 
|
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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.
MethodFrom 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.
ResultsThe 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.
DiscussionThere 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 callumw@adhb.govt.nz
References:
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| | Current
issue | Search journal |
Archived issues | Classifieds
| Hotline (free ads) Subscribe | Contribute | Advertise | Contact Us | Copyright | Other Journals |
|