Investigating Golgi and Endoplasmic Reticulum Disorders

Golgi and endoplasmic reticulum disorders (congenital defects of glycosylation)

Attaching sugar molecules to proteins or lipids (glycosylation) is mediated by the Golgi apparatus or complex and by the endoplastic reticulum and is necessary for numerous biochemical functions.

Defects may be divided into soluble and structural abnormalities.

The 'soluble' congenital defects of glycosylation (CDG) - predominantly defects of N-glycosylation - are many and increasing in number but by far the most important is CDG1a. 'structural' defects of O-glycosylation comprise congenital and later onset muscular dystrophies and are investigated by completely different methods.

Clinical clues to CDG

The symptomatology may be highly variable even within the same family but some of the following features may be seen:

• facial and hand dysmorphism often mild
• Fat pads, particularly on the buttocks
• Flat or inverted nipples (inverted nipples are more common in those without CDG!)
• Slow cognitive development
• Slow motor development
• Strabismus
• Feeding difficulties
• Stroke-like episodes (hemipareses)
• Epileptic seizures (not as an isolated phenomenon)
• Retinopathy
• Hepatomegaly or disorder of liver function
• Cardiomyopathy
• Palpable kidneys
• Endocrine defects, e.g. hypothyroidism, hyperinsulinism, hypergonadotrophic hypogonadism (in females)
• Miscellaneous defects, skeleton, etc.

Neorological phenotypes similar to those well recognized in mitochondrial disorders may be seen and it is wise to ensure that congenital defects of glycosylation have been excluded before one proceeds to invasive investigation for mitochondrial disorders.

Investigation Result in CDG

Isoelectric focusing (IEF) for transferrins (sialotransferrins) is the major primary diagnostic investigation. The clinical spectrum of CDG is so wide that transferrin IEF must always be done when the diagnosis is a possibility.

Other investigations that may be abnormal in CDG and may give clues towards the diagnosis are as follows:

• EEG during stroke-like episodes showing repetitive spike complexes contralateral to the hemiparesis
• Slow nerve conduction
• Cerebellar atrophy or pontocerebellar atrophy and particularly progressive cerebellar atrophy
• CSF protein increase
• Coagulation abnormality, in particular decreased factor IX and antithrombin III, protein C and protein S
• Abnormal liver function tests, especially increased transaminases.

The precise biochemical defect causing the CDG can be elucidated by performing leukocyte or fibroblast enzyme assays and then by DNA mutation studies in cases where the clinical phenotype points towards a specific enzymatic deficiency. Where this is not the case, powerful tandem mass spectrometry techniques can be utilized to provide information on the glycoprotein in question, hence providing a clue towards the precise enzymatic block.