Alpha-mannosidosis: a case with novel ultrastructural and light microscopy findings.

OBJECTIVES: Alpha-mannosidosis is a rare genetic lysosomal storage condition leading to the systemic buildup of oligomannoside. Clinical presentation and associated conditions, as well as the full extent of histopathologic changes associated with this disease process, are not fully understood. CASE PRESENTATION: We present the case of an 8-year-1-month old patient with persistent anemia and who was initially diagnosed with Celiac disease before ultimately being diagnosed with alpha-mannosidosis. As part of his diagnostic work-up, duodenal and bone marrow biopsies were examined by pathology. Duodenal biopsies showed foamy plasma cells expanding the lamina propria which triggered a workup for a genetic storage disease; features suggestive of Celiac disease which resolved on gluten-free diet were also noted by pathology. Bone marrow analysis via electron microscopy showed cytoplasmic granules and inclusions in multiple immune cell lines. CONCLUSIONS: Alpha-mannosidosis can occur with Celiac disease and milder forms may only be suspected from incidental pathology findings. The ultrastructural bone marrow findings from this case, the first to be reported from human, show numerous disease-associated changes in multiple immune cell lines whose contribution to disease-associated immunodeficiency is unclear.

Hearing impairment as an early sign of alpha-mannosidosis in children with a mild phenotype: Report of seven new cases.

Alpha-mannosidosis (AM) is a very rare (prevalence: 1/500000 births) autosomal recessive lysosomal storage disorder. It is characterized by multi-systemic involvement associated with progressive intellectual disability, hearing loss, skeletal anomalies, and coarse facial features. The spectrum is wide, from very severe and lethal to a milder phenotype that usually progresses slowly. AM is caused by a deficiency of lysosomal alpha-mannosidase. A diagnosis can be established by measuring the activity of lysosomal alpha-mannosidase in leucocytes and screening for abnormal urinary excretion of mannose-rich oligosaccharides. Genetic confirmation is obtained with the identification of MAN2B1 mutations. Enzyme replacement therapy (LAMZEDER ) was approved for use in Europe in August 2018. Here, we describe seven individuals from four families, diagnosed at 3-23 years of age, and who were referred to a clinical geneticist for etiologic exploration of syndromic hearing loss, associated with moderate learning disabilities. Exome sequencing had been used to establish the molecular diagnosis in five cases, including a two-sibling pair. In the remaining two patients, the diagnosis was obtained with screening of urinary oligosaccharides excretion and the association of deafness and hypotonia. These observations emphasize that the clinical diagnosis of AM can be challenging, and that it is likely an underdiagnosed rare cause of syndromic hearing loss. Exome sequencing can contribute significantly to the early diagnosis of these nonspecific mild phenotypes, with advantages for treatment and management.

Severe periodontal destruction in alpha-mannosidosis: a case series.

Alpha-mannosidosis is a rare genetic lysosomal storage disorder that is inherited in an autosomal recessive pattern. Severe periodontal breakdown in alpha-mannosidosis patients has not previously been reported in the literature. The purposes of this paper are to: present the cases of 2 siblings diagnosed with alpha-mannosidosis, each of whom had varying severity of periodontal destruction; and provide an overview of alpha-mannosidosis, the possible reasons for the periodontal destruction, and the periodontal management in the 2 affected siblings. Both had preventive and nonsurgical periodontal therapy followed by a 5-year period of supportive therapy. Their pattern of bone loss was consistent with those with periodontitis as a manifestation of systemic diseases, with the extent of periodontal destruction being related to the severity of the alpha-mannosidosis. Alpha-mannosidosis patients present with social disfigurements and, to prevent tooth loss that can add to this, early periodontal diagnosis is important to optimize management and intervention.

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.

Cemented total hip arthroplasty in a patient with alpha-mannosidosis: a case report.

Mannosidosis is an extremely rare genetic disease occurring due to deficiency of the lysosomal enzyme, alpha-mannosidase. Patients with this disorder often suffer from musculoskeletal abnormalities and muscular weakness leading to joint destruction and severe morbidity along with other major systems involvement. We present here such a case of a 27-year-old male that highlights the challenges in management of hip joint destruction secondary to Mannosidosis.

