Disorders of Glycoprotein Metabolism
Introduction to Disorders of Glycoprotein Metabolism
Disorders of glycoprotein metabolism encompass a diverse group of genetic conditions that affect the synthesis, processing, or degradation of glycoproteins. These disorders can impact multiple organ systems and often present with a wide range of clinical manifestations.
Key points:
- Glycoproteins are proteins with attached carbohydrate chains (glycans)
- These disorders can affect either the synthesis (e.g., CDG) or degradation (e.g., oligosaccharidoses) of glycoproteins
- Most are inherited in an autosomal recessive manner
- Clinical presentations can vary widely, from severe multisystem disorders to milder, later-onset forms
- Diagnosis often requires specialized biochemical and genetic testing
Congenital Disorders of Glycosylation (CDG)
CDG are a group of disorders affecting the synthesis and processing of glycans attached to proteins or lipids.
Classification:
- Type I CDG: Defects in glycan assembly
- Type II CDG: Defects in glycan processing
Clinical Features:
- Developmental delay and intellectual disability
- Hypotonia
- Failure to thrive
- Seizures
- Liver dysfunction
- Coagulation abnormalities
- Dysmorphic features
- Skeletal abnormalities
- Retinopathy
Diagnosis:
- Transferrin isoelectric focusing (most common screening test)
- Apolipoprotein C-III isoelectric focusing
- Genetic testing
- Enzyme assays in some cases
Examples:
- PMM2-CDG (formerly CDG-Ia)
- MPI-CDG (formerly CDG-Ib)
- ALG3-CDG
- COG7-CDG
Mucolipidoses
Mucolipidoses are disorders that combine features of both mucopolysaccharidoses and sphingolipidoses. They are characterized by defects in the trafficking of lysosomal enzymes.
Types:
- Mucolipidosis II (I-cell disease)
- Mucolipidosis III (Pseudo-Hurler polydystrophy)
- Mucolipidosis IV
Clinical Features:
- Coarse facial features
- Skeletal abnormalities
- Developmental delay
- Organomegaly
- Corneal clouding
Diagnosis:
- Elevated serum lysosomal enzymes
- Genetic testing
- Enzyme assays in cultured fibroblasts
Specific Features:
Mucolipidosis II (I-cell disease): Most severe form, presents in infancy
Mucolipidosis III: Milder form with later onset
Mucolipidosis IV: Characterized by severe neurological impairment and eye abnormalities
Oligosaccharidoses
Oligosaccharidoses are disorders of glycoprotein catabolism, resulting in the accumulation of oligosaccharides in lysosomes.
Types:
- α-Mannosidosis
- β-Mannosidosis
- Fucosidosis
- Aspartylglucosaminuria
- Schindler disease/Kanzaki disease
General Clinical Features:
- Progressive intellectual disability
- Coarse facial features
- Skeletal abnormalities
- Hearing loss
- Hepatosplenomegaly
Diagnosis:
- Urine oligosaccharide analysis
- Enzyme assays in leukocytes or fibroblasts
- Genetic testing
Specific Features:
α-Mannosidosis: Immunodeficiency, hearing loss, intellectual disability
Fucosidosis: Angiokeratomas, visceromegaly, neurological deterioration
Aspartylglucosaminuria: Predominantly affects individuals of Finnish descent
Sialidoses
Sialidoses are lysosomal storage disorders caused by deficiency of neuraminidase (sialidase).
Types:
- Type I (Cherry-red spot myoclonus syndrome)
- Type II (Mucolipidosis I)
Clinical Features:
- Cherry-red spot in the macula
- Progressive visual loss
- Myoclonus
- Ataxia
- Seizures
Specific Features:
Type I: Later onset, milder course, primarily neurological symptoms
Type II: Earlier onset, more severe, with dysmorphic features and organomegaly
Diagnosis:
- Urine oligosaccharide analysis
- Enzyme assay for neuraminidase
- Genetic testing of NEU1 gene
Diagnosis of Disorders of Glycoprotein Metabolism
Diagnosis of these disorders often requires a combination of clinical, biochemical, and genetic approaches:
Clinical Evaluation:
- Detailed medical history
- Physical examination
- Developmental assessment
Biochemical Testing:
- Urine oligosaccharide analysis
- Serum transferrin isoelectric focusing (for CDG)
- Enzyme assays in leukocytes, fibroblasts, or dried blood spots
Genetic Testing:
- Next-generation sequencing panels
- Whole exome or whole genome sequencing
Other Investigations:
- Neuroimaging (MRI, CT)
- Ophthalmological examination
- Skeletal surveys
- Tissue biopsies in some cases
Early diagnosis is crucial for appropriate management and genetic counseling. However, the rarity and heterogeneity of these disorders can make diagnosis challenging.
