Comprehensive cardiopulmonary assessment in α mannosidosis.

INTRODUCTION: α Mannosidosis is an extremely rare, progressive, and complex lysosomal storage disease, characterized by mental retardation, hearing impairment, coarse facial features, skeletal abnormalities, and pulmonary involvement. While bone marrow transplantation has been the only therapeutic option to date, nowadays new treatment options are being explored, which may affect pulmonary and exercise capacity. AIM AND METHODS: To assess cardiopulmonary involvement in patients with α mannosidosis by pulmonary function tests, cardiopulmonary exercise testing, and low irradiation chest computed tomography (CT). RESULTS: Five patients aged 11 to 28 years were followed in our Respiratory-Metabolic Clinic. All five had pulmonary symptoms and received inhaled therapy. Three patients underwent bone marrow transplantation. Parenchymal lung disease was evident in 3/5 chest CT tests. Pulmonary function tests were abnormal in all patients and showed obstructive/restrictive impairment with air trapping. All five patients showed reduced peak oxygen uptake (median 23.1; range 20.4-32.2 mL/minute/kg, median %predicted 62; range %predicted 59-79). CONCLUSIONS: Pulmonary involvement is a known complication in this rare disease. Comprehensive cardiopulmonary evaluation is feasible among these patients and may help in assessing disease progression and response to new treatment modalities.

Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice.

Alpha-mannosidosis is a glycoproteinosis caused by deficiency of lysosomal acid alpha-mannosidase (LAMAN), which markedly affects neurons of the central nervous system (CNS), and causes pathognomonic intellectual dysfunction in the clinical condition. Cognitive improvement consequently remains a major therapeutic objective in research on this devastating genetic error. Immune-tolerant LAMAN knockout mice were developed to evaluate the effects of enzyme replacement therapy (ERT) by prolonged administration of recombinant human enzyme. Biochemical evidence suggested that hippocampus may be one of the brain structures that benefits most from long-term ERT. In the present functional study, ERT was initiated in 2-month-old immune-tolerant alpha-mannosidosis mice and continued for 9months. During the course of treatment, mice were trained in the Morris water maze task to assess spatial-cognitive performance, which was related to synaptic plasticity recordings and hippocampal histopathology. Long-term ERT reduced primary substrate storage and neuroinflammation in hippocampus, and improved spatial learning after mid-term (10weeks+) and long-term (30weeks+) treatment. Long-term treatment substantially improved the spatial-cognitive abilities of alpha-mannosidosis mice, whereas the effects of mid-term treatment were more modest. Detailed analyses of spatial memory and spatial-cognitive performance indicated that even prolonged ERT did not restore higher cognitive abilities to the level of healthy mice. However, it did demonstrate marked therapeutic effects that coincided with increased synaptic connectivity, reflected by improvements in hippocampal CA3-CA1 long-term potentiation (LTP), expression of postsynaptic marker PSD-95 as well as postsynaptic density morphology. These experiments indicate that long-term ERT may hold promise, not only for the somatic defects of alpha-mannosidosis, but also to alleviate cognitive impairments of the disorder.

The natural course and complications of alpha-mannosidosis--a retrospective and descriptive study.

Most alpha-mannosidosis patients described have been children and information on the natural course of the disorder has been based on a very limited number of observations. In order to assess the disease presentation in detail and to study disease characteristics, a study was started in 1991 and has been ongoing for over 20 years. Patients with confirmed alpha-mannosidosis were recruited through The International Society for Mannosidosis and Related Diseases (ISMRD) where families affected with alpha-mannosidosis received a questionnaire on general clinical information to be filled out by the responsible physician. The questionnaire was returned by 125 patients (64%). Of these, 45 patients were 15 years old or older at the time of evaluation. The questionnaire allowed us to assess the following features: Facial dysmorphism, columnar disease, arthritis, myopathy, hearing impairment, mental impairment, psychosis, bone disease and motor function as well as general health. This study describes the progression of alpha-mannosidosis and may be helpful in determining the clinical characteristics for assessments of prognosis.

Alpha-mannosidosis: a report of 2 siblings and review of the literature.

Alpha-mannosidosis is a rare lysosomal storage disorder with a heterogeneous clinical presentation. We describe a set of siblings with alpha-mannosidosis. The older child presented with a severe phenotype with multisystem involvement and had progressive deterioration in her motor and cognitive functioning. She had a poor outcome. The second child has a less severe disease course. He is being managed symptomatically only because of the family's poor socioeconomic circumstances. Therapeutic options in this condition are limited to bone marrow transplant early in the disease course. These disorders, although rare, should be considered in the approach to a child with dysmorphism, developmental delay, skeletal deformities, and visceromegaly.

