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| Journal of the New Zealand Medical Association,
21-September-2007, Vol 120 No 1262
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The failure to diagnose inborn errors of
metabolism in New Zealand: the case for expanded newborn screening
Callum Wilson, Nicola J Kerruish, Bridget Wilcken,
Esko Wiltshire, Dianne Webster
Inborn errors of metabolism are genetic defects of
biochemistry that may result in clinical illness. Individually they are rare
conditions, but collectively they are not uncommon with an overall prevalence
approaching 1:1000.1,
2
A group of conditions—disorders of
intermediary metabolism—involve the catabolism of fats and protein. These
are the fatty acid oxidation disorders and the amino and organic acidopathies.
The former involve defects in the mitochondrial oxidation of fatty acids and
present (classically) with hypoglycaemia, inappropriately low ketones, and
subsequent encephalopathy often following a period of fasting and/or
intercurrent illness in a child. The latter result in massive accumulation of
specific amino and organic acids, sometimes with associated hyperammonaemia, and
clinically often present with neonatal encephalopathy or alternatively with
varied presentations later in life.
Because the diseases are rare, and the clinical phenotypes
encountered are much more frequently seen in conditions such as sepsis, the
correct underlying diagnosis is frequently missed. This leads to catastrophic
outcomes, as death is likely if an accurate diagnosis is not made. In fact even
when a correct diagnosis is made during the initial presentation the outcome can
be poor as neurological damage has already occurred. Thus diagnosis and
treatment prior to clinical illness is ideal.
Expanded newborn screening (ENBS), using tandem mass
spectrometry, accurately detects marker compounds in the dried blood spot from
the neonatal Guthrie card The technique is highly sensitive and specific and,
once initial setting up costs are meet, is relatively cheap when added to an
existing newborn screening service.3
ENBS allows for the identification of around 30 different
disorders—provided the sample is taken at the correct time, transported
quickly to the screening laboratory, and analysed appropriately, and treatment
is started prior to the child becoming
unwell.4 The
newborn screening service in New South Wales, one of the pioneers of ENBS, has
recently shown that this leads to significant improvements in diagnostic rates
and outcome.5, 6
The purpose of this study was to evaluate the incidence
rates of the disorders of intermediary metabolism in New Zealand (NZ), based on
the numbers of clinical diagnosis, from January 2004 till the commencement of
ENBS in December 2006 and to compare these to the incidence rates, obtained
mostly via EBNS, in New South Wales (NSW).
MethodFrom January 2004, paediatricians in NZ were sent
monthly questionnaires (via email or regular post) from the New Zealand
Paediatric Surveillance Unit (NZPSU). It asked whether they had diagnosed an
inborn error of metabolism over the previous month. If they had then they were
sent a further questionnaire regarding the exact diagnosis along with aspects of
the clinical presentation and immediate outcome.
This study was approved by the Lower South Regional
Ethics Committee. In addition 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 contacted and ask to report cases.
The numbers of patients diagnosed with disorders of
intermediary metabolism diagnosed clinically (thus excluding PKU which is
diagnosed by already established screening methods) in NZ from 2004–2006
were compared to those obtained from childhood clinical presentations and the
expanded newborn screening programme (see Table 1 for a list of diseases
screened that can be diagnosed by ENBS) based at The Children’s Hospital
at Westmead in Sydney, New South Wales during the same period.
The latter facility screens all newborns in New South
Wales and the Australian Capital Territory (these two areas will be referred to
as ‘NSW’ in this document).
ResultsFrom 2004–2006 inclusive there were approximately
175,000 births in NZ7 and 270,000 births in
NSW.8
During the 3-year study period, 15 cases of disorders of
intermediary metabolism were reported in NZ (Table 2). One of these (Maple Syrup
Urine Disease, MSUD) was diagnosed by the newborn screening programme (NZ is
somewhat unusual internationally in that it had an established screening
programme specific for this disorder during the period 2004-6); one was
diagnosed prenatally (ornithine transcarbamylase deficiency, OTC) following a
sibling diagnosis; and in 13 cases the diagnosis was made following metabolic
investigations performed during the clinical investigation of a symptomatic
patient. Eight cases (including one adult) were diagnosed with disorders on
intermediary metabolism that could have been detected by ENBS.
