Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA): An Unconventional Mitochondrial Disorder.

Alessia Indrieri,Brunella Franco

doi:10.3390/genes12020263

Abstract

Mitochondrial disorders, although heterogeneous, are traditionally described as conditions characterized by encephalomyopathy, hypotonia, and progressive postnatal organ failure. Here, we provide a systematic review of Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA), a rare, unconventional mitochondrial disorder which presents as a developmental disease; its main clinical features include microphthalmia with different degrees of severity, linear skin lesions, and central nervous system malformations. The molecular basis of this disorder has been elusive for several years. Mutations were eventually identified in three X-linked genes, i.e., HCCS, COX7B, and NDUFB11, which are all endowed with defined roles in the mitochondrial respiratory chain. A peculiar feature of this condition is its inheritance pattern: X-linked dominant male-lethal. Only female or XX male individuals can be observed, implying that nullisomy for these genes is incompatible with normal embryonic development in mammals. All three genes undergo X-inactivation that, according to our hypothesis, may contribute to the extreme variable expressivity observed in this condition. We propose that mitochondrial dysfunction should be considered as an underlying cause in developmental disorders. Moreover, LSDMCA should be taken into consideration by clinicians when dealing with patients with microphthalmia with or without associated skin phenotypes.

Highlights

An Historical PerspectiveIn the early 1990s, females with a specific phenotypic combination of short stature with developmental abnormalities, including microphthalmia and linear skin defects of the face and neck, were reported
The condition defined by the clinical features observed in females was denominated Microphthalmia with Linear Skin defects (MLS) syndrome (MIM # 309801)
Given the presence of aborted fetuses in familial cases and the absence of males with X-chromosomal rearrangements and a classical MLS phenotype, it was defined as an X-linked dominant male-lethal trait (alternatively named Microphthalmia Dermal Aplasia and Sclerocornea (MIDAS))

Summary

Introduction

In the early 1990s, females with a specific phenotypic combination of short stature with developmental abnormalities, including microphthalmia and linear skin defects of the face and neck, were reported. Given the presence of aborted fetuses in familial cases and the absence of males with X-chromosomal rearrangements and a classical MLS phenotype, it was defined as an X-linked dominant male-lethal trait (alternatively named Microphthalmia Dermal Aplasia and Sclerocornea (MIDAS)). This condition was subsequently demonstrated to be genetically heterogeneous and, following identification of three responsible genes, has been renamed Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA) 1, 2, and 3 (OMIM # 309801, OMIM # 300887, and OMIM # 300952), respectively. There is still room for additional causative genes as mutation analysis has demonstrated that not all reported cases can be explained by the causative genes so far described (BF, unpublished)

The Molecular Basis of LSDMCA

The Clinical Spectrum of LSDMCA

The Role of X-Chromosome and X-Chromosome Inactivation

Findings

LSDMCA as an Unconventional Mitochondrial Disorder