Natural history of alpha mannosidosis a longitudinal study.

BACKGROUND: Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of the enzyme alpha-Mannosidase. Clinically it is characterized by hearing impairment, skeletal and neurological abnormalities and mental retardation. In order to characterize the clinical features and disease progression of patients affected by alpha-Mannosidosis, a survey study was conducted. 43 patients from 4 European countries participated in this longitudinal study. Age range of the participants was 3 to 42 years. For each patient a medical history, complete physical and neurological examination, joint range of motion and assessment of physical endurance and of lung function were completed. In addition, serum and urinary oligosaccharide levels were analysed. METHODS: In this multicenter longitudinal study clinical data of 43 alpha-Mannosidosis patients were collected. In addition to objective clinical measurements biochemical assays were performed. RESULTS: Data analysis revealed a wide spectrum of clinical presentation regarding the severity and disease progression. Most clinical abnormalities were observed in the musculoskeletal and neurological system. All patients showed mental retardation and hearing loss from early childhood. An impairment in physical endurance was revealed by the 6-minute walk and 3-minute stair stair climb tests. There was only slight progression of a few clinical findings: Psychiatric troubles in both groups essentially, and respiratory dysfunction under 18 years. The serum and urinary oligosaccharide levels were increased in all affected individuals and correlated well with the 6-minute walk and 3-minute stair climb test results. CONCLUSIONS: This study confirms that alpha-Mannosidosis is a very heterogeneous disorder regarding both, disease severity and progression. As it has been shown that Mannosidosis patients are able to perform lung function tests and the 6MWT and stair-climb test, these clinical parameters apparently can be used as clinical endpoints for clinical trials. Oligosaccharide levels appeared correlated with functional testing and may serve as biomarkers of disease severity, progression and response to treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier = NCT00498420 and EuropeanCommission FP VI contract LHSM-CT-2006-018692.

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.

Behavioural characterisation of the alpha-mannosidosis guinea pig.

alpha-Mannosidosis is a lysosomal storage disorder resulting from a functional deficiency of the lysosomal enzyme alpha-mannosidase. This deficiency results in the accumulation of various oligosaccharides in the lysosomes of affected individuals, causing somatic pathology and progressive neurological degeneration that results in cognitive deficits, ataxia, and other neurological symptoms. We have a naturally occurring guinea pig model of this disease which exhibits a deficiency of lysosomal alpha-mannosidase and has a similar clinical presentation to human alpha-mannosidosis. Various tests were developed in the present study to characterise and quantitate the loss of neurological function in alpha-mannosidosis guinea pigs and to follow closely the progression of the disease. General neurological examinations showed progressive differences in alpha-mannosidosis animals from approximately 1 month of age. Significant differences were observed in hind limb gait width from 2 months of age and significant cognitive (memory and learning) deficits were observed from 3 months of age. Evoked response tests showed an increase in somatosensory P1 peak latency in alpha-mannosidosis guinea pigs from approximately 2 months of age, as well as progressive hearing loss using auditory brainstem evoked responses. The alpha-mannosidosis guinea pig therefore appears to exhibit many of the characteristics of the human disease, and will be useful in evaluating therapies for treatment of central nervous system pathology.

Neurocognitive and psychotiform behavioral alterations and enhanced hippocampal long-term potentiation in transgenic mice displaying neuropathological features of human alpha-mannosidosis.

Mice with alpha-mannosidase gene inactivation provide an experimental model for alpha-mannosidosis, a lysosomal storage disease with severe neuropsychological and psychopathological complications. Neurohistological alterations in these mice were similar to those in patients and included vacuolations and axonal spheroids in the CNS and peripheral nervous system. Vacuolation was most prominent and evenly distributed in neuronal perikarya of the hippocampal CA2 and CA3 regions, whereas CA1 and dentate gyrus were weakly or not affected. Field potential recordings from CA1 region in hippocampal slices showed enhanced theta burst-induced long-term potentiation (LTP) in alpha-mannosidase-deficient mice. Longitudinal assessment in age-matched alpha-mannosidase-deficient and wild-type littermates, using an extended test battery, demonstrated a neurocognitive and psychotiform profile that may relate to the psychopathological alterations in clinical alpha-mannosidosis. Brainstem auditory-evoked potentials and basic neuromotor abilities were not impaired and did not deteriorate with age. Exploratory and conflict tests revealed consistent decreases in exploratory activity and emotional blunting in the knock-out group. alpha-Mannosidosis mice were also impaired in aversively motivated learning and acquisition of signal-shock associations. Acquisition and reversal learning in the water maze task, passive avoidance learning in the step-through procedure, as well as emotional response conditioning in an operant procedure were all impaired. Acquisition or shaping of an appetitive instrumental conditioning task was unchanged. Appetitive odor discrimination learning was only marginally impaired during shaping, whereas both the discrimination and reversal subtasks were normal. We propose that prominent storage and enhanced LTP in hippocampus have contributed to these specific behavioral alterations in alpha-mannosidase-deficient mice.

