Glycosylation in Patients With Galactosaemia

August 14, 2014 updated by: Children's University Hospital, Ireland

Galactosaemia, a Modifiable Multi-system Glycosylation Disorder?

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

26

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Ireland
      • Dublin, Ireland, 1
        • National Centre for Inherited Metabolic Disorders, Children's University Hospital, Temple Street

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 36 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Classical galactosaemia
  • Q188R Genotype
  • On lactose-free diet
  • No complications, condition well controlled
  • Male/femal adults and children aged between 5-12 yrs.
  • Informed consent /assent
  • Patient attend the Galactosaemia Clinic, NCIMD Dublin

Exclusion Criteria:

  • Complications, such as cataracts
  • Galactosaemia varaint, no Q188R-Genotype
  • Poor compliance
  • Intercurrent illness
  • Individual may not complete follow up
  • Children below 5 years of age
  • Unable to provide informed consent
  • Patient not under the care of Galactosaemia Clinic, NCIMD Dublin

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: lactose-free diet
lactose-free diet (standard therapy) vs. lactose-free diet plus temporary oral galactose supplements
Other: lactose-free diet
standard diet
Other Names:
  • On established lactose-free diet
Active Comparator: lactose free diet
lactose-free diet (standard therapy)
Dietary supplement: Temporary oral galactose supplements
galactose supplements in the range of physiological galactose production
Other Names:
  • In addition to lactose-free diet

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with Classical Galactosaemia on a lactose-free diet in Ireland with disease specific complications
Time Frame: 2 years
clinical monitoring and biochemical assessment to determine the number of patients with classical galactsaemia in Ireland with disease specific complications
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants with Classical Galactosaemia with variations in their glycosylation status in the Irish cohort
Time Frame: 2 years
Glycosylation analysis: IgG N-glycan analysis (serum test)
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's University Hospital, Ireland

Collaborators

University College Dublin
Health Research Board, Ireland
Medical Research Charities Group Ireland

Investigators

  • Principal Investigator: Eileen Treacy, MD, Prof, University Children's Hospital Dublin Irleland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2012

Primary Completion (Actual)

August 1, 2014

Study Completion (Actual)

August 1, 2014

Study Registration Dates

First Submitted

August 7, 2014

First Submitted That Met QC Criteria

August 14, 2014

First Posted (Estimate)

August 18, 2014

Study Record Updates

Last Update Posted (Estimate)

August 18, 2014

Last Update Submitted That Met QC Criteria

August 14, 2014

Last Verified

August 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 12020
  • grant PAC number 12.64 (Other Grant/Funding Number: MRCG/HRB)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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