Table 1. Inborn errors of metabolism that can
be diagnosed by expanded newborn screening
Fatty acid oxidation
disorders
Carnitine uptake defect
Carnitine palmityltransferase 1
deficiency (CPT1)
Carnitine palmityltransferase 2
deficiency (CPT2)
Carnitine-acylcarnitine
translocase deficiency
Medium chain acyl-CoA
dehydrogenase deficiency (MCAD)
Long-chain L-3-OH acyl-CoA
dehydrogenase deficiency (LCHAD)
Very long-chain acyl-CoA
dehydrogenase deficiency (VLCAD)
Trifunctional protein deficiency
Multiple acyl-CoA dehydrogenase
deficiency (MADD)
Aminoacidopathies
Phenylketonuria (PKU)
Homocystinuria (Hcy)
Maple syrup urine disease
(MSUD)
Argininase deficiency
Argininosuccinic acidaemia
Citrullinaemia type 1 (CIT
I)
Citrullinaemia type 2 (CIT
II)
Tyrosinaemia type II (TYR)
Organic
acidopathies
Glutaric acidaemia type 1
(GA1)
Beta ketothiolase
deficiency
Isovaleric acidaemia
Methylmalonic acidaemia
(Cobalamin disorders- CblC)
Methylmalonic acidaemia (mutase
deficiency) (MMA)
Holocarboxylase synthetase
deficiency (HCS)
Propionic acidaemia
HMG-CoA lyase deficiency
2 Methyl 3 hydoxybutyric
acidaemia
3 Methyl glutaconic
acidaemia
3 Methylcrotonyl carboxylase
deficiency (3-MCC)
Other
Vitamin B-12 deficiency
Table 2. Disorders of intermediary metabolism
diagnosed in New Zealand: 2004–06
MCAD=Medium chain acyl Co-A dehydrogenase deficiency;
GA1=Glutaric acidaemia type I; HCS=Holocarboxylase synthetase (deficiency);
MADD=Multiple acyl Co-A dehydrogenase deficiency; VLCAD=Very long-chain acyl-CoA
dehydrogenase deficiency; NKH=Non-ketotic hyperglycinaemia; OTC=Ornithine
transcarbamylase (deficiency).
Table 3. Disorders of intermediary metabolism
diagnosed in New South Wales: cohort born 2004-06 (N=45)
CblC=Cobalamin C deficiency; MMA=Methylmalonic acidaemia;
CIT 1=Citrullinaemia type I; CIT II=Citrullinaemia type II; TYR=Tyrosinaemia;
Hcy=Homocystinuria; 3-MCC=3-Methylcrontonyl carboxylase deficiency.
During the same period, 45 children were diagnosed in NSW
(Table 3). Thirty-nine cases were disorders of intermediary metabolism diagnosed
via ENBS. An additional two cases, potentially diagnosable by ENBS, were
diagnosed prior to screening; one prenatally and one symptomatically in the
first few days of life. Of the other four cases, three were diagnosed clinically
after screening (two of non-ketotic hyperglycinaemia [NKH] and one of ornithine
transcarbamylase [OTC] deficiency, and one prenatally [OTC]).
Three mothers were diagnosed, based on the results’ of
their children’s newborn screening, with the probably benign condition
3-methylcrontonylcarboxylase (3-MCC) deficiency. In addition, the ENBS programme
diagnosed two neonates with vitamin B-12 deficiency.
Specifically looking at the disorder—medium chain acyl
Co-A dehydrogenase deficiency (MCAD)—two cases were diagnosed in NZ (1 in
87,500) and 24 in NSW (1 in 11,250).
DiscussionThe duration of this study and the numbers involved are not
sufficient to prove or disprove the effectiveness of ENBS. However larger
studies (many of them from the NSW screening programme) have addressed this
issue.4–6 This study does, however,
illustrate a number of important points pertaining to the recent introduction of
ENBS in NZ.