Alpha-mannosidosis and mutational analysis in a Turkish patient.

We present a case of alpha-mannosidosis with its mutational analysis. She was referred to our hospital with the provisional diagnosis of mucolipidosis. She was the first child of second-degree relative parents. She had a coarse face with flat and wide nasal bridge, hepatosplenomegaly, umbilical hernia, lumbar gibbus, motor and mental retardation and deafness. On peripheral blood smear, lymphocytes revealed vacuoles and neutrophils contained some granules resembling Reilly bodies seen in mucopolysaccharidosis (MPS). Based on these findings, the diagnosis of alpha-mannosidosis was suspected. Her urine oligosaccharide chromatography showed an abnormal pattern with a heavy trisaccharide band. Enzyme studies on white cells confirmed a deficiency of alpha-mannosidase activity, which was 2.6 micromol/g/hr. Her DNA analysis showed a S453Y mutation.

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

Beta-mannosidosis is an autosomal recessive lysosomal storage disease resulting from a deficiency of the lysosomal enzyme beta-mannosidase. The clinical manifestations of this disease in reported human cases are very heterogeneous ranging from relatively mild to moderately severe. This is in contrast with the severe prenatal onset seen in ruminant beta-mannosidosis. In humans, mental retardation, hearing loss, frequent infections, and behavioral problems are relatively common. Dysmorphology and skeletal involvement such as those seen in ruminants are unusual. The purpose of this study is to determine the range of clinical expression in human beta-mannosidosis resulting from null mutations. We determined that the beta-mannosidase gene consists of 17 exons. Intron-based PCR primers were designed and used to amplify each of the exons in genomic DNA isolated from patient fibroblasts. We identified two patients with null mutations. Results of the analysis showed that one patient was heterozygous for nonsense mutations G334T (E83X) in exon 2 and C1363T (Q426X) in exon 10, resulting in truncation of the deduced peptide sequence from 879 to 82 and 425 amino acids, respectively. The second patient was homozygous for a deletion mutation in exon 11 (1541delAT). This deletion causes a reading frame shift and 26 out of frame amino acids before a stop codon occurs in exon 12, resulting in truncation of the deduced peptide sequence from 879 to 510 amino acids. Because disease presentation in these patients with null mutations is very variable, ranging from mild to severe, we conclude that beta-mannosidosis in humans may indeed be milder than typical of other lysosomal storage disorders.

Histopathology, electrodiagnostic testing, and magnetic resonance imaging show significant peripheral and central nervous system myelin abnormalities in the cat model of alpha-mannosidosis.

Alpha-mannosidosis is a disease caused by the deficient activity of alpha-mannosidase, a lysosomal hydrolase involved in the degradation of glycoproteins. The disease is characterized by the accumulation of mannose-rich oligosaccharides within lysosomes. The purpose of this study was to characterize the peripheral nervous system (PNS) and central nervous system (CNS) myelin abnormalities in cats from a breeding colony with a uniform mutation in the gene encoding alpha-mannosidase. Three affected cats and 3 normal cats from 2 litters were examined weekly from 4 to 18 wk of age. Progressively worsening neurological signs developed in affected cats that included tremors, loss of balance, and nystagmus. In the PNS, affected cats showed slow motor nerve conduction velocity and increased F-wave latency. Single nerve fiber teasing revealed significant demyelination/remyelination in affected cats. Mean G-ratios of nerves showed a significant increase in affected cats compared to normal cats. Magnetic resonance imaging of the CNS revealed diffuse white matter signal abnormalities throughout the brain of affected cats. Quantitative magnetization transfer imaging showed a 8%-16% decrease in the magnetization transfer ratio in brain white matter of affected cats compared to normal cats, consistent with myelin abnormalities. Histology confirmed myelin loss throughout the cerebrum and cerebellum. Thus, histology, electrodiagnostic testing, and magnetic resonance imaging identified significant myelination abnormalities in both the PNS and CNS that have not been described previously in alpha-mannosidosis.

Human beta-mannosidase deficiency associated with peripheral neuropathy.

