# Hemoglobin Disorders Associated with Neurological Impairment: First Report of ATR-X Syndrome and Recessive Congenital Methemoglobinemia Type II in Tunisia

## TL;DR

This paper reports the first cases of two rare hemoglobin-related disorders in Tunisia, linking them to neurological impairments through genetic analysis.

## Contribution

The study identifies ATRX and CYB5R3 mutations in Tunisian families, marking the first report of these disorders in the region.

## Key findings

- X-linked alpha-thalassemia with intellectual development was confirmed by the ATRX: p.Arg2131Gln mutation.
- Recessive congenital methemoglobinemia type II was confirmed by the CYB5R3: p.Ala179Thr mutation.
- These mutations were previously reported globally but are newly identified in the Tunisian population.

## Abstract

Hemoglobin disorders are among the most common inherited diseases worldwide. Their clinical manifestations range from anemia to more severe forms associated with neurological impairments. These complications can result as secondary consequences of the disease’s clinical manifestations or be directly linked to genetic mutations. In this study, we present two families with neurological impairments who were referred to us for complementary hematological and biochemical analyses. Complete blood count, methemoglobin level, and methemoglobin reductase activity were assessed. Molecular analyses were performed using whole-exome sequencing, and the segregation of the identified mutations was confirmed with direct sequencing. Their pathogenicity and conservation were evaluated using various bioinformatics tools. Clinical and hematological findings suggested X-linked alpha-thalassemia/impaired intellectual development syndrome in the first family and recessive congenital methemoglobinemia type II in the second. This was confirmed by the identification of pathogenic mutations ATRX: p.Arg2131Gln and CYB5R3: p.Ala179Thr, respectively. Although these variants have been previously reported worldwide, they were identified for the first time in our population. Our results contribute to the understanding of the pathogenesis of these rare disorders and provide a basis for diagnosis, treatment, and genetic counseling. The mechanisms by which these mutations contribute to neurological symptoms are discussed.