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Clinical analysis of inborn errors of metabolism in adulthood

Introduction

Inborn errors of metabolism (IEMs) are disorders associated with a defect in the biosynthesis or breakdown of substances within specific pathways that were recognised by specific biochemical tests and sometimes treatable by metabolic intervention (primarily dietary manipulation, cofactor supplementation). The majority of these conditions manifest in childhood, and over 50 years ago newborn screening was introduced in Ireland to identify affected infants  in the hope that early recognition and management would lead to healthy lives. Although most IEMs are manageable, they are largely incurable diseases, with patients requiring healthcare supervision between periods of illness.

In 2013, as a natural progression of established programmes (such as the introduction of the newborn screening programme (NSP) and the development of the National Centre for Inherited Metabolic Disorders (NCIMD) at Children’s University Hospital (CUH), Temple Street), a service for the diagnosis and management of adult patients with IEMs was established at the Mater Misericordiae University Hospital (MMUH), Dublin, under the auspices of Prof Eileen Treacy (part-time, 0.2 FTE), a metabolic specialist dietitian and clinical nurse specialist. Later that year, I joined as the second consultant (0.8 FTE MMUH).

Adult IEM

Adult patients with an IEM currently seen and for planned transition to the MMUH from the NCIMD at the CUH include those who have reached the age of 18 years and older, with a diagnosis established: (1) following detection through the NSP (ie, phenylketonuria (PKU), homocystinuria, maple syrup urine disease (MSUD) and galactosaemia), or (2) in the course of evaluation for a suspected metabolic disorder in childhood (eg, fatty acid oxidation defect, glutaric aciduria type, which includes those subsequently shown to have a lysosomal storage disorder (LSDs) or mitochondrial defect (primarily involving complexes of the respiratory chain). As defects that transpire within the confines of an organelle, LSDs and mitochondrial defects are not fully responsive to dietary manipulation. Moreover, affected patients often have multisystemic involvement, necessitating multidisciplinary care. Without central co-ordination, these patients’ care can be fragmented across a variety of specialists based at different facilities within the country.

Additionally, a significant number of patients with adult-onset presentations (and not part of the CUH cohort) suspected or known to have an IEM have been referred to the team at MMUH. This group includes patients who have presented with rhabdomyolysis, subsequently diagnosed with very long chain fatty acid oxidation defect, relatives of an individual with cardiomyopathy attributed to Fabry disease (LSD caused by deficiency of α-galactosidase), and patients who have suffered a stroke, have hearing loss and diabetes (identified as a mitochondrial defect), among others.

An increasing number of patients have also been referred or seen because of concerns regarding a pungent odour, in a proportion of whom the diagnosis of trimethylaminuria (TMAU) has been made. TMAU is a disorder in which the body is unable to break down trimethylamine, a chemical compound that has been described as smelling like rotting fish. The nature of this condition is such that it can be associated with one’s view of self (esteem) and problems with interpersonal relationships. In this particular example, behavioural counselling is essential to help with depression and other psychological symptoms. In fact, psychosocial services are a critical component of care for adults with an IEM, to help them deal with the life-long strain of chronic illness.

We anticipate, based on population-frequency estimates, the number of these adult patients  the service will need to care for  will increase significantly, and ultimately will represent a higher proportion of individuals within Ireland living with an IEM.

Transition and care of adult patients

Ideally, patients with an IEM who have aged-out of a paediatric facility but continue to require specialist care should go through a formal process of transition, defined as “a purposeful, planned process which addresses medical, psychosocial and educational/vocational needs of those with chronic physical and medical conditions”. In these situations, transition is not a simple transfer of care, but an activity undertaken after care has been optimised and patients are stable and not unwell (to avoid ‘crash-landings’).

For the patient and their families, this is a major, life-changing event, with comfort from having developed a skill set drawn from experiences within a child-centred healthcare system, to learning how to navigate within an adult-orientated facility and dealing with a new group of healthcare providers. Understandably, it can be very stressful unless the process has been carefully mapped out beforehand, and with the patient’s readiness to engage in the process assessed in a thoughtful way.

Transition can be particularly challenging when patients have cognitive deficits, and parents are advancing in age, or themselves have developed medical problems.

