J. Inherit. Metab. Dis.

28 (2005) 457^465
# SSIEM and Springer. Printed in the Netherlands

Breastfeeding experience in inborn errors

of metabolism other than phenylketonuria
G. Huner*, T. Baykal, F. Demir and M. Demirkol
Department of Pediatric Nutrition and Metabolism, Istanbul Medical Faculty,
Istanbul University, Istanbul, Turkey
*Correspondence: Department of Pediatric Nutrition and Metabolism, Istanbul
Medical Faculty, Istanbul University, Capa 34093 Istanbul, Turkey.
E-mail: ghuner@istanbul.edu.tr
MS received 19.04.04 Accepted 23.12.2004

Summary: Breastfeeding has been recommended for the dietary treatment of

infants with phenylketonuria, but studies documenting clinical experience in other
inborn errors of metabolism are very few. Seven infants diagnosed with
methylmalonyl-CoA mutase deficiency (n 2), ornithine carbamoyltransferase
deficiency (n 1), propionic acidaemia (n 1), isovaleric acidaemia (n 1),
maple syrup urine disease (n 1) and glutaric acidemia type I (n 1) were tried
with breastfeeding over two years. After the control of acute metabolic problems,
an initial feeding period with a measured volume of expressed breast milk plus
a special essential amino acid mixture was continued with breastfeeding on
demand and with the addition of a special essential amino acid mixture. Two
patients with methylmalonic acidaemia and one patient with glutaric acidaemia
type I tolerated breastfeeding on demand very well, with good growth and meta-
bolic control for periods of 18, 8 and 5 months, respectively. In the patient with
propionic acidaemia, on-demand breastfeeding continued for 3 months but
was terminated after two acute metabolic episodes. The patient with isovaleric
acidaemia had insufficiency of breast milk and formula supplementation ended
with breast milk cessation. In the patient with severe ornithine carbamoyltrans-
ferase deficiency, breastfeeding was stopped owing to poor metabolic control.
The patient with maple syrup urine disease also experienced problems, both in
metabolic control and in insufficiency of breast milk, resulting in termination
of breastfeeding. Breastfeeding of infants with inborn errors of protein catabolism
is feasible, but it needs close monitoring with attention to such clinical parameters
as growth, development and biochemistry, including amino acids, organic acids
and ammonia.

Breastfeeding provides complete nutrition for an infant, oers immunological and

nutritional benets, and has important advantages especially for infants with inborn

