Journal of the New Zealand Medical Association, 20-January-2012, Vol 125 No 1348
Diagnosis of disorders of intermediary metabolism in New Zealand before and after expanded newborn screening: 2004–2009
Callum Wilson, Nicola J Kerruish, Bridget Wilcken, Esko Wiltshire, Kathy Bendikson, Dianne Webster
Inborn errors of intermediary metabolism (IEMs) are genetic defects resulting in enzyme deficiencies of biochemical pathways and in particular those of amino acid, organic acid and fatty acid metabolism. The corresponding medical conditions are known as the aminoacidopathies, organic acidemias and the fatty acid oxidation disorders (FAODs) respectively. The clinical features of these diseases include symptoms such as encephalopathy that results from the accumulation of a toxic substrate, such as leucine in the aminoacidopathy maple syrup urine disease, or from the deficiency of energy providing products such as ketones in the FAODs.
The IEMs are individually rare, clinically heterogeneous, conditions that primarily affect young children. Without treatment the outcome is often poor. However with early diagnosis and treatment the prognosis for most conditions is favourable. A previous report documented that these IEMs were under-diagnosed in New Zealand and concluded that this was almost certainly due to the absence of newborn screening for these conditions.1
With the advent of expanded newborn screening (ENBS), a procedure by which amino acids and acylcarnitines are quantified in the newborn Guthrie card blood spot using tandem mass spectrometry, it was hoped that the under-diagnosis of these conditions would be rectified as over 20 different metabolic diseases can be identified with this technique (Table 1).
Table 1. Inborn errors of metabolism that can be diagnosed by expanded newborn screening
The purpose of this study was to compare the numbers of patients with disorders of intermediary metabolism diagnosed in New Zealand in the 3 years before the commencement of ENBS in December 2006, with the numbers diagnosed in the first 3 years of ENBS.
From January 2004 to December 2009 cases diagnosed by the Newborn Metabolic Screening Unit at LabPlus in combination with the Starship Children’s Hospital clinical metabolic team in Auckland were notified to the New Zealand Paediatric Surveillance Unit (NZPSU). In addition, paediatricians in New Zealand were sent monthly questionnaires, via email or regular post, from the NZPSU, asking whether they had diagnosed an inborn error of metabolism over the previous month. If they had they were sent a further questionnaire regarding the exact diagnosis along with aspects of the clinical presentation and immediate outcome. The Auckland, Wellington, and Christchurch laboratories that either perform the relevant metabolic investigations or facilitate samples being sent to the appropriate tertiary laboratories in Australia were also contacted and asked to report cases.
Cases were identified to the authors by initials, diagnosis and date of birth and notifications were screened to remove multiple notifications of single cases.
The cases diagnosed during the period December 2006–December 2009 when expanded newborn screening was available in NZ were compared to those diagnosed in the previous 3 years from January 2004 to December 2006. During this time ENBS was not available and thus these patients were diagnosed clinically or following a previous sibling being diagnosed.
Patients with phenylketonuria were not included in this study as this relatively common condition has been screened for in New Zealand for a number of decades and while the screening methodology has changed recently to mass spectrometry it is most unlikely that this has led to any change in the incidence..
This study was approved by the Lower South Regional Ethics Committee.
The number of patients with IEMs diagnosed in New Zealand during the study period 2004–2009 can be seen in Tables 2 and 3.
Table 2. Disorders of intermediary metabolism diagnosed in New Zealand: 2004–2006
See Table 1 for full names of detected conditions.
From Jan 2004–Dec 2006 inclusive there were approximately 175,000 births in New Zealand.2 During this period the majority of patients were diagnosed clinically apart from the one maple syrup urine disease patient who was diagnosed by a specific newborn screening test in use at the time, identifying elevated leucines by enzymatic assay The total number of patients diagnosed was 15, of whom four had non-ketotic hyperglycinaemia (NKH) while three had ornithine transcarbamylase (OTC) deficiency. Only small numbers of each other individual metabolic condition were diagnosed with the overall incidence being 1 in 11,666 (Table 2).
Table 3. Disorders of intermediary metabolism diagnosed in New Zealand: December 2006–2009
See Table 1 for full names of detected conditions.
From Dec 2006–Dec 2009 inclusive there were approximately 185 000 births in New Zealand.2 During this time 30 cases of IEMs were diagnosed via EBNS. Two additional cases were diagnosed after investigation of older siblings in the families of these EBNS cases. Seven cases presented clinically with IEMs either because they had conditions that are not detectable with EBNS (NKH and OTC) or they presented as older children born prior to December 2006 (homocystinuria and L-2(OH) glutaric aciduria). Three cases of carnitine-acylcarnitine translocase deficiency (CACT) presented on day 1 with symptoms and were diagnosed prior to the day 2 sample for EBNS being obtained (Table 3). Medium chain acyl-CoA dehydrogenase deficiency (MCAD), with 14 cases, was by far the biggest contributor to the overall incidence of 1 in 4302 during this period
Excluding NKH and OTC, disorders not able to be detected by current ENBS, some 22 extra cases of IEM were diagnosed by ENBS during the period.