The majority of patients with an IEM currently identified through NSPs and who have adhered to medical and dietary advice tend to do well. However, there can be situations where rigorous monitoring is required or emergent care becomes necessary. Examples include: (1) a woman with PKU who is planning pregnancy or currently expecting, in whom levels need to be kept within target ranges to avoid adverse foetal outcomes, and (2) adults with MSUD who decompensate; that is, become unwell with toxic levels of certain metabolites, potentially requiring dialysis to turn the situation around. Unfortunately, for some patients with galactosaemia, long-term follow-up has revealed complications such as language delay, speech defects, learning problems, cognitive and psychological impairment, tremor, ataxia, dystonia and, in females, premature ovarian insufficiency, despite adherence to diet.

Thus, even for metabolic conditions with which specialists have had a long experience in management, there is much that needs to be learned and for which better therapeutic strategies are required to achieve a good outcome.

So, for young adults with an IEM who look forward to a career, financial independence and having a family of their own, the team must work carefully with the patients to ensure they remain healthy and achieve fulfilling lives.

Currently, the Adult Metabolic Service is manned by one FTE consultant (Prof Gregory M Pastores and Prof Eileen Treacy), two full-time metabolic specialists, dietitians and two clinical nurse specialists (CNS2), and 0.5 FTE medical social worker (additional information can be found on the MMUH website). A position has been established to accommodate one NCHD and 0.5 FTE clinical psychologist to facilitate further transition of patients from CUH to MMUH in the next few weeks.

A significant number of adult patients are still cared for at the NCIMD at CUH and it is our hope that over the next two years as the Adult Metabolic Service expands, we will be in a position to transition more of these individuals and perhaps by 2018 on, have a seamless process in place — as a routine — for those turning 18 years old in January or later that year. This means that the number of adult patients with an IEM requiring specialist care will continue to rise and without an age cut-off (as with a paediatric service) and unless these individuals’ lives are prematurely curtailed by their disease, there will ultimately be a greater proportion of patients with an IEM requiring care within an adult-based facility. Ultimately, there may be a need to develop expertise within certain parts of the country to obviate the need for patients outside the capital to come to Dublin.

Current perspective and future prospects

To ascertain the needs and required resources of an Adult Metabolic Service, it will be essential to have a registry which lists the number of patients according to diagnosis. This is critical, in part because the complexity of dietary management and staff engagement is influenced by the underlying nature of the problem. As an example, patients with MSUD require more frequent monitoring than those with PKU (except women of reproductive age who are planning pregnancy or currently expecting). Within the constraints of the health service, a careful analysis and ongoing audit will help identify the needs of the service so care can be delivered in the most cost-efficient manner, with outcomes of value to both the patient and society.

For certain conditions, primarily LSDs for which enzyme replacement therapy (ERT) is available, the high cost of recombinant enzyme infusions is placing a huge demand on the health service and may benefit from a ring-fenced budget and oversight, with management directed by a team of experts working in conjunction with local healthcare providers. Over the last decade, it has become evident that ERT for certain LSDs, such as Fabry disease and the various MPS disorders (of glycosaminoglycans metabolism) has altered the natural history of the disease (that is, rate of progression and severity). However, it is also true that a significant proportion of treated patients experience a significant burden of disease or go on to develop major complications. Careful monitoring will be required to establish the benefit of therapy, in relation to the significance patients deem they are receiving from their commitment to these life-long infusions.

Investigations into the pathophysiology of IEMs have provided great insights regarding the normal functioning of the cell. In some cases, studies of these rare diseases have shed light on common disorders encountered in an ageing population. For instance, mutations (gene defects) that lead to Gaucher disease (LSD caused by deficiency of β-glucosidase) have been shown to increase the risk for Parkinson’s disease (PD), even among individuals who are carriers of the trait (that is, with one defective allele). The basis for this increased risk and the factor(s) that eventually influence its expression are not completely understood; however, it is hoped that further investigations into the relevant metabolic pathways will lead to a treatment strategy for PD.

It can be anticipated that the care of adult patients with an IEM will improve, as more effective and better targeted treatments become available. Realistically, and based on recent examples, this will mean an increasing number of high-cost therapies may be required by a small number of patients within a diverse group of metabolic conditions. Meticulous planning will be necessary so that we can be certain no one is disenfranchised.

Within an Adult Metabolic Service, the focus remains on viewing patients as valued members of society: helping them achieve fulfilling lives, loving relationships, enduring work when feasible, and an overall positive world view. 

Personally, I view this opportunity — to be a member of the metabolic team during these exciting times, as we build a programme together — a unique privilege to make ‘lives that matter at the Mater’. Indeed, as I was writing this report, I was struck by a message that I came upon today: ‘Children are the living messages we send to a time we will not see.’ We remain encouraged, with our colleagues’ help and support from the HSE, that we can be there for them into their adulthood.

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