Treatment of Disorders of Glycoprotein Metabolism
Treatment approaches vary depending on the specific disorder and often involve multidisciplinary care:
General Approaches:
- Supportive care
- Management of symptoms and complications
- Physical, occupational, and speech therapy
- Nutritional support
Specific Therapies:
- Enzyme Replacement Therapy (ERT): Available for some disorders (e.g., α-mannosidosis)
- Substrate Reduction Therapy: Under investigation for some conditions
- Bone Marrow Transplantation: Considered in select cases
- Gene Therapy: Experimental approach in research phase
Management of Complications:
- Anticonvulsants for seizure control
- Cardiac management
- Orthopedic interventions
- Ophthalmological care
Emerging Therapies:
- Chaperone therapy
- Antisense oligonucleotides
- Small molecule approaches
Treatment is typically lifelong and requires regular monitoring and adjustment. The development of new therapies is an active area of research for many of these rare disorders.
Disorders of Glycoprotein Metabolism
- What is the primary function of glycoproteins in the human body?
Glycoproteins play crucial roles in cell recognition, signaling, and structural support. - Which enzyme deficiency is responsible for aspartylglucosaminuria?
Aspartylglucosaminidase deficiency - What is the inheritance pattern of most glycoprotein metabolism disorders?
Autosomal recessive - In Fucosidosis, which enzyme is deficient?
Alpha-L-fucosidase - What is the main storage material in I-cell disease?
Glycoproteins and glycolipids - Which organelle is primarily affected in most glycoprotein metabolism disorders?
Lysosomes - What is the alternative name for Sialidosis Type I?
Cherry-red spot myoclonus syndrome - In which disorder is there a deficiency of beta-mannosidase?
Beta-mannosidosis - What is the primary clinical feature of Schindler disease?
Neurodegeneration - Which glycoprotein metabolism disorder is characterized by coarse facial features and hepatosplenomegaly?
Mucolipidosis III (Pseudo-Hurler polydystrophy) - What is the enzyme deficiency in alpha-mannosidosis?
Alpha-mannosidase - Which diagnostic test is commonly used to screen for glycoprotein metabolism disorders?
Urine oligosaccharide analysis - What is the primary treatment approach for most glycoprotein metabolism disorders?
Supportive care and symptom management - In which disorder is there accumulation of sialic acid-containing compounds?
Sialidosis - What is the typical age of onset for infantile free sialic acid storage disease?
Birth to early infancy - Which glycoprotein metabolism disorder is associated with skeletal dysplasia and corneal clouding?
Mucolipidosis IV - What is the primary storage material in Schindler disease?
Glycopeptides and oligosaccharides - Which enzyme is deficient in Galactosialidosis?
Cathepsin A (Protective protein) - What is the characteristic feature of I-cell disease on electron microscopy?
Inclusion bodies in fibroblasts - Which glycoprotein metabolism disorder is associated with a cherry-red spot in the macula?
Sialidosis - What is the main biochemical abnormality in Fucosidosis?
Accumulation of fucose-containing glycolipids and glycoproteins - Which organ systems are commonly affected in glycoprotein metabolism disorders?
Central nervous system, skeletal system, and visceral organs - What is the primary diagnostic method for confirming a specific glycoprotein metabolism disorder?
Enzyme activity assay in leukocytes or cultured fibroblasts - Which glycoprotein metabolism disorder is associated with angiokeratoma corporis diffusum?
Fucosidosis - What is the genetic basis of most glycoprotein metabolism disorders?
Mutations in genes encoding lysosomal enzymes or transport proteins - Which imaging technique is commonly used to assess brain involvement in glycoprotein metabolism disorders?
