Catabolic pathways: lysosomal storage disorders, e.g., mucopolysaccharidoses (MPS), oligosaccharidoses, type II glycogenosis
- single system disorders
- direct morphological manifestations
- easier to study

Anabolic pathways: congenital defects in glycosylation (CDG)
- multisystem disorders
- often nonspecific morphological features
- harder to study

Lysosomal disorders

1. Mucopolysaccharidoses (MPS)
2. Oligosaccharidoses
3. Mucolipidoses
4. Type II dlycogenosis

Defining features of lysosomal disorders:

• Lysosomes are vacuolated
• Lysosomal vacuolar contents are glycosaminoglycams
• Lysosomal storage in nearly every organ and cell type

• MPS V has been eliminated as it has been found to be allelic to MPS I (Scheie type)
• MPS IV-B involves lysosomal beta-galactosidase, and is allelic to GM1-gangliosidosis
• mucolipidosis II also called I cell disease (for "inclusions" in cultured cells)
• mucolipidosis III also called pseudo-Hurler polydystrophy
• infantile type II glycogenosis is also called Pompe's disease
• epidemiology varies between disorders, but most are rare, with some geographical variation, e.g., Salla disease and aspartyl-glucosaminouria are more common in Finland
• all are autosomal recessive, except MPS II which has X-linked inheritance

Embryology

• lysosomal storage begins before birth
• mental retardation
• skeletal deformities - dysostosis multiplex
• organomegaly
• coarse face, short stature
• milder forms can be delayed

Clinical features

Mucopolysaccharidoses

• MPS I (Hurler phenotype)
  • normal at birth, early psychomotor retardation
  • coarsening of facial features, skeletal changes, hepatospelnomegaly, frequent ear infections
  • mental reardation and delcine, growth retardation, restriction of joint mobility, carpal tunnel syndrome
  • corneal clouding, macrocephaly, hydrocephalus from meningeal thickening
  • life expectancy <2 decades
  • radiological findings of dysostosis multiplex
• MPS I (Scheie phenotype)
  • milder, normal height and mentation
  • mild skeletal changes
  • carpal tunnel and cardiac valve disease
• MPS II (Hunter) - X-linked
  • same as Hurler, except no corneal clouding
• MPS III
  • mainly neurological features, with mental retardation and psychomotor regression and hyperactive behaviour
  • thick hair, minimal skeletal changes
• MPS IV and V
  • no direct CNS involvement, mostly skeletal
  • can have hydrocephalus from meningeal thickening
  • can have cord compression from atlanto-axial dislocation
  • can have carpal tunnel sundrome
• MPS VII
  • very rare, like Hurler, but spectrum from hydrops fetalis to almost unaffected

Oligosaccharidoses

• Mannosidosis
  • features similar to Hurler, but variable severity
  • hearing loss
• Fucosidosis
  • wide picture
  • severe neurological picture, mild skeletal changes, hepatomegaly
  • angiokeratoma of the skin is suggestive but not specific
• Aspartylglycosaminuria
  • mainly in Finland
  • language delay, mental retardation
  • mild facial coarsening amd skeletal abnormalities
• Galactosialidosis
  • severe disease in infancy resembling GM1-gangliosidosis and sialidosis
  • juvenile form starts with extrapyramidal symptoms and ataxia, followed by myoclonus, mental decline
  • mild skeletal features
• Salla disease
  • mental retardation, ataxia, progressive psychomotor decline
• ISSD (infantile sialic storage disease)
  • more severe than Salla disease, although same mutation

Mucolipidoses

• Sialidosis (mucolipidosis I)
  • severe disorder in early childhood, or a juvenile form
  • action polymyoclonus, ataxia, seizures, gradual mental decline and visual loss
  • macular cherry red spot
  • no organomegaly
• Mucolipidosis II
  • coarse facial features and dysostosis myltiplex
• Mucolipidosis III
  • milder than II, though same mutation
• Mucolipidosis IV
  • mental retardation and visual decline with corneal opacities

Macroscopy

• thickening of the leptomeninges, sometimes occluding the outflow of CSF and hydrocephalus
• dura can also thicken, impairing the width of the spinal canal and compression
• wide Virchow-Robin spaces, especiallly in the white matter
• enlargement of the choroid plexus from lysosomal vacuolation

Histopathology

• wide-spread lysosomal vacuolation leading to intracellular vacuolation of mesenchymal cells
• cells affected include blood vessels
• zebra bodies - lamellar/membranous appearance of ganglioside-containing lysosomes
• late onset disease is associated with increased lipopigments in neurons (e.g., MPS III), including subunit C of mitochondrial ATP synthase (also seen in neuronal ceroid lipofuscinosis)
• neuronal storage especially in the subcortical grey matter, including the spinal cord

• meganeurite - can also affect the proximal axon

• asteroid body - lysosomal storage in dendrites of Purkinje cells
• neuronal loss and gliosis
• type II glycogenosis
  • ubiquitous storage of lysosomal glycogen in skeletal/heart muscles, nerve cells, glial cells, Schwann cells, etc.
  • especially in subcortical grey matter and ballooned anterior horn cells of spinal cord

Immunohistochemistry and ultrastructural findings

• immunohistochemistry for lysosomal storage disorders not well developed
• ultrastructural findings useful in diagnosis
• lysosomal vacuoles with ill-defined contents
• may see glycogen granules
• "zebra bodies" in MPS
• lipopigments in the form of curvilinear profiles (like in NCL)

Lysosomal vacuoles and zebra bodies in mucopolysaccharidosis (mitral valve)

Lysosomal vacuoles in mucolipidosis (skin biopsy)

Biochemistry

• abnormal substrate levels from degradation disorders are excreted in the urine as mucopolysaccharides, oligosaccharides, and sialic compounds
• sometimes hydrolases can be measured in the serum or in cultured cells, e.g., fibroblasts

Differential Diagnosis

• ultrastructural analysis can divide between vacuolar and nonvacuolar lysosomal residual bodies
• defining the disorder requires clinical, biochemical, and molecular information

Pathogenesis

• reduced or absent lysosomal enzymes resulting in build up of substrates, damaging intracellular metabolism