There has been a dramatic increase in the number of cases of IEMs that have been diagnosed in New Zealand since the advent of ENBS. The overall rate of diagnosis has risen from around 1 in 12000 to either 1 in 4400 if all conditions are included or 1 in 6000 if those conditions that are general thought to be benign are excluded (3-MCC and benign forms of citrullinaemia and IVA). This increase has been mainly due to the ability to screen for MCAD, a disease that is generally considered to fulfil most screening criteria.3–5 MCAD is a disorder resulting in a relative inability to convert medium chain fat into energy. This process is needed during times of catabolic stress.
The condition is especially important in young children as they have reduced glycogen stores and are more prone to significant intercurrent illness. It is during these times that the children become catabolic and as they cannot produce ketones adequately they become hypoglycaemic and encephalopathic. They often die if left untreated for a few hours in this state. This disease is easily and successfully treated with patient/parent education stressing the need to feed the child a high calorie diet during times of unwellness and if the child is not taking this feed or there are any other concerns then to have a low threshold for admission to hospital for intravenous feeding until they are well enough to feed normally.
Without screening roughly a third of MCAD children present clinically with life-threatening hypoglycaemia and encephalopathy and are eventually diagnosed while a third either never get diagnosed correctly despite presenting with classical clinical features or die from their disease prior to a diagnosis. The remaining third never have symptoms and thus don’t get diagnosed.6–9 It is thus clear that lives will have been saved in the 3 years since screening for MCAD, as part of ENBS, commenced.
Three cases of glutaric academia type I (GA-1), all with as yet good outcome, were diagnosed in the later cohort compared with one case, with a poor outcome, in the early cohort. GA 1 is another disease that also often presents secondary to an intercurrent illness. Unlike MCAD which tends to result in either death or a relatively normal outcome GA-1 often results in severe neurodisability.10,11 While not all patients with GA 1 suffer disease, most do, and it seems likely that at least two of the children diagnosed through screening would have had very significant if not fatal disease without ENBS.11,12
No cases of clinically significant metabolic diseases from the other organic acidemias (for instance methylmalonic and propionic acidemia) were diagnosed by screening during the 2006–2009 period. This is likely to reflect chance as we have no evidence that such a diagnosis was missed.
The optimal time, regarding sensitivity and specificity, for EBNS is at 48hours of age with a subsequent small delay of a few days to allow for transport and laboratory processing of the Guthrie card. Thus patients can become unwell prior to the results being available. During the study period three neonates presented with profound hypoglycaemia and cardiac dysfunction on day 1; symptoms classical for the long chain fatty acid oxidation disorders. All three, despite being unrelated and from different ethnic groups were later shown to have the extremely rare condition CACT, a disorder in the transport of fat into the mitochondria.
While it was extremely useful to be able to establish the diagnosis rapidly with the local availability of tandem mass spectrometry in two of the cases the diagnosis was already strongly suspected clinically and successful treatment commenced while in the third clinical management was, for a variety of reasons, less than optimal and the child died. However, it is likely that the availability of expanded newborn screening increases the awareness of the possibility of an IEM, and improves the likelihood of a final diagnosis being reached in such cases.
One of the MCAD cases was also significantly symptomatic with hypoglycaemia and liver disease secondary to metabolic decompensation prior to the results of EBNS becoming available. This illustrates the importance of clinicians who care for neonates to continue to request urgent metabolic investigations if they have clinical suspicion of an IEM rather than waiting for the results of screening.
The very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) cases represent an area of difficulty with ENBS. The phenotype is dependent on both the genotype and the environmental or more correctly the physiological state. VLCAD is another disorder resulting in a relative inability to convert fat into energy. Patients with severe VLCAD defects can present, like CACT, prior to a screening result becoming available, during the normal early neonatal catabolic phase. However the majority of patients diagnosed with VLCAD, especially during the era of ENBS, have a mild form of the disease whereby they become symptomatic not with childhood illnesses and moderate periods of starvation like MCAD patients but with prolonged exercise, during which time, if not accompanied by a good oral intake of calories, they can experience rhabdomyolysis and cardiac dysfunction.13 Thus some patients diagnosed with a disease in the first week of life via ENBS may not be at any risk of symptoms until much later in life, if at all.
Our two cases, one from each cohort, illustrate this. The patient from 2004–2006 was diagnosed as an adult after recurrent episodes of rhabdomyolysis during periods of moderately severe exercise (2 hours plus mountain biking) accompanied by relatively poor caloric intake while the case from 2006–2009 has never been symptomatic despite a few typical childhood illnesses, albeit with the precaution of the parents knowing to maintain a good oral intake during these times, after being diagnosed by ENBS.