Human beta-mannosidosis is an inherited lysosomal storage disorder described in only seven families. We present a further case in a black African 14-year-old boy with severely deficient beta-mannosidase activity, bilateral thenar and hypothenar amyotrophy, electrophysiologically demonstrable demyelinating peripheral neuropathy, and cytoplasmic vacuolation of skin fibroblasts and lymphoid cells. The clinical and biochemical features of our patient are compared to those of previously reported patients.

Ectopic dendrites occur only on cortical pyramidal cells containing elevated GM2 ganglioside in alpha-mannosidosis.

In a variety of neuronal storage diseases, cortical pyramidal cells elaborate ectopic dendrites at the axon hillock. A feature common to all the diseases characterized by ectopic dendrites is an elevated level of GM2 ganglioside in cerebral cortex. In cats with one such disease, alpha-mannosidosis, the number of pyramidal cells bearing ectopic dendrites is small; the present study shows that GM2 ganglioside is stored only in those pyramidal neurons exhibiting ectopic dendrites. Using a Golgi-electron microscopy method with periodic acid-Schiff (PAS) staining, we first established that pyramidal cells bearing ectopic dendrites contained PAS+ membranous inclusions, consistent with storage of glycolipids. In contrast, those with smooth axon hillocks accumulated PAS- floccular inclusions, consistent with storage of oligosaccharides. Next, application of a monoclonal antibody against GM2 ganglioside revealed that subsets of both pyramidal and intrinsic neurons contained GM2-like immunoreactivity. Every GM2+ cell contained PAS+ membranous inclusions, indicating that pyramidal cells bearing ectopic dendrites stored GM2 ganglioside. In cats with alpha-mannosidosis induced by swainsonine, some pyramidal neurons showed GM2-like immunoreactivity after 4 weeks of treatment, whereas ectopic dendrites only became evident after 7 weeks of treatment. Thus, GM2 ganglioside accumulated in pyramidal neurons before ectopic dendrites emerged from the axon hillock. We propose that the reinitiation of dendrite growth on mature pyramidal cells is brought about by accumulated GM2 ganglioside.

Thyroid structure and function in bovine beta-mannosidosis.

In bovine beta-mannosidosis, the thyroid in the affected newborn shows marked cytoplasmic vacuolation. There is an associated reduction in the serum concentrations of thyroxine and tri-iodothyronine.

Clinical, neurophysiological, biochemical and morphological features of eyes in Persian cats with mannosidosis.

The clinical, neurophysiological, morphological and biochemical manifestation of eyes from Persian kittens affected with alpha-mannosidosis were studied. Clinically the disease is characterized by progressive corneal and lenticular opacification. In addition there is asymmetry in shape and latency of signal conductions which were demonstrated by visual evoked potential studies. Morphological and histochemical studies revealed vacuolization of various ocular cell types which stained positively with Concanavalia ensiformis agglutinin (Con A) and wheat germ agglutinin (WGA). Biochemical studies illustrated low activity of acid alpha-mannosidase in cultured keratocytes and abnormal storage of partially degraded oligosaccharides in these cells, in vitreous humor and lens. This comprehensive study of ocular alpha-mannosidosis demonstrates enzyme deficiency which leads to abnormal storage of oligosaccharides in affected cells and is manifested by morphological alterations and functional impairment.

Caprine beta-mannosidosis. Abnormal thyroid structure and function in a lysosomal storage disease.

Deficient activity of the lysosomal enzyme beta-mannosidase leads to widespread tissue accumulation of oligosaccharides in caprine beta-mannosidosis, an autosomal recessive neurovisceral storage disease. Severe thyroid morphologic abnormalities found in a previous light microscopic survey of tissues from neonatal affected goats suggested the possibility of impairment of function. Since considerable evidence indicates that thyroid hormone plays an important role in regulation of myelination, thyroid hormone deficiency, if present during central nervous system development, could be a factor in the hypomyelination seen in affected animals. Thus, this study was designed to characterize thyroid structure and function in beta-mannosidosis. To investigate developmental aspects of structural abnormalities, thyroids from six pairs of affected and control animals ranging in age from 96/150 days gestation to 3 days postnatal were analyzed by light and electron microscopy. Major findings in thyroids from affected animals, as early as 96/150 days gestation, included follicle irregularities and pronounced presence of lysosomal storage vacuoles in all cell types, particularly in follicular cells. The degree of cytoplasmic vacuolation increased with advancing age. To assess thyroid function, thyroid hormone concentrations were determined in six age-matched, neonatal pairs of affected and control goats. Significantly decreased thyroid hormone concentrations were present in affected animals. It is hypothesized that thyroid hormone deficiency plays a role in the pathogenesis of hypomyelination in affected animals. This study comprises, to our knowledge, both the most complete description of developmental abnormalities and the first report of abnormal function in an endocrine organ in a lysosomal storage disease. Further, this report suggests that systemic perturbations induced by a genetically determined deficiency of a lysosomal hydrolase could be a factor in the pathogenesis of central nervous system lesions.

