Mannosidosis

Lysosomal glycoprotein storage disease with mental retardation, hearing loss, and recurrent infections (upper or lower respiratory tract, and gastrointestinal tract). Other clinical features include coarse face, prominent forehead, prominent jaw, diffuse dysfunction of the brain, severe ataxia, deafness, scoliosis, rheumatoid arthritis, hypotonia, and muscle pain. Two types are described: α and β. α-Mannosidosis displays clinical heterogeneity, ranging from very serious to very mild forms. β-Mannosidosis causes a severe disorder that affects the peripheral and central nervous systems.

Lysosomal Mannosidosis Deficiency Syndrome.

First reported in 1967 by Oeckerman in Lund, Sweden, who described a boy affected with mental retardation, increased tissue total mannose concentration, and susceptibility to infection.

Rare; approximately 100 cases of α-mannosidosis and 10 to 15 cases of β-mannosidosis have been described. Found in all ethic groups in Europe, America, Africa, and Asia.

Autosomal recessive genetic disorder, 2.5:1 male preponderance. The α-mannosidase gene maps to chromosome 19p13.2-q12. The β-mannosidase gene is located at chromosome 4q22-25. Prenatal diagnosis is possible.

α-Mannosidosis is a disorder of glycoprotein catabolism associated with abnormal levels and excretion of mannose-rich oligosaccharides, caused by a deficiency of its catabolic enzyme α-mannosidase. β-Mannosidosis results from β-mannosidase deficiency with an increase in the corresponding oligosaccharide. Both enzymes are located in the lysosomes.

Usually made by measuring enzyme activity in white blood cells and eventually by measuring certain substances in urine. Increased urinary oligosaccharides as measured by thin-layer chromatography confirms the type. Measuring activity in lymphoblasts correlates with severity. Pathology shows multiple vacuoles in lymphocytes and hepatocytes. Clinical history and physical findings are considered important in the diagnosis.

Facies: The very typical facial characteristics of mannosidosis are a coarse face, a prominent forehead, a flattened nasal bridge, a small nose, and prominent jaw. Cerebral symptoms: The disease causes a diffuse dysfunction of the brain characterized by delayed early landmarks of neural development and severe ataxia. Hearing problems: Central and peripheral deafness. Immunodeficiency: Recurrent infections are a main feature of the disease. These infections are in the upper or lower respiratory tract, middle ear, or gastrointestinal tract. Skeletal: Scoliosis, rheumatoid arthritis, ataxia. Muscular: Muscular pain and weakness, which is caused by accumulation of storage material in the muscle and usually contributes to the immobilization of the patient.

α-Mannosidosis: Type I or severe infantile phenotype (onset between 3 and 12 months) includes rapid, progressive mental retardation, coarse facies resembling mucopolysaccharidosis, hepatosplenomegaly, dysostosis multiplex, recurrent bacterial infections with death between 3 and 12 years. Type II or juvenile-adult phenotype (onset between 1 and 4 years) is milder and slowly progressive with survival into adulthood. Other clinical features include spastic paraplegia (vertebral bodies abnormalities) and pancytopenia. In both types, deafness, cataracts, corneal opacifications, and vacuolated lymphocytes are present. Recurrent infections could be caused by a defect in leukocyte chemotaxis. Dysostosis multiplex causes skeletal dysplasia, ovoid configuration or flattening of the vertebral bodies, and kyphosis.

β-Mannosidosis: Rarer, and ranges from mild features (mental retardation, behavioral problems, angiokeratomas, mild facial dysmorphism) to severe (status epilepticus, quadriplegia, and early death). Respiratory infections are common, caused by swallowing difficulties or abnormal esophageal motility.

Successful bone marrow transplantation has been reported in both cases.

Chest radiography and SpO2 (arterial oxyhemoglobin saturation) because frequent respiratory infections. Check neurologic and stability of the vertebral spine. ECG may be indicated (short PR interval reported). Liver function tests, CBC, coagulation screen if hepatosplenomegaly.

Airway manipulation may be problematic if the cervical spine is unstable. Gingival hyperplasia is sometimes present. Neuraxial regional blockade might be difficult because of skeletal dysplasia. Avoid tachycardia if short PR interval. Postoperative ventilation and reverse isolation (pancytopenia) might be necessary.

Avoid succinylcholine if there is paraparesis. Interactions with antiepileptic drugs.

Hurler Syndrome: Most severe form of mucopolysaccharidosis. It is characterized by a deficiency of the enzyme α-liduronidase, which results in accumulation of dermatan and heparan sulfates. Symptoms of the disorder first become evident at age 6 months to 2 years. Affected infants may experience developmental delays, recurrent urinary and upper respiratory tract infections, noisy breathing, and persistent nasal discharge. Additional physical problems may include clouding of the cornea of the eye, an unusually large tongue, severe deformity of the spine, and joint stiffness. Mental development begins to regress at approximately age 2 years. The clinical features observed with α-mannosidosis resemble closely the Hurler syndrome.

Sialidosis: Characterized by progressive lysosomal storage of sialidated glycopeptides and oligosaccharides caused by deficiency of the enzyme neuraminidase. There are two types of mucoliposis: type I and type II. Type I is the milder form, also known as the normosomatic type or the cherry-red spot myoclonus syndrome. Some patients classified as mucolipidosis I proved to have mannosidosis. Sialidosis type II is the more severe form with an earlier onset; it is also known as the dysmorphic type. Type II has been subdivided into juvenile and infantile forms. The clinical characteristics of mucoliposis type I include neurologic abnormalities, muscular hypotonia and hypotrophy, ataxia, myoclonus, seizures, coarse facies (Hurler-like facies), short trunk, barrel chest, spinal deformity, deafness, cherry-red spot, and severe mental retardation.

Mucolipidosis III (Pseudo-Hurler Polydystrophy): Characterized by painless joint stiffness, decreased mobility, dwarfism, coarse Hurler-like facial features, mild mental retardation, multiple defective bone formations, and aortic valve heart disease. Mobility may gradually diminish until puberty and then stabilize. It is considered a milder form of I-cell disease (mucolipidosis II).

Mucopolysaccharidosis (MPS) Type III: Characterized by hyperactivity, sleep disorders, mental retardation, dysarthria (progressive loss of previously acquired skills), sensory hearing loss, and delays in attaining developmental milestones (e.g., crawling and walking). Affected individuals may experience seizures, ataxia, and aggressive behavior. Affected individuals may eventually lose the ability to walk. Four types have been described (A, B, C, and D), which are identified according to the enzyme deficiency. Many of the clinical findings observed in patients affected with mannosidosis resembled those in patients with mucopolysaccharidosis III.