Because of this problem of potentially diagnosing patients who will only become symptomatic if exposed to quite significant physiological stress it has become important to clarify where the screening laboratory/metabolic service ‘draws the line in the sand’ as to what one ‘calls’ a disease and thus notifies the family about. As yet, there is no clear international agreement on whether biochemical, enzymological or molecular findings for VLCAD are the best discriminators for defining likely future disease.14,15 A close working relationship between the screening laboratory and the clinical metabolic team is thus essential with the latter having enough resources to provide a rapid and thorough service to the whole of the country.
There are a number of IEMs that are probably not clinically significant and yet are diagnosable by ENBS. There remains considerable debate about some of these conditions. Centres in Australasia, for example, consider short chain acyl Co-A dehydrogenase deficiency (SCAD) to be a benign condition and thus should not be screened for whereas many centres in the United States and continental Europe feel that this is indeed a condition that warrants screening.16–18
There are some reports of the negative consequences of informing a family of a ‘disease’ that is not really a disease at all.19,20 In New Zealand we have a particularly high incidence of a benign form of citrullinaemia due to a high rate of this in the Niuean population and a secondary molecular test has been developed to identify these patients rapidly and the decision what to inform the family is based on this. 21
Likewise there are diseases such as multiple acyl CoA dehydrogenise deficiency (MADD) which in some instances are not always responsive to optimal treatment and if one considers the ability to successfully treat to be one of the main tenets of screening then the merits of EBNS for this disorder could be debated. However many of these conditions are themselves clinically heterogeneous and there is little doubt that some forms are very responsive to treatment. In addition, the ability to successfully treat a condition should not be seen as the sole reason for screening as there are other advantages of early diagnosis such as the avoidance of a ‘diagnostic odyssey’ and potential for future pregnancy risk to be discussed through genetic counselling.
The case of carnitine uptake disorder illustrates the interesting phenomenon whereby biochemical abnormalities in the screened child may reflect primary disease in the mother. With this case it was the mother who had a defect in the transporter for carnitine, a substance required for the metabolism of fatty acids and whose deficiency can lead to hypoglycaemia and encephalopathy. Her subsequent low carnitine levels resulted in the fetus also having very low levels and thus being at risk of disease. A simple short course of carnitine supplements cured the baby while the mother requires life-long carnitine supplements. Vitamin B12 deficiency in women, usually due to dietary reasons, can also be diagnosed in a similar manner based on the elevated levels of Vitamin B12 dependent substrates in the blood of the screened newborn.
During the short study period we had no evidence that conditions that are diagnosable by ENBS were missed with screening and presented clinically at a later date
Non ketotic hyperglycaemia (NKH) and ornithine transcarbamylase deficiency (OTC) are two relatively common disorders of intermediary metabolism that are not easily detected by ENBS due to a lack of specificity of key diagnostic metabolites. They are diagnosed on an episodic clinical basis and there has been understandably no change in the incidence between the two periods.
Although they have arguably characteristic phenotypes of severe neonatal seizures and unexplained encephalopathy respectively it is likely that they remain under-diagnosed, based on the dramatic increase in prevalence in the equally clinically characteristic ENBS condition of MCAD with the commencement of screening. Additionally, ‘mild’ cases of these disorders, who would benefit greatly from appropriate management, certainly cannot be detected at present. This is especially relevant in New Zealand as both NKH and OTC have a high incidence in the Māori and Pacific peoples respectively.22
There are many other metabolic diseases that are not currently screened for currently by ENBS, including the glycogen storage diseases, mitochondrial disorders, the peroxisomal diseases, and the various disorders of purines, pyrimidines, lipids, metals, protein glycosylation, creatine, cholesterol, and neurotransmitters. These conditions are also likely to be under-diagnosed.
In summary this study has shown the ENBS has resulted in an increase in the number of patients diagnosed with IEMs. While it is too early to be definitive regarding how beneficial this has been it is likely that this has resulted in a number of lives per year being saved. This study supports the findings from a number of other centres that ENBS in an important recent addition to newborn screening and to the diagnosis of metabolic diseases.
Competing interests: None declared.
Author information: Callum Wilson, Metabolic Paediatrician, Newborn Metabolic Screening Unit, LabPlus, Auckland City Hospital, Auckland; Nikki Kerruish, Paediatric Research Fellow, Department of Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, Dunedin; Bridget Wilcken, Metabolic Physician, Director, NSW Biochemical Genetics and Newborn Screening Services, The Children’s Hospital at Westmead, Sydney, Australia; Esko Wiltshire, Senior Lecturer, Department of Paediatrics and Child Health, University of Otago Wellington; Kathy Bendikson, Newborn Metabolic Screening Programme, Ministry of Health, Penrose, Auckland; Dianne Webster, Director, Newborn Metabolic Screening Programme, LabPlus, Auckland City Hospital, Auckland
Correspondence: Dr Callum Wilson, Metabolic Paediatrician, Newborn Metabolic Screening Unit, PO Box 872, Auckland, New Zealand. Fax: +64 (0)9 3074978; email firstname.lastname@example.org
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