Variable clinical presentation of lysosomal β-mannosidosis in patients with null mutations

Bedilu, Rebecca; Nummy, Katherine A.; Cooper, Alan; Wevers, Ron A.; Smeitink, Jan A.M.; Kleijer, Wim J.; Friderici, Karen H.

doi:10.1016/s1096-7192(02)00172-5

Cited by 52 publications

(46 citation statements)

References 37 publications

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“…Regionally specific myelin deficiency is present in the CNS but not in peripheral nerves Lovell and Jones 1983;Boyer et al 1990). In contrast with ruminant b-mannosidosis, human cases have a milder and heterogeneous clinical expression, even when caused by functionally null mutations (Alkhayat et al 1998;Bedilu et al 2002;Cooper et al 1990). The most severe cases are associated with intellectual disability, developmental delay, dysmorphology, frequent infections, and hearing loss.…”

Section: Discussionmentioning

confidence: 99%

“…b-Mannosidosis is characterized by the intracellular accumulation of small oligosaccharides (mainly disaccharides and trisaccharides) in selected cell types (Jones and Laine 1981). In human cases of b-mannosidosis, the clinical symptoms, including intellectual disability, are relatively mild and are variable, even in patients with null mutations (Bedilu et al 2002); however, little is known about the pathology of the disease. In contrast, the two ruminant animal models (goats and cows) have a severe clinical presentation at birth Abbitt et al 1991) and pathology includes extensive regionally variable myelin deficits as well as widespread cytoplasmic vacuolation (Patterson et al 1991;Jones 1983,1985).…”

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confidence: 99%

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Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent

et al. 2013

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Neurological dysfunction is common in humans and animals with lysosomal storage diseases. b-Mannosidosis, an autosomal recessive inherited disorder of glycoprotein catabolism caused by deficiency of the lysosomal enzyme b-mannosidase, is characterized by intracellular accumulation of small oligosaccharides in selected cell types. In ruminants, clinical manifestation is severe, and neuropathology includes extensive intracellular vacuolation and dysmyelination. In human cases of b-mannosidosis, the clinical symptoms, including intellectual disability, are variable and can be relatively mild. A b-mannosidosis knockout mouse was previously characterized and showed normal growth, appearance, and lifespan. Neuropathology between 1 and 9 months of age included selective, variable neuronal vacuolation with no hypomyelination. This study characterized distribution of brain pathology in older mutant mice, investigating the effects of two strain backgrounds. Morphological analysis indicated a severe consistent pattern of neuronal vacuolation and disintegrative degeneration in all five 129X1/SvJ mice. However, the mice with a mixed genetic background showed substantial variability in the severity of pathology. In the severely affected animals, neuronal vacuolation was prominent in specific layers of piriform area, retrosplenial area, anterior cingulate area, selected regions of isocortex, and in hippocampus CA3. Silver degeneration reaction product was prominent in regions including specific cortical layers and cerebellar molecular layer. The very consistent pattern of neuropathology suggests metabolic differences among neuronal populations that are not yet understood and will serve as a basis for future comparison with human neuropathological analysis. The variation in severity of pathology in different mouse strains implicates genetic modifiers in the variable phenotypic expression in humans.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent

et al. 2013

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“…To the best of our knowledge, there have been 20 cases in 16 families reported in the medical literature, since it was first described in humans in 1986 by 2 independent groups (Cooper et al 1986;Wenger et al 1986). While the age of presentation ranges from a few weeks (Dorland et al 1988) to adulthood (Gort et al 2006), overall the disease has been thought to generally be less severe than that found naturally occurring in goats or cows (Bedilu et al 2002), where frank dysmorphism and severe neonatal onset neurological disease is the norm (Jones et al 1983;Abbitt et al 1991). This has in part been attributed to the fact that b-mannosidosis deficient ruminants accumulate the trisaccharide Man(b1-4) GlcNAc (b1-4) GlcNAc to a greater extent than the disaccharide Man(b1-4) GlcNAc (Jones et al 1992).…”

Section: Case Reportmentioning

confidence: 99%

“…In a review of the literature, Bedilu found that the main phenotypic traits in man were developmental delay and hearing loss (Bedilu et al 2002), although many of the more recent cases do not have the hearing impairment. Both of these features were present in our patient, with the hearing loss being suspected from an extremely early age.…”

Section: Case Reportmentioning

confidence: 99%

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A Clinically Severe Variant of β-Mannosidosis, Presenting with Neonatal Onset Epilepsy with Subsequent Evolution of Hydrocephalus

et al. 2013

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Atypical Gilles de la Tourette Syndrome With β-Mannosidase Deficiency

Sedel

Friderici²,

Nummy³

et al. 2006

Arch Neurol

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Background: ␤-Mannosidosis is a rare inborn error of metabolism with various phenotypes, including mental retardation, behavioral problems, hearing loss, and recurrent airway infections in childhood. To our knowledge, there is no published description of Gilles de la Tourette syndrome in association with this enzymatic deficiency. Objective: To describe a unique case of Gilles de la Tourette syndrome associated with ␤-mannosidosis. Setting: University hospital. Patient: An 18-year-old man exhibited motor and vocal tics since childhood, attention-deficit/hyperactivity disorder, impulsivity, and aggressiveness compatible with Gilles de la Tourette syndrome. A screen for inborn errors of metabolism was made because of the atypical association with slight mental retardation and bilateral perceptive hypoacousia. Results: Urinary analysis showed disacchariduria, and leukocyte analysis revealed a profound deficit in ␤-mannosidase activity. Two novel mutations in the ␤-mannosidase gene were found: a new splice mutation in one allele, and a unique 10-base-pair insertion in the other. Conclusions: This case illustrates the phenotypic variability of inborn errors of metabolism in adults and demonstrates the need to screen inborn errors of metabolism in atypical Gilles de la Tourette syndrome.

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Variable clinical presentation of lysosomal β-mannosidosis in patients with null mutations

Cited by 52 publications

References 37 publications

Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent

Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent

A Clinically Severe Variant of β-Mannosidosis, Presenting with Neonatal Onset Epilepsy with Subsequent Evolution of Hydrocephalus

Atypical Gilles de la Tourette Syndrome With β-Mannosidase Deficiency

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