Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease caused by mutations in TYMP, the gene encoding for the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of thymidine and 2’-deoxyuridine and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. MNGIE is characterised by gastrointestinal dysmotility, cachexia, peripheral neuropathy, ophthalmoplegia, ptosis and leukoencephalopathy. The disease is progressively degenerative and leads to death at an average age of 37.6 years. Patients invariably encounter misdiagnoses, diagnostic delays, and non-specific clinical management. Despite its rarity, MNGIE has invoked much interest in the development of therapeutic strategies, mainly because it is one of the few mitochondrial disorders where the molecular abnormality is metabolically and physically accessible to manipulation. This review provides a résumé of the current diagnosis and treatment approaches and aims to increase the clinical awareness of MNGIE and thereby facilitate early diagnosis and timely access to treatments, before the development of untreatable and irreversible organ damage.

Aim: This is the first computer-assisted study focused on the craniofacial features of the intellectual disability (ID)/developmental delay (DD) syndrome related to haploinsufficiency of the SETD5 gene (SET domain-containing protein 5, MIM#615743), which is a chromatin regulator. The purpose of this novel research is to better delineate the facial phenotype of this condition and identify the associated dysmorphic features to consider for clinical diagnosis.

Methods: A total of 18 2D frontal images of previously published pediatric individuals (aged 1-14 years, Caucasian ethnicity) with SETD5 mutations (SETD5, cohort 1) were uploaded to the RESEARCH application of the Face2Gene online platform (V.19.1.3) (FDNA Inc., Boston, MA, USA). Images from this group of patients were compared with 36 photos of individuals with two other known chromatin disorders, specifically KBG (KBGS, cohort 2, 18 images) and Koolen-de Vries syndromes (KdVS, cohort 3, 18 images), which share with the SETD5-related ID syndrome a very similar facial gestalt and peculiar dysmorphisms. An additional cohort of 18 unaffected controls that were matched for age and ethnicity (Ctrl., controls, cohort 4) was also included in the comparison experiment.

Results: Results obtained from the binary comparison analysis were expressed in terms of Area Under the Curve and its Receiver Operating Characteristic curve for aggregated splits. A high facial overlap between the SETD5-related phenotype and KBGS was demonstrated. Other conditions considered for the study were well recognized by the system and differentiated using the unaffected controls.

Conclusion: This study confirms the presence of distinctive dysmorphic features that characterize the SETD5-related facial phenotype, providing observations about its possible role in facial morphogenesis.