Alfa-manosidosis tipo II / Alpha-mannosidosis

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Early onset alpha-mannosidosis with slow progression in three Hispanic males.

Alpha-mannosidosis (AMS) is an autosomal recessive lysosomal storage disorder which results from a deficiency of lysosomal alpha-mannosidase [corrected] activity and displays a wide range of clinical phenotypes. Patients have traditionally been divided into type I, a more severe form that presents in infancy, and type II, a milder form that typically presents in later childhood. We describe three Hispanic males who presented in infancy with relatively mild forms of AMS. They were aged between 6 and 24 years at their last assessment. Homozygous mutations in the MAN2B1 gene were found in all three patients, one of which is a newly reported mutation. Two of the patients were brothers who were homozygous for the same MAN2B1 mutation. Despite being homozygous for the same mutation, the older brother had more severe developmental delay, hearing loss, and growth retardation. This report illustrates the difficulty in determining a strict genotype-phenotype correlation in AMS, and supports screening for oligosaccharides in children with neurodevelopmental delay with mild phenotypic signs and symptoms.

Bilateral patellar dislocation associated with alpha-mannosidase deficiency.

Mannosidosis is an extremely rare genetic disease characterized by a deficiency of the lysosomal enzyme, alpha-mannosidase. This enzyme is necessary for cleavage of mannose from many glycoproteins. In the absence of this enzyme, mannose accumulates in cells throughout the body, including the joints and the synovium. This disease causes many skeletal changes including dysostosis multiplex, synovial hypertrophy, and Charcot-type joints. We report the case of a girl, aged 9 years and 6 months, who developed bilateral patellar dislocation and severe synovial hypertrophy secondary to alpha-mannosidase deficiency. Her disease was further complicated by Charcot elbow and bilateral hip and elbow avascular necrosis.

Late-onset retinal dystrophy in alpha-mannosidosis.

alpha-Mannosidosis is a rare lysosomal storage disease that is caused by an inherited deficiency of the lysosomal alpha-mannosidase. Clinical symptoms include coarse facial features, skeletal involvement (dysostosis multiplex), hearing disabilities, mental retardation and hepatosplenomegaly. Only few cases with ocular symptoms have been reported, mainly with lenticular opacities. We report on two brothers with complex neurological symptoms who presented with late-onset retinal dystrophy and were followed up for 6 years.

[Unusual course of alpha-mannosidosis with symptoms of paranoid-hallucinatory psychosis]. / Ungewöhnlicher Verlauf einer alpha-Mannosidose mit Symptomen einer paranoid-halluzinatorischen Psychose.

We report the case of a 27-year-old female with recurrent paranoid-hallucinatory episodes who was initially diagnosed as suffering from schizophrenic psychosis. After 10 years of treatment under this diagnosis, alpha-mannosidosis was identified to be the underlying cause of her psychiatric symptoms. alpha-Mannosidosis is a rare autosomal recessive lysosomal storage disorder associated with decreased activity of the enzyme mannosidase. In the present case, diagnosis was made late in the illness after failure of a response to antipsychotic treatment and with the patient additionally showing progressive cognitive decline. Only after extensive investigation was the diagnosis made by showing decreased alpha-mannosidase enzyme activity in serum and blood leukocytes. This case demonstrates that an unusual clinical course or striking symptom patterns, especially in association with somatic comorbidity, in psychotic patients should lead to diagnostic consideration of inherited metabolic disease.

Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation.

