to explain the microphthalmia.

A 2016 case report describes a 4-year-old Colombian male with syndromic microphthalmia-3, bilateral microphthalmia, short stature, neurodevelopmental delay, genital anomalies, and maternal exposure to glyphosate during pregnancy. Genetic testing detected a previously reported pathogenic heterozygous mutation in the SOX2 gene. The authors recommend that whenever a patient presents with bilateral microphthalmia, it must be determined whether it is isolated or syndromic, and genetic testing should be performed to offer effective genetic counselling. A 1995 paper discusses the microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene, but this is a molecular biology study not directly addressing the clinical disorder.

What is still missing is a clear understanding of the genetic basis for most cases of nonsyndromic microphthalmia, as linkage studies have identified loci but no causative mutations. No drug treatment is mentioned in any of these abstracts. The field lacks sufficient funding for large-scale sequencing of affected families, well-designed trials to test any potential interventions, and better patient stratification by genetic subtype to make sense of the heterogeneity.