MCAD is by far the most prevalent disorder of intermediary
metabolism (excluding PKU which has been screened for separately in NZ since the
late 1960s), and thus the most important condition clinically. Classically it
presents with hypoketotic hypoglycaemia and encephalopathy, following a period
of catabolic stress such as a viral gastroenteritis, during the early childhood
years.
Without screening, approximately 25% of cases die from MCAD
prior to or without a diagnosis.9–11 A
slightly smaller percentage have at least one admission with characteristic
clinical features (hypoglycaemia, encephalopathy) prior to a correct diagnosis
being made. This is unfortunate as treatment is simple and cheap, and once a
diagnosis is made, the outcome is excellent with a very low mortality and
morbidity.6, 10
The key to treatment is patient/parent education. Parents
are instructed to make sure the child has a regular oral energy intake,
especially when they are unwell and prior to going to sleep at night. During
times of intercurrent illness they should commence the emergency regimen (Table
4). While some of the other disorders of intermediary metabolism require
somewhat more complicated diets and medications, the emergency regimen is an
important aspect in the treatment of all.
Perhaps a third of children with MCAD do not present
clinically. They are the subgroup that for whatever reason (most likely an
avoidance of significant childhood illnesses) are never subjected to significant
catabolic stress and thus avoid situations where they are fully reliant on their
bodies’ ability to metabolise fatty acids.
It could be argued that ENBS is in fact harmful to these
patients as it potentially introduces psychological stress to a family that were
never going to have problems. However the ability to prevent mortality in the
symptomatic children outweighs this probably minor concern. Increasing evidence
also shows that the initial presentation of MCAD is not confined to the
childhood years—and events such as self-induced alcohol intoxication,
prolonged labour with unexpected fasting, and unrelated medical illnesses can
precipitate metabolic decompensation in adulthood.12,
13 There is also evidence that some patients with MCAD can have chronic
problems with fatigue, muscle pain, and exercise
intolerance.11
Table 4. The Emergency Regimen for the initial
home treatment of suspected metabolic decompensation in disorders of
intermediary metabolism
Two cases of MCAD were diagnosed in NZ during the study
period and thankfully both had a good outcome. However, presuming a similar
incidence as NSW, it is likely that 16 children (95% confidence interval:
9–22) were born with the condition during the study period. Of these, 3-4
children would have died.9,10
We are aware of two NZ children dying from confirmed MCAD
over the last 6 years. Thus purely for this one condition it is possible to make
a good case for ENBS in NZ. A cost-benefit analysis commissioned by the New
Zealand National Testing Centre in 2002 found that (over a 7-year period) the
cost per death avoided would be $11,500 and the cost per life year gained
$590.14
Another problem that has emerged with the advent of MCAD
screening is the realisation that the mutation profile of patients with MCAD
deficiency diagnosed by ENBS is somewhat different from that of those diagnosed
clinically, in that the proportion of alleles with the common MCAD mutation in
children who are diagnosed symptomatically is greater than in those that are
diagnosed via ENBS.15,16
This suggests that there are a group of MCAD patients
identified by screening who, while having the typical blood biochemical profile,
are at a lesser risk than those with the ‘classical’ form of the
condition. This is hardly surprising as several other metabolic diseases (for
instance MSUD and PKU) are known to have milder or intermediate forms. This
phenomenon is likely to be seen in other conditions and illustrates the evolving
nature of ENBS knowledge.
Most of the other fatty acid oxidation disorders (FAODs) are
also readily diagnosed by ENBS. They tend to present in a similar manner to
MCAD. Some, such as LCHAD, have an even poorer prognosis without
screening.17 Others such as late-onset VLCAD
tend not to present with childhood hypoglycaemia—but (as seen with the
case diagnosed in NZ during the study period) with exercise induced
rhabdomyolysis in adulthood. Thus, while still a useful disease to diagnose
early (the patient in question had many years of exercise induced muscle
problems that could have been prevented with a high calorie oral carbohydrate
intake prior to and during activity), one may encounter a situation in which a
disease that is not going to cause problems for many years is diagnosed soon
after birth.
