Glycosylation in Patients With Galactosaemia

NCT ID: NCT02218632

Last Updated: 2014-08-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2014-08-31

Brief 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.

Conditions

Classical Galactosaemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

lactose-free diet

lactose-free diet (standard therapy) vs. lactose-free diet plus temporary oral galactose supplements

Group Type: ACTIVE_COMPARATOR

lactose-free diet

Intervention Type: OTHER

standard diet

lactose free diet

lactose-free diet (standard therapy)

Group Type: ACTIVE_COMPARATOR

Temporary oral galactose supplements

Intervention Type: DIETARY_SUPPLEMENT

galactose supplements in the range of physiological galactose production

Interventions

lactose-free diet

standard diet

Intervention Type: OTHER

Temporary oral galactose supplements

galactose supplements in the range of physiological galactose production

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

On established lactose-free diet; In addition to lactose-free diet

Eligibility Criteria

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

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Health Research Board, Ireland

OTHER

Sponsor Role: collaborator

Medical Research Charities Group Ireland

UNKNOWN

Sponsor Role: collaborator

University College Dublin

OTHER

Sponsor Role: collaborator

Children's University Hospital, Ireland

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eileen Treacy, MD, Prof

Role: PRINCIPAL_INVESTIGATOR

University Children's Hospital Dublin Irleland

Locations

National Centre for Inherited Metabolic Disorders, Children's University Hospital, Temple Street

Dublin, , Ireland

Countries

Ireland

References

Coss KP, Hawkes CP, Adamczyk B, Stockmann H, Crushell E, Saldova R, Knerr I, Rubio-Gozalbo ME, Monavari AA, Rudd PM, Treacy EP. N-glycan abnormalities in children with galactosemia. J Proteome Res. 2014 Feb 7;13(2):385-94. doi: 10.1021/pr4008305. Epub 2013 Dec 20.

Reference Type: RESULT

PMID: 24359113 (View on PubMed)

Knerr I, Coss KP, Doran PP, Hughes J, Wareham N, Burling K, Treacy EP. Leptin levels in children and adults with classic galactosaemia. JIMD Rep. 2013;9:125-131. doi: 10.1007/8904_2012_191. Epub 2012 Nov 7.

Reference Type: RESULT

PMID: 23430559 (View on PubMed)

Other Identifiers

grant PAC number 12.64

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

12020

Identifier Type: -

Identifier Source: org_study_id