Intranasal dexmedetomidine and intravenous ketamine for procedural sedation in a child with alpha-mannosidosis: a magic bullet?

BACKGROUND: Procedural sedation is increasingly needed in pediatrics. Although different drugs or drugs association are available, which is the safest and most efficient has yet to be defined, especially in syndromic children with increased sedation-related risk factors. CASE REPORT: we report the case of a five-year-old child affected by alpha-mannosidosis who required procedural sedation for an MRI scan and a lumbar puncture. We administered intranasal dexmedetomidine (4 µg/kg) 45 min before intravenous cannulation, followed by one bolus of ketamine (1 mg/kg) for each procedure. The patient maintained spontaneous breathing and no desaturation or any complication occurred. CONCLUSION: intranasal dexmedetomidine and intravenous ketamine could be a feasible option for MRI and lumbar puncture in children with alpha-mannosidosis needing sedation.

The effects of early and late bone marrow transplantation in siblings with alpha-mannosidosis. Is early haematopoietic cell transplantation the preferred treatment option?

This article documents both the neurological and physical outcomes of the first published set of siblings undergoing transplantation at differing ages for α-mannosidosis. The older brother, the index case, was diagnosed at the age of 3 years and underwent transplantation at 13 years for the treatment of increasing somatic problems and recurrent infections. The younger brother had undergone transplantation pre-symptomatically at 6 months of age. Their clinical, radiological and developmental outcomes are documented and compared with the previous published cases, with the case for early transplantation being weighted against other potential therapies.

In utero transplantation of monocytic cells in cats with alpha-mannosidosis.

BACKGROUND: Lysosomal storage diseases are devastating illnesses, in large part because of their neurologic consequences. Because significant morbidity occurs prenatally, in utero (IU) therapy is an attractive therapeutic approach. METHODS: We studied the feasibility and efficacy of IU injections of monocytic cells (derived from normal marrow) in feline alpha-mannosidosis. Heterozygous cats were interbred to produce affected (homozygous) and control (heterozygous and wild-type) offspring. Thirty-seven pregnancies were studied in which fetuses were transplanted intraperitoneally (1x10 cells/kg recipient) at gestational days 27 to 33 and then each week for 2 weeks (term=63 days). After birth, affected kittens were evaluated clinically and pathologically, tissue alpha-mannosidase levels were assayed, and in many studies, the numbers of alpha-mannosidase-containing cells were enumerated. When male donor cells were transplanted into female recipients, engraftment was also quantified using polymerase chain reaction to amplify a Y chromosome-specific sequence. RESULTS: We establish methods to transplant cats intraperitoneally while IU using ultrasound guidance, thus, describing a new large animal model for prenatal therapy. We show that the donor monocytic cells engraft and persist (for up to 125 days) in the brain, liver, and spleen, albeit at levels below those needed to alter the clinical or pathological progression of the alpha-mannosidosis. CONCLUSIONS: This is the first study of monocyte transplantation in a large animal model of a lysosomal storage disorder and demonstrates its feasibility, safety, and promise. Delivering cells IU may be a useful strategy to prevent morbidities before a definitive therapy, such as hematopoietic stem-cell transplantation, can be administered after birth.

Destructive joint disease in alpha-mannosidosis. A case report and review of the literature.

Storage of oligosaccharides due to a deficiency of alpha-mannosidase can lead to joint destruction in children and young adults. Treating hip destruction with a prosthesis might be successful in some of these patients, although diminished bone quality increases the risk of loosening of the prosthesis.

Hearing loss due to mannosidosis and otitis media with effusion. A case report and review of audiological assessments in children with otitis media with effusion.

A case of a child with mannosidosis and bilateral otitis media with effusion (OME) is reported here along with some discussion of relevant literature to emphasize the need for age appropriate audiometric assessment before and after insertion of grommets for glue ear (OME). There is a need for multidisciplinary teamwork in the management of children with hearing loss. If OME is treated surgically, age-appropriate hearing assessment is required before and after insertion of grommets. The need for audiological assessments will be relevant even if children had passed the newborn hearing screening test.

Bone marrow transplantation corrects the enzyme defect in neurons of the central nervous system in a lysosomal storage disease.

Neuronal storage disorders are fatal neurodegenerative diseases of humans and animals that are caused by inherited deficiencies of lysosomal hydrolase activity. Affected individuals often appear normal at birth but eventually develop progressive neurologic symptoms including sensory and motor deficits, mental retardation, and seizures. We have examined efficacy of bone marrow transplantation as a means of enzyme replacement, using cats with the lysosomal storage disease alpha-mannosidosis. Treated animals showed little or no progression of neurologic signs 1-2 years after transplant, whereas untreated cats became severely impaired and reached endstage disease by 6 months of age. Increased lysosomal alpha-mannosidase activity was found in brain tissue of the treated animals, and electron microscopy revealed no evidence of lysosomal storage within most neurons. Histochemical localization of acidic alpha-D-mannoside mannohydrolase (EC 3.2. 1.24), using 5-bromo-4-chloro-3-indolyl alpha-D-mannopyranoside, showed that functional enzyme was present in neurons, glial cells, and cells associated with blood vessels. This study provides direct evidence that bone marrow transplantation as treatment for a neuronal storage disease can lead to significant levels of a missing lysosomal hydrolase within neurons of the central nervous system and to compensation for the genetic metabolic defect.

Bone marrow transplantation in the treatment of alpha-mannosidosis.

Bone marrow transplantation was performed in a patient with alpha-mannosidosis. To our knowledge this is the first time such treatment has been attempted. The patient died 18 weeks after successful grafting and specimens of tissues were obtained at necropsy. Alpha-mannosidase activity in spleen and liver was just below normal (spleen 102 mumol/g/hour, control 113-330; liver 29 mumol/g/hour, control 30-131). Splenic alpha-mannosidase activity was indistinguishable from the control enzyme with respect to the Michaelis constant, heat stability, and inhibition by cobalt ions, as was 86% of the liver enzyme. In brain tissue alpha-mannosidase activity was 7% of controls, and less than one third had the properties of the normal enzyme. Oligosaccharides were present only in small amounts in liver and spleen, whereas they were greatly increased in brain tissue. Electron microscopic pictures of liver and spleen tissue showed normal morphology, but brain tissue showed definite vacuolation. These findings suggest that transplantation reversed the somatic changes of alpha-mannosidosis but did not affect lysosomal storage within brain tissue. It is concluded that marrow transplantation may not be a suitable treatment for alpha-mannosidosis.