The Diagnostic Odyssey of a Biochemically Confirmed Case of ML II : The First Western Patient With LYSET Deficiency

ABSTRACT The LYSET gene encodes the LYSET transmembrane protein, which regulates lysosome biogenesis by activating the mannose‐6‐phosphate (M6P) pathway. This is an autosomal recessive, ultrarare, and severe progressive skeletal dysplasia with coarse facies, distended abdomen, short stature, and severe physical disability. In a diagnostic odyssey, we report a female patient, born in 2008, daughter of consanguineous parents, with hand contractures and a typical facial appearance since 5 months old. She was clinically diagnosed at 2 years old with contractures and severe dysplasia. Systolic murmur, thickening of mitral and aortic valves, and tricuspid regurgitation were observed. Nine enzymes showed increased levels in plasma, and seven showed decreased levels in fibroblasts. Abnormal sialic acid profile and GAGs (glycosaminoglycans) were detected in urine. No variants were identified during more than a decade of investigation. A whole‐genome analysis identified the homozygous nonsense variant NM_001098621.4:c.112C>T (p.Gln38Ter) in the LYSET gene. The patient had not been diagnosed before due to the recent association of the gene with the lysosomal hydrolase labeling pathway. She died in 2018 from respiratory causes. The discovery of the relationship between the LYSET gene and lysosomal biogenesis was determinative of the diagnostic conclusion. Cases of dysostosis multiplex can be highly challenging due to the rarity of the disease and its clinical similarity to mucopolysaccharidosis (MPS) and mucolipidosis II/III (MLII/III). This is the first western report of a challenging case of an extensive diagnostic odyssey and demonstrates that the LYSET gene must be considered in the differential diagnosis when M6P‐labeled lysosomal enzymes are altered.