Magnetic Resonance Imaging (MRI) - What is the primary storage material in alpha-mannosidosis?
Mannose-rich oligosaccharides - Which glycoprotein metabolism disorder is characterized by the presence of vacuolated lymphocytes?
Sialidosis - What is the typical life expectancy for severe forms of glycoprotein metabolism disorders?
Often reduced, with many patients not surviving beyond childhood or early adulthood - Which therapeutic approach shows promise for some glycoprotein metabolism disorders but is still under investigation?
Enzyme replacement therapy
Mucolipidoses
- What is the primary characteristic of mucolipidoses?
Combined storage of mucopolysaccharides and lipids - How many types of mucolipidoses are currently recognized?
Four main types (I, II, III, and IV) - Which mucolipidosis is also known as sialidosis?
Mucolipidosis I - What is the alternative name for Mucolipidosis II?
I-cell disease - Which enzyme is deficient in Mucolipidosis III?
N-acetylglucosamine-1-phosphotransferase - What is the inheritance pattern of mucolipidoses?
Autosomal recessive - Which mucolipidosis is characterized by psychomotor retardation and corneal clouding?
Mucolipidosis IV - What is the primary cellular defect in I-cell disease (Mucolipidosis II)?
Missorting of lysosomal enzymes - Which gene is mutated in Mucolipidosis IV?
MCOLN1 (Mucolipin-1) - What is the typical age of onset for Mucolipidosis II?
Birth or early infancy - Which mucolipidosis is also known as pseudo-Hurler polydystrophy?
Mucolipidosis III - What is the primary biochemical defect in Mucolipidosis II and III?
Defective phosphorylation of lysosomal enzymes - Which diagnostic test is used to confirm Mucolipidosis II?
Elevated lysosomal enzyme activity in serum - What is the primary storage material in Mucolipidosis IV?
Gangliosides and mucopolysaccharides - Which clinical feature distinguishes Mucolipidosis III from Mucolipidosis II?
Milder symptoms and later onset - What is the characteristic finding in fibroblasts of patients with I-cell disease?
Inclusion bodies (I-cells) - Which organ systems are commonly affected in Mucolipidosis II?
Skeletal, cardiovascular, and central nervous systems - What is the life expectancy for patients with Mucolipidosis II?
Usually less than 10 years - Which imaging technique is commonly used to assess bone abnormalities in mucolipidoses?
X-ray radiography - What is the primary treatment approach for mucolipidoses?
Supportive care and symptom management - Which mucolipidosis is associated with a defect in the GNPTAB gene?
Mucolipidosis II and III - What is the characteristic eye finding in Mucolipidosis IV?
Corneal clouding - Which mucolipidosis is characterized by the least severe clinical presentation?
Mucolipidosis III - What is the primary cellular compartment affected in mucolipidoses?
Lysosomes - Which diagnostic test can be performed prenatally to detect mucolipidoses?
Enzyme activity assay in cultured amniotic fluid cells or chorionic villi - What is the characteristic facial appearance in severe forms of mucolipidoses?
Coarse facial features - Which mucolipidosis is associated with achlorhydria and iron deficiency anemia?
Mucolipidosis IV - What is the primary neurological symptom in Mucolipidosis I (Sialidosis)?
Myoclonus - Which therapeutic approach is being investigated for some forms of mucolipidoses?
Gene therapy - What is the characteristic finding on electron microscopy of skin biopsies in Mucolipidosis IV?
Cytoplasmic inclusions with concentric lamellae
Congenital Disorders of Glycosylation (CDG)
- What is the primary defect in Congenital Disorders of Glycosylation?
Abnormal glycosylation of proteins and lipids - How many types of CDG have been identified to date?
Over 100 different types - What is the most common type of CDG?
PMM2-CDG (formerly known as CDG-Ia) - Which enzyme is deficient in PMM2-CDG?
Phosphomannomutase 2 - What is the inheritance pattern of most CDGs?
Autosomal recessive - Which diagnostic test is considered the gold standard for screening CDGs?
Transferrin isoelectric focusing - What are the two main categories of CDGs?
Type I (defects in glycan assembly) and Type II (defects in glycan processing) - Which organ systems are commonly affected in CDGs?
Central nervous system, gastrointestinal system, and musculoskeletal system - What is a characteristic clinical feature of PMM2-CDG?