OBJECTIVES: To study the efficacy of hematopoietic stem cell transplantation (HCT) for ameliorating the clinical manifestations of alpha-mannosidosis. STUDY DESIGN: Four patients with alpha-mannosidosis underwent allogeneic HCT at the University of Minnesota. Diagnosis was established by assay of leukocyte alpha-mannosidase activity level. Physical features, donor engraftment, leukocyte alpha-mannosidase activity, neuropsychologic function, and hearing were monitored before and after transplantation, with follow-up ranging from 1 to 6 years. RESULTS: All 4 patients showed slowing of their neurocognitive development and sensorineural hearing loss before HCT. All patients are alive, with normalization of leukocyte enzyme activity after HCT. Intellectual function has stabilized, with improvement in adaptive skills and verbal memory function in 3 of 4 patients. Hearing has improved to normal or near normal for speech frequencies in 3 patients. No new skeletal abnormalities have developed. CONCLUSIONS: HCT can halt the progressive cognitive loss in patients with alpha-mannosidosis. Early diagnosis and treatment with HCT is critical for optimal results.

Sisters with alpha-mannosidosis and systemic lupus erythematosus.

UNLABELLED: Alpha-mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal alpha-mannosidase (LAMAN). Here, we report two sisters with alpha-mannosidosis who developed systemic lupus erythematosus (SLE). The sisters were both homozygous for a one bp deletion within the LAMAN gene resulting in a truncated gene product. The coincidence of alpha-mannosidosis and SLE are discussed with regard to both clinical and molecular findings. CONCLUSION: alpha-mannnosidosis may contribute to the onset of systemic lupus erythematosus in predisposed patients.

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.

Late occurrence of chronic immune-mediated axonal polyneuropathy following bone marrow transplant for juvenile-onset alpha-mannosidosis.

A 23-year-old woman with juvenile-onset alpha-mannosidosis developed an axonal polyneuropathy more than a year following successful unrelated donor (URD) BMT complicated by chronic graft-versus-host disease (GVHD). Progressive muscle weakness and paresthesias developed over at least 4 months, and made her nonambulatory. Nerve conduction and EMG studies demonstrated an axonal sensorimotor neuropathy. Cerebral spinal fluid (CSF) IgG was elevated with two peaks not identified in serum. Strength improved after a single course of plasma exchange and continued to improve over 12 months. The response to plasma exchange, elevated CSF IgG production, and evidence of a serum IgM peak suggest an immune-mediated mechanism. Chronic polyneuropathies following BMT are rare and are usually temporally related to GVHD or infection. This patient's disease was unusual because of its late occurrence and chronic onset in the face of resolved GVHD and in the absence of infection.

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.

Immunodeficiency in alpha-mannosidosis: a matched case-control study on immunoglobulins, complement factors, receptor density, phagocytosis and intracellular killing in leucocytes.

UNLABELLED: Patients with the autosomal recessive lysosomal storage disease alpha-mannosidosis suffer from recurrent infections. To study the mechanisms of this immunodeficiency, six patients were matched against six healthy controls and their humoral and cellular immunocompetence investigated. No differences in the number of circulating leucocytes including B-cells, levels of immunoglobulin main classes, nor IgG subclasses were observed. However, post-immunisation serum levels of specific antibodies against poliovirus, diphtheria toxin and tetanus toxin were significantly reduced. In patients, the density of the complement-binding receptor CD11b and the Fc-receptor CD16 was significantly enhanced on monocytes and polymorphonuclear neutrophils (PMN) and the number of phagocytosing PMN was significantly increased in the presence of pooled human serum. This was not observed in the presence of autologous serum, indicating altered opsonic properties. Also in normal PMN, phagocytosis was inhibited by a factor in the serum from the patients. Despite maintained oxidative burst, patient PMN demonstrated insufficient intracellular bacterial killing. CONCLUSION: Our data indicate that patients with alpha-mannosidosis have an immunodeficiency at both the humoral and cellular level.

Mannosidosis: an unusual cause of a deforming arthropathy.

We report on a case of a deforming arthropathy in a young man with a lysosomal storage disorder. A 31-year-old man with a known diagnosis of mannosidosis presented with a painful swollen right elbow. Radiographs of his right elbow showed a disorganised joint with multiple fragments resembling the appearances of a neuropathic joint. This case provides further evidence that a deforming arthropathy may occur as part of the spectrum of skeletal abnormalities seen in mannosidosis.