While the case for ENBS for the FAODs (in particular MCAD)
is strong, the situation is less clear for some of the amino and organic
acidopathies.18 These disorders of protein
catabolism generally present with encephalopathy and the long-term outcome is
often dependent on the degree of neurological damage suffered during the first
presentation.
Some, such as glutaric aciduria type 1 (GA I) and beta
ketothiolase deficiency, tend to present after the neonatal period, and as
treatment is available and screening can easily be added (with minimal
additional cost to the screening programme for the FAODs), a good case for
screening can be made.
The known case of GA I that presented during the study
period in NZ resulted in severe disability that could have been prevented with
early detection. Based on the NSW figures, it is possible (even likely) that
there are were other similar cases in NZ—although they remain undiagnosed
and thus remain unreported.
NSW reported 41 children (1 in 6585) with treatable inborn
errors of metabolism that can be detected by ENBS; 2 of these were diagnosed
prior to screening. In NZ we diagnosed 7 children (1 in 25,000) during the same
period, 1 (MSUD) by established screening, and 1 clinically in the first few
days of life.
Assuming a similar incidence in both populations, as well as
the 14 ‘missed’ cases of MCAD described above, there may have been
an additional 6 (95% confidence interval: 2–10) cases of other inborn
errors that were not diagnosed correctly, or (less likely) have not yet
presented clinically.
In some conditions, such as the classical severe forms of
methlymalonic aciduria and MSUD, the children are likely to be becoming sick
within the first few days of life. This is illustrated by the NZ patient with
MSUD who was diagnosed by the existing screening programme on the day following
the child’s admission to hospital with encephalopathy. While an even
earlier diagnosis would have been optimal, the screening diagnosis allowed for a
much earlier diagnosis than would have been obtained on clinical grounds and
thus undoubtedly improved the child’s outcome.
Thus in order to optimise outcome and screening programme
effectiveness it is critical that the Guthrie card is obtained early (as soon is
practical after 48 hours of age) and just as importantly transported quickly to
the screening laboratory.
There are some disorders that ENBS cannot reliably diagnose.
This is because the key metabolites in affected patients are not in a range that
is significantly different from the extremes of the normal population and thus
NBS is not sufficiently specific.
OTC deficiency—the most common of the urea cycle
disorders and thus a disease in which it would be beneficial to screen
for—is probably the most important of these. Therefore it is vital that
clinicians remain alert for the possibility of an inborn error of metabolism in
sick children and do not assume that just because the child has had a normal
newborn screen that they do not have a metabolic disorder.
Direct communication with the screening laboratory and/or
the related clinical metabolic service can be very useful in these cases. Based
on the numbers of metabolic investigations performed there appears to be lesser
index of suspicion of metabolic disease in symptomatic individuals in NZ
compared to Australian centres.
Some disorders cannot be diagnosed by ENBS and in addition
there is no effective treatment. Classical NKH, a condition characterised by
early neonatal seizures and encepahalopathy, is the best example of this. This
is particularly relevant in New Zealand where NKH appears to have a high
incidence in the Māori population as illustrated by the four cases
diagnosed during the study period.
Another condition with a high incidence in New Zealand is
biotin-resistant holocarboxylase synthetase (HCS)
deficiency.19 Typically classical HCS presents
in the first few months of life, is easily treated with oral biotin, and is thus
a good candidate disease for NBS. However in the Samoan population, due to the
presence of a particularly pathogenic common mutation, it presents (on day 1 of
life) with severe lactic acidosis and encepahalopathy and treatment with biotin
is overall disappointing. (However, newborn screening may assist families, by
ensuring that a diagnosis is made, if all children are tested.)