Inverted nipples and abnormal fat distribution - Which type of CDG is associated with a defect in dolichol-phosphate-mannose synthase?
DPM1-CDG - What is the primary treatment approach for most CDGs?
Supportive care and symptom management - Which CDG type is associated with severe hypoglycemia and liver dysfunction?
ALG1-CDG - What is the characteristic finding on brain MRI in many CDG patients?
Cerebellar atrophy - Which CDG is associated with ichthyosis and liver cirrhosis?
MPDU1-CDG - What is the typical age of onset for most CDGs?
Infancy or early childhood - Which CDG is characterized by severe epilepsy and microcephaly?
SRD5A3-CDG - What is the primary biochemical pathway affected in most Type I CDGs?
N-linked glycosylation - Which CDG is associated with cutis laxa and skeletal dysplasia?
ATP6V0A2-CDG - What is the characteristic eye finding in many CDG patients?
Strabismus - Which CDG is associated with congenital cataracts and growth hormone deficiency?
PMM2-CDG - What is the primary laboratory finding in most Type I CDGs?
Decreased glycosylation of serum transferrin - Which CDG is characterized by severe intellectual disability and seizures?
ALG3-CDG - What is the role of dietary mannose supplementation in some CDGs?
It can improve glycosylation in certain types, such as MPI-CDG - Which CDG is associated with recurrent thrombosis and protein-losing enteropathy?
TMEM165-CDG - What is the primary diagnostic method for confirming a specific CDG type?
Genetic testing - Which CDG is characterized by hyperinsulinemic hypoglycemia and enteropathy?
PGAP3-CDG - What is the role of glycosylation in normal cellular function?
It is crucial for protein folding, stability, and cell-cell interactions - Which CDG is associated with skeletal dysplasia and retinal degeneration?
COG1-CDG - What is the primary challenge in diagnosing CDGs?
Clinical and biochemical heterogeneity among different types - Which therapeutic approach shows promise for some CDGs but is still under investigation?
Gene therapy and enzyme replacement therapy
Oligosaccharidoses
- What are oligosaccharidoses?
Lysosomal storage disorders characterized by defective breakdown of oligosaccharides - Which enzyme deficiency causes alpha-mannosidosis?
Alpha-mannosidase - What is the inheritance pattern of most oligosaccharidoses?
Autosomal recessive - Which oligosaccharidosis is caused by a deficiency of beta-mannosidase?
Beta-mannosidosis - What is the primary storage material in Fucosidosis?
Fucose-containing glycolipids and glycoproteins - Which diagnostic test is commonly used to screen for oligosaccharidoses?
Urine oligosaccharide analysis - What is the enzyme deficiency in Aspartylglucosaminuria?
Aspartylglucosaminidase - Which oligosaccharidosis is characterized by angiokeratoma corporis diffusum?
Fucosidosis - What is the primary clinical feature of Schindler disease?
Neurodegeneration - Which enzyme is deficient in Pompe disease?
Acid alpha-glucosidase (GAA) - What is the characteristic facial appearance in severe forms of oligosaccharidoses?
Coarse facial features - Which oligosaccharidosis is associated with cherry-red spots in the macula?
GM1 gangliosidosis - What is the primary storage material in alpha-mannosidosis?
Mannose-rich oligosaccharides - Which organ systems are commonly affected in oligosaccharidoses?
Central nervous system, skeletal system, and visceral organs - What is the enzyme deficiency in GM1 gangliosidosis?
Beta-galactosidase - Which oligosaccharidosis is characterized by severe skeletal dysplasia?
Sialidosis type II - What is the primary treatment approach for most oligosaccharidoses?
Supportive care and symptom management - Which imaging technique is commonly used to assess brain involvement in oligosaccharidoses?
Magnetic Resonance Imaging (MRI) - What is the characteristic eye finding in many oligosaccharidoses?
Corneal clouding - Which oligosaccharidosis is associated with intellectual disability and psychiatric symptoms?
Aspartylglucosaminuria - What is the primary cellular compartment affected in oligosaccharidoses?
Lysosomes - Which diagnostic method is used to confirm a specific oligosaccharidosis?
