Glycosylation in Patients With Galactosaemia
Condition: Classical Galactosaemia
MeSH terms: Galactosemias
Study type: Interventional

Summary: 
      Galactosaemia is an inherited condition caused by a lack of an enzyme (catalyst) which
      normally breaks down galactose (the sugar found in milk products). This affects 1:19,000
      births annually in Ireland (the highest incidence worldwide) and is screened for by the
      National Newborn Screening Programme. When an affected infant is diagnosed, galactose is
      immediately restricted from the diet. This prevents often fatal liver disease and other
      immediate complications. However, despite early treatment the majority of affected patients
      go on to develop long-term complications such as intellectual impairment, neurological
      complications, speech difficulties and infertility in females. The underlying mechanisms for
      these complications are unclear. The investigators have shown in detailed biochemical and
      gene analysis studies that major abnormalities affecting the function of complex molecules in
      the body, particularly glycoproteins, (consisting of sugar chains attached to proteins)
      persist in treated individuals which may lead to disturbances of the body's intrinsic
      cellular machinery and relate to the complications seen.

      In this research the investigators expand on from their earlier studies to see if they can
      identify biomarkers and parts of the galactose/glycosylation pathways which could be modified
      or changed with new treatments to improve outcomes for this condition (i.e., IgG N glycans).

      In more detail, the investigators test the use of the most abundant glycoprotein in human
      plasma (IgG) as an improved clinical test for monitoring the galactose control needed in
      patients and also to see if some patients (including children aged 5-12 yrs) might have a
      better predicted outcome with moderate increases of galactose in the diet. The investigators
      believe that these studies greatly improve the understanding of Galactosaemia with a view to
      improving current treatment options and future outcomes.
    

Detailed description: 
      Classical Galactosaemia is an inherited disorder of galactose metabolism caused by profound
      deficiency of galactose-1-phosphate uridyltransferase (GALT: EC 2.7.712). This results in a
      systemic accumulation of toxic galactose intermediates and a decrease in the level of
      UDP-galactose, a required sugar for glycosylation. Galactosaemia has a relatively high
      incidence in Ireland, (1:19,000 births) presenting a particular public health problem. The
      neonatal life-threatening phenotype (liver disease, coagulopathy and sepsis) is rescued by
      restriction of dietary galactose. However, outcomes of treatment are disappointing beyond the
      neonatal period (even after successful newborn screening, early treatment and long term
      compliance). The majority of Irish patients harbour the severe Q188R Galt mutation.

      56.5% of Irish patients ≥ 6yrs have IQs ≤ 79; and 91.2% of Irish female patients ≥ 13yrs have
      Premature Ovarian Insufficiency (POI). Unfortunately, the basic pathophysiology of this
      condition remains enigmatic with limited treatment approaches.

      In their earlier work, the investigators reported very considerable variation in patient
      outcomes, even among siblings. The investigators have proposed that these differences are
      determined by variation in galactose accessory pathways (beyond the GALT deficiency). This
      may result in variable galactose tolerance in patients with linked variation in glycosylation
      pathways which could allow for enhanced UDP-galactose bioavailability essential for
      glycosylation. In their previous and current work the investigators have identified ongoing
      dysregulation of glycoprotein formation and expression of genes involved in glycan
      biosynthesis and cell signalling pathways in treated Galactosaemia patients.

      The present proposal, which builds on published previous work, enables the investigators to
      establish that Galactosaemia is a modifiable, multi-systemic glycosylation defect. The
      overall objectives of the work are to progress the development of biochemical markers (IgG
      N-glycan analysis) as prognostic indices for potentially modifiable relevant pathways. The
      investigators consider how the phenotype could be relaxed in some patients with Classical
      Galactosaemia, initially by studies of modification of exogenous galactose requirements to
      identify if the ongoing glycan processing defects identified may be improved reflecting
      accessory pathways of galactose disposal.

      Study Aim: Expand previous and published work using IgG N-glycan analysis to examine the
      glycosylation status of treated adult Galactosaemia patients in a larger study and develop
      this test as a reliable diagnostic tool. The investigators also carry out a pilot study to
      examine the effects of diet relaxation in paediatric patients (5-12 yrs) aiming to determine
      optimum galactose intake levels for this cohort with the hope of preventing long-term
      complications later in life. The investigators propose that this research offers new insights
      into the ongoing pathophysiology of this rare disorder with the possibility of developing new
      treatment targets, which over time could be cost-effective by preventing major disability.
    

Intervention name(s): lactose-free diet; Temporary oral galactose supplements
Intervention type(s): Other; Dietary Supplement
Intervention description(s): standard diet; galactose supplements in the range of physiological galactose production
Other intervention name(s): On established lactose-free diet; In addition to lactose-free diet
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Galactosaemia; Dysglycosylation; Diet