Additional early evidence shows that several other metabolic
diseases occur with particularly high frequency in the Pacific communities,
probably due to a gene founder affect.20
Similarly, ethnic groups where consanguinity is not uncommon also have a high
incidence. Thus the unique ethnic demographics of the NZ population need to be
considered when interpreting international recommendations regarding ENBS
Some metabolic diseases detectable by ENBS are probably
benign conditions in most patients. 3-methylcrotonyl carboxylase (3-MCC) and
short chain acyl Co-A dehydrogenase deficiency are two such conditions. The NSW
screening programme diagnosed three mothers with 3-MCC deficiency by detecting
the relevant raised metabolites in the Guthrie card of the newborn infant. The
child’s metabolism had not yet had a chance to clear these maternal
compounds that had accumulated in utero.
SCAD deficiency has now been removed from the list of
screened conditions. Similarly, although more clinically significant, woman who
are vitamin B-12 deficient can be detected by noting a raised propionyl
carnitine levels in their child’s Guthrie card sample. The children are
also B-12 deficient and are at significant risk as they are likely to be exposed
to a low B-12 diet during infancy.
There have been a small but regular number of infants
suffering from catastrophic complications of B-12 deficiency in NZ in recent
years and hopefully ENBS will help to address this problem.
A high degree of specificity is important in all screening
programmes. ENBS measures a number of key metabolites (corresponding to one or
more disease), each with cut-off limits, outside of which a second sample is
requested. Thankfully the highly accurate nature of mass spectrometry means that
despite screening for 20 plus diseases, the cumulative false positive rate is
only around 0.2%. Thus in NZ we may expect to ask for second samples in around
120 patients annually. The second sample is nearly always normal and reflects
the normalisation of the neonates biochemistry rather than an inaccurate first
test.
Nevertheless false positives can led to heightened parental
anxiety,21 and improved communication and
education of all parties involved in screening has been suggested as the optimal
strategy in reducing this.22
Expanded newborn screening using tandem mass spectrometry is
an important recent development in screening and paediatrics. Unlike most
screening programmes whereby a single test is used to screen for a single
disease, ENBS uses a single sample to measure a large number of compounds to
look for a range of diseases.
With some of these diseases there is good evidence that
current clinical detection methods are inadequate and likely to be leading to
unnecessary mortality and thus a strong case can be made for newborn screening.
With other conditions the supporting evidence for screening
is not yet available, usually because of the rarity of the individual disease,
although clinical experience suggests there are likely to be benefits provided
unnecessary delay is avoided in the collection, transport, and processing of the
samples.
The change from a ‘one test-one disorder’ to a
‘one test-many disorders’ paradigm has added complexity to decision
making in newborn screening. The National Screening Unit of the Ministry of
Health, who have governance over the Newborn Metabolic Screening Programme, was
required to examine in detail the implications of ENBS. Securing the required
capital to purchase the tandem mass spectrometer was problematic and required a
generous contribution from the Starship
Foundation.23
For these reasons, and despite evidence supporting the
benefits of ENBS accumulating since the
mid-1990s,24,25 NZ was the last (commenced in
December 2006) of the newborn screening programme countries in the Asia-Pacific
region to introduce ENBS.
Competing interests: None.
Author information: Callum Wilson,
Metabolic Paediatrician, Newborn Metabolic Screening Unit, LapPlus, Auckland
City Hospital, Auckland; Nicola J 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, NSW, Australia; Esko Wiltshire, Paediatrician,
Paediatric Department, Wellington Hospital, Wellington; Dianne Webster,
Director, Newborn Metabolic Screening Programme, LapPlus, Auckland City
Hospital, Auckland
Acknowledgements: Dr Kerruish received
funding for this study through a Freemasons of New Zealand Postgraduate
Fellowship in Paediatrics and Child Health. We also thank Peter Reed
(Statistician, Department of Paediatrics, University of Auckland) for advice
regarding confidence intervals and members of the Newborn Metabolic Screening
Unit for support in establishing expanded newborn screening.
Correspondence: Dr Callum Wilson, Metabolic
Paediatrician, Newborn Metabolic Screening Unit, PO Box 872, Auckland. Fax: (09)
307 4978; email: callumw@adhb.govt.nz
References:
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