Enzyme activity assay in leukocytes or cultured fibroblasts - What is the typical age of onset for infantile forms of oligosaccharidoses?
Birth to early infancy - Which oligosaccharidosis is characterized by the presence of vacuolated lymphocytes?
Sialidosis - What is the role of bone marrow transplantation in treating some oligosaccharidoses?
It can provide enzyme-producing cells and slow disease progression in some cases - Which oligosaccharidosis is associated with hepatosplenomegaly and cardiac involvement?
Pompe disease - What is the primary biochemical abnormality in Schindler disease?
Accumulation of glycopeptides and oligosaccharides - Which therapeutic approach is being investigated for some oligosaccharidoses?
Enzyme replacement therapy and gene therapy - What is the characteristic finding on electron microscopy of skin biopsies in oligosaccharidoses?
Vacuoles or inclusion bodies in various cell types - Which oligosaccharidosis is associated with a defect in the MANBA gene?
Beta-mannosidosis
Sialidoses
- What is the primary enzyme deficiency in sialidoses?
Neuraminidase (sialidase) - How many main types of sialidoses are recognized?
Two main types (Type I and Type II) - What is the alternative name for Sialidosis Type I?
Cherry-red spot myoclonus syndrome - Which gene is mutated in sialidoses?
NEU1 gene - What is the inheritance pattern of sialidoses?
Autosomal recessive - What is the characteristic eye finding in sialidoses?
Cherry-red spot in the macula - Which type of sialidosis has a later onset and milder symptoms?
Sialidosis Type I - What is the primary neurological symptom in Sialidosis Type I?
Myoclonus - Which type of sialidosis is associated with hydrops fetalis?
Sialidosis Type II (congenital form) - What is the primary storage material in sialidoses?
Sialic acid-containing oligosaccharides and glycopeptides - Which diagnostic test is used to confirm sialidoses?
Neuraminidase enzyme activity assay in cultured fibroblasts or leukocytes - What is the typical age of onset for Sialidosis Type I?
Second or third decade of life - Which clinical feature distinguishes Sialidosis Type II from Type I?
Presence of dysmorphic features and organomegaly - What is the characteristic finding in peripheral blood smears of sialidosis patients?
Vacuolated lymphocytes - Which organ systems are commonly affected in Sialidosis Type II?
Central nervous system, skeletal system, and visceral organs - What is the primary treatment approach for sialidoses?
Supportive care and symptom management - Which imaging technique is commonly used to assess brain involvement in sialidoses?
Magnetic Resonance Imaging (MRI) - What is the life expectancy for patients with Sialidosis Type I?
Often normal or near-normal life expectancy - Which subtype of Sialidosis Type II has the earliest onset?
Congenital or hydropic form - What is the primary biochemical abnormality in urine samples of sialidosis patients?
Increased excretion of sialyloligosaccharides - Which therapeutic approach is being investigated for sialidoses?
Enzyme replacement therapy and gene therapy - What is the characteristic facial appearance in Sialidosis Type II?
Coarse facial features - Which neurological symptom is common in both types of sialidoses?
Ataxia - What is the role of genetic counseling in sialidoses?
To inform families about the risk of recurrence and available prenatal testing options - Which diagnostic technique can be used for prenatal diagnosis of sialidoses?
Enzyme activity assay in cultured amniotic fluid cells or chorionic villi - What is the primary cellular compartment affected in sialidoses?
Lysosomes - Which type of sialidosis is associated with skeletal abnormalities?
Sialidosis Type II - What is the role of neuraminidase in normal cellular function?
It cleaves terminal sialic acid residues from glycoproteins and glycolipids - Which clinical feature can help differentiate sialidoses from other lysosomal storage disorders?
Presence of cherry-red spot without organomegaly in Type I - What is the primary challenge in developing treatments for sialidoses?
Difficulty in delivering enzyme or gene therapy across the blood-brain barrier
Further Reading
- GeneReviews - Congenital Disorders of Glycosylation Overview
- GeneReviews - α-Mannosidosis
- GeneReviews - Mucolipidosis II
- GeneReviews - Sialidosis
- Orphanet - Congenital disorder of glycosylation
- Biochemical and Molecular Diagnosis of Congenital Disorders of Glycosylation - Clinics in Laboratory Medicine
