Abstract
A term male infant, born to a 20-year-old primigravida, was admitted for respiratory distress. A prenatal ultrasound examination showed shortened long bones. The parents were orthodox Jews and there was history of second-degree consanguinity. A deceased paternal cousin was diagnosed with mucolipidosis. Birthweight (2175 g), length, and head circumference were below the third percentile. On physical examination, the infant had a prominent forehead with a large fontanelle, low set ears, prominent eyes, telecanthus, maxillary hypoplasia, gingival hyperplasia, a narrow chest, distended abdomen, short limbs, bowing of the lower extremities, and generalized hypotonia. Radiographs revealed a bell-shaped chest, small thoracic cavity, small lung volumes with bilateral rib fractures (Figure, C ), diffuse osteopenia and, subperiosteal bone destruction and new formation, and decreased size of the vertebral bodies (Figure, A-G). Lysosomal enzyme hydrolase levels in plasma were high, with normal activity in leukocytes. Urinary glycosaminoglycans and oligosaccharides were negative and the diagnosis of mucolipidosis II was confirmed on genetic testing. Mucolipidosis II alpha/beta or inclusion cell disease is an autosomal-recessive lysosomal storage disorder caused by a mutation of the gene GNPTAB (alpha and beta subunits of N-acetylglucosamine-1-phosphotransferase), which is located on chromosome 12q23.2. This alteration leads to a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase that normally transfers phosphate to mannose residues. This deficiency disrupts the normal post-translational modification of lysosomal acid hydrolases and leads to increased extracellular secretion and a profound intracellular deficiency of acid hydrolases, thereby leading to accumulation of substrates, which is the usual pathology in lysosomal storage diseases. Because it is characterized by the presence of vacuole-like inclusions in lymphocytes it is also called inclusion cell disease. In early infancy, radiographic features may resemble rickets or hyperparathyroidism with decreased bone mineralization, periosteal “cloaking,” ossification delay, epiphyseal dysplasia, platyspondyly (butterfly or anterior beaking) of the vertebral bodies, wide oar-shaped ribs, hypoplasia of ilea with shallow acetabular fossae, and pelvic dysplasia. Because this disorder is progressive, later signs may include sclerosis, stippling, and joint restriction and other multisystem effects such as severe neuropsychomotor developmental disorder. Potential management of several lysosomal storage disorders, including mucopolysaccharidosis, includes enzyme replacement therapy, enzyme enhancement therapeutics, substrate reduction therapy, small molecule therapy, hematopoietic stem cell transplantation, gene therapy, and clustered regularly interspaced short palindromic repeats based genome editing. In mucolipidosis II alpha/beta, treatment such as hematopoietic stem cell transplantation, even when instituted in the first few months of life, have not proven to be beneficial. Some of the difficulties encountered are related to the inability of genome edited cells or genome editing machinery to cross the blood brain barrier and early diagnosis and treatment. Other reasons for limited improvement after the delivery of active phosphotransferase enzyme after hematopoietic stem cell transplantation could be due to the number of pathways affected. Studies on ultrasound-mediated blood-brain barrier disruption, cell penetrating peptides, and nanoparticle delivery systems are ongoing. At present, treatment is supportive.
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