Investigation of dysmyelinogenesis in caprine beta-mannosidosis: in vitro characterization of oligodendrocytes.

Central nervous system myelin deficiency is a consistent feature of caprine beta-mannosidosis, an autosomal recessive neurovisceral lysosomal storage disease. To investigate the possibility of an intrinsic oligodendrocyte defect in beta-mannosidosis, oligodendrocyte-enriched glial cultures from the cerebral hemisphere white matter of two affected and six control goats were compared with respect to culture yield and morphology. Fewer oligodendrocytes were cultured per gram of white matter from affected animals than from control animals. Galactocerebroside-positive oligodendrocytes from all animals were similar morphologically at all stages of culture by phase contrast and fluorescence microscopy. These findings are consistent with in vivo morphological observations and suggest that differentiated oligodendrocytes from affected animals do not show morphological abnormalities in culture. However, increased numbers of galactocerebroside-negative bipolar cells, which may be glial progenitor cells, were present in cultures from affected animals. This observation suggests the possibility of a defect in differentiation to mature oligodendrocytes, with persistence of the undifferentiated glia during late stages of development.

Caprine beta-mannosidosis: development of glial and myelin abnormalities in optic nerve and corpus callosum.

In caprine beta-mannosidosis, an inherited dysmyelinating disorder, the myelin deficit shows substantial variation throughout the nervous system. In this study morphometric analysis of optic nerve and corpus callosum sections at selected developmental stages was conducted in order to investigate development and persistence of myelin sheaths, the population of axons ensheathed, and the extent of myelin deficits and glial cell abnormalities. The results show that the myelin deficit is severe at very early stages of development and persists to about the same extent into postnatal life. The corpus callosum, much more severely involved than the optic nerve, contains a substantially smaller percentage of myelinated axons when compared to control. In both regions, larger axons are preferentially myelinated. In the corpus callosum before myelination begins, many glial cells appear abnormal, suggesting an early cellular defect. In the postnatal, myelin-deficient corpus callosum, there is a substantial decrease in glial cell density as compared to control, with abnormal appearance of many of the remaining cell profiles. These results define developmental characteristics of the dysmyelination in caprine beta-mannosidosis and document both the early appearance and the persistence of glial cell body and myelin abnormalities.

Ectopic dendritogenesis and associated synapse formation in swainsonine-induced neuronal storage disease.

Ectopic dendrite growth and new synapse formation are known to occur on select kinds of neurons in a wide variety of neuronal storage diseases. As these changes in connectivity occur just proximal to the axonal initial segment, it has been hypothesized that they underlie the generation of abnormal neuronal function in these diseases. We have studied certain aspects of this phenomenon through the use of a plant-derived indolizadine alkaloid, swainsonine, which specifically inhibits the lysosomal hydrolase, alpha-mannosidase. These studies fully document the close morphological similarity between swainsonine-induced and inherited feline alpha-mannosidosis. This includes the presence of clear and floccule-filled storage vacuoles, as seen with routine EM, and axon hillock neurite growth on select cell types, as seen with Golgi staining. The latter was found only on cortical pyramidal neurons and multipolar cells of amygdala, and these same cell types are known to be involved in ectopic neuritogenesis in other storage diseases. Combined Golgi-electron-microscopic studies demonstrated the presence of normal-appearing synapses on these aberrant neuritic processes and also unusual, membranous inclusions specifically within the neurite-bearing pyramidal cells. The latter may be indicative of unique metabolic changes in these neurons and is consistent with the hypothesis that storage of gangliosides or other glycolipids underlies the recapitulation of dendritic growth features in these diseases. Experimental manipulation of the disease process using the swainsonine model indicated that induction of cortical pyramidal neuron neurite growth could be influenced by both age of onset and intensity of intraneuronal storage. Although Golgi studies clearly demonstrated neuritic sprouting in animals with disease onset as late as at 1 year, cortical pyramidal cells of older, adult animals appeared to undergo significant storage without a similar induction of neurite growth. These studies support the view that induced neuritogenesis in neuronal storage disease is associated with changes in metabolism, specifically within the neurite-bearing cells, that this change possibly involves gangliosides, and that the neuritogenic response may be limited to pre-adult stages of brain maturation.