106 Diversity of clinical phenotype of patients with pyruvate dehydrogenase deficiency due to PDHA1 gene mutations

Abstract

regulated by a numerous enzymes that modify and transfer sugar residues to amino acid side chains.Over 150 different types of CDGs have been described. The most common are phosphomannomutase 2 (PMM2-CDG) and -1,3-glucosyltransferase deficiency (ALG6-CDG). Symptoms common to all CDGs are seizures, psychomotor delay, hypotonia, feeding disorders, liver disease and coagulopathy. Diagnosis is based on clinical presentation and sialotransferrin profiling and confirmed by gene analysis. Early diagnosis is critical in disorders for which specific therapy exists.Female infant was born from a third, uneventful pregnancy. Parents are not related and older siblings are healthy. Since birth, the infant was severely hypotonic and exhibited developmental delay, feeding disorder and failure to thrive. At the age of three months she was transferred to our Department for further work-up. At that time, she had low body weight (4314 g, 1.c) and was hypotonic with reduced spontaneous movements. We had noticed dysmorphic features-hypertelorism, micrognathia, abnormal ears, flattened nose, rhizomelic limbs, inverted mamillae and abnormal fat distribution. She was fed with elemental infant formula through the nasogastric tube. The patient had small intestine malrotation that manifested with recurrent vomiting which was resolved after surgical intervention. She developed thrombosis of the brain venous sinuses due to coagulopathy (low concentration of antithrombin III, protein C and coagulation factors IX and XI). She was also diagnosed with hypothyreosis and suffered from generalised oedema with hypoalbuminemia as a consequence of protein losing enteropathy, treated with albumin infusions. Protein losing enteropathy improved on elemental formula.Severe epilepsy was drug-resistant. Sialotransferrin profiling pointed towards a glycosylation defect (elevated di-sialotransferrins, lowered penta-and tetra-sialotransferrins). Gene analysis revealed biallelic mutations in the ALG6 gene, which codes for glycosilation enzyme -1,3-glucosyltransferase.ALG6-CDG has a recognizable phenotype characterised by hypotonia and proximal muscle weakness, extrapyramidal signs, pharmacoresistant epilepsy, coagulopathy, protein losing enteropathy and dysmorphic features. Described patients had poor prognosis. There is no specific therapy available. Early diagnosis is important to predict and treat symptoms and to stop diagnostic odyssey. It enables prenatal diagnostics in future pregnancies.