Inborn errors of metabolism affecting the synthesis and processing of N-linked glycans. This includes all stages from synthesis of nucleotide-linked sugars to final processing in the Golgi apparatus. Technically, this also includes mucolipidoses II (I-cell disease) and III (pseudo-Hurler polydystrophy) due to affected synthesis of mannose-6-phosphate.

O-linked glycan synthesis defects also cause disease, e.g., progeroid form of Ehlers-Danlos sundrome, familial exostosis, Fukuyama muscular dystrophy, Muscle-Eye-Brain disease, Walker Warburg Syndrome, LGMD2I.

Congenital disorders of glycosylation are multisystem disorders, with prominent nervous system involvement. Type Ib has no CNS involvement.

Epidemiology

• CDG 1a is most common, with frequency of 1 in 40,000 to 60,000 in Sweden and Denmark
• incidence elsewhere unknown
• CDG 1c next most common
• other than 1b, other forms so rare that is likely underdiagnosed due to nonspecific symptoms
• all are autosomal recessive
• present congenitally or early childhood
• if survives early critical multisystem phase, can have more stable nonprogressive course into adulthood

Clinical Features

• Type Ia (most common and well known)
  • present in early infancy with multisystem disease, hypotonia, alternating strabismus, feeding difficulties, hepatopathy, tubulopathy, pericardial effusions
  • dysmorphism with inverted niples, unusually distributed subcutaneous fatpads on buttocks, joint contractures
  • severity is variable
  • initial mortality 20%
  • if survive, psychomotor retardation, hypotnoia, ataxia, polyneuropathy, retinitis pigmentosa, transient stroke-like episodes, seizures
  • osteopenia, skeletal deformities
  • no evidence for degenerative process - stable after initial phase
  • milder forms with borderline cognitive impairment
  • neuroimaging shows pontocerebellar atrophy
  • blood tests show coagulopathy with decreased AT III and factor XI, other endocrine abnormalities
• Type Ic - milder neurological involvement without cerebellar atrophy and little multisystem disease
• Type Ib - no major neurological involvement, protein losing enteropathy, hepatic fibrosis, hypoglycemia

Macroscopy

• type Ia shows shrunken cerebellum with firm, prominent foliae
• flattened pons
• cerebral hemispheres unremarkable
• general autopsy shows enlarged liver and kidneys

Histopathology

• gliotic cerebellar cortex with prominent loss of Purkinje and granular cells
• rare club-shaped expansions of Purkinje dendrites
• relative preservation of the dentate nucleus
• neuronal loss and gliosis in the pontine nuclei and transverse pontine fiber atrophy
• neuronal loss in the inferior olivary nucleus
• moderate cell loss in the cerebral cortex
• liver cirrhosis, fibrosis, fatty infiltration, giant cell hepatitis

Immunohistochemistry and Ultrastructural Findings

• axonal swellings with mitochondria and lamellar bodies have been observed in the ventral-medial and ventral-lateral thalamus
• myelin-like fibrillary lysosomal inclusions in hepatocytes, Schwann cells, and endoneural/epineural fibroblasts
• only defects in the ER or pre-ER stages result in lysosomal inclusions (not Golgi apparatus-based defects)

Differential Diagnosis

• other olivo-ponto-cerebellar atrophy (OPCA) conditions, including Norman's disease (granular layer aplasia) - may be allelic condition to CDG I

Biochemistry

• all the disorders affect N-glycan synthesis
• Types Ia and Ib both affect cytoplasmic synthesis of guanosine diphosphate mannose, needed for this glycosylation
• many glycoproteins affected, e.g., transferrin, which is used for diagnosis of CDG (not sensitive for type IIb and IIc, false positives with chronic alcohol consumption, galactosemia, and hereditary fructose intolerance)
• other proteins include alpha-1-antitrypsin and hexosaminidase

Pathogenesis

• glycosylation defects affect many secreted, membrane-bound, and intracellular proteins causing a wide range of symptoms
• N-linked glycosylation is important in protein stabilty, protein trafficking, protein function, molecular recognition, cell adhesion, and antigenicity
• complete interruption of the synthesis is incompatible with development
• high metabolic rate organs more affected with decreased enzymatic activity, e.g., liver
• unclear why CNS is so affected

Treatment

• Type Ib has been successfully treated with high dose mannose therapy
• this has not worked in type Ia
• Oral fucose therapy sucessful to treat CDG IIc