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Study Indicates Lysosomal Disorder May Lead to Failure to Thrive in Infancy

Christina T. Loguidice
Published Online: Monday, Feb 23, 2015

The term failure to thrive refers to children whose weight or rate of weight gain is considerably lower than that of other age- and sex-matched children. It can have numerous etiologies, including medical causes (eg, gastrointestinal diseases, hormonal imbalances, psychological disorders) and environmental causes (eg, abuse, poverty). In some cases, the cause remains unknown. A study recently published in PLoS Genetics revealed that neonatal intestinal disorders resulting in failure to thrive may be caused by defects in the lysosomal system that occur before weaning. This is the first time such a connection has been made, potentially opening the door to new treatments.
 
The study investigators, led by Jaime García-Añoveros, PhD, associate professor, Department of Anesthesiology, Neurology and Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, found that mouse models lacking lysosomal proteins mucolipin-1 and mucoliptin-3 developed an intestinal disorder that caused pathological vacuolation of enterocytes, diminished apical endocytosis from the intestinal lumen, diarrhea, and failure to thrive from birth to weaning.
 
The investigators note that intestinal digestion during the nursing period is different from adult digestion and digestion after weaning. During the nursing period, proteins remain intact until they reach the intestinal lumen, where intestinal enterocytes richly endowed with endosomes and lysosomes facilitate the uptake and intracellular digestion of proteins. Upon weaning, mature intestinal enterocytes replace those rich in lysosomes, and these enterocytes instead absorb the amino acids produced when extracellular enzymes in the intestinal lumen digest proteins.
The mice that were missing mucolipin-1 and mucolipin-3, the lysosomal proteins normally expressed by enterocytes, were not able to properly digest the milk proteins and vacuolated pathologically within hours of birth and remained so until weaning.
 
“Ultrastructurally and chemically these fast-forming vacuoles resembled those that systemically appear in epithelial cells of mucolipidosis type IV (MLIV) patients, which bear mutations in Trpml1,” noted the investigators in their article.
 
Based on their findings, the authors surmise that infants with lysosome disorders may be affected with intestinal pathologies, including transient intestinal dysfunction leading to failure to thrive. More research will be needed to determine whether this sort of lysosomal dysfunction occurs in humans, but dysfunctional lysosomes have been implicated in numerous genetic disorders with a range of symptoms. Further investigation into how the lysosomal system impacts the intestines may just open the door to new and more effective interventions for infants whose fail to thrive is poorly understood.

Reference

Remis NN, Wiwatpanit T, Castiglioni AJ, Flores EN, Cantú JA, García-Añoveros J. Mucolipin co-deficiency causes accelerated endolysosomal vacuolation of enterocytes and failure-to-thrive from birth to weaning. PLoS Genet. 2014;10(12):e1004833.

Figure courtesy of PLoS, an open source journal.  (A–D) Hematoxylin and eosin (H&E) staining of paraffin-embedded sections of intestine reveals abnormal vacuolation in (A) Trpml3−/−;Trpml1−/− pups, but not in (C) wild type, (B) Trpml3−/− or (D) Trpml1−/− pups. (E,F) Periodic acid-Schiff (PAS) staining of paraffin-embedded sections of neonatal intestines reveals that (E) the vacuolated intestinal cells of Trpml3−/−;Trpml1−/− mice are not mucin-filled, goblet cells (labeled red), which show a distribution undistinguishable from (F) Trpml3−/−, (H) Trpml1−/− and (G) wild type controls. (I,J) PAS staining of adult intestines reveals (I) no vacuolation of enterocytes from Trpml3−/−;Trpml1−/− mice and no other signs of pathology when compared with (J) Trpml3−/− littermate and wild type controls. All scale bars are 100 µm. doi:10.1371/journal.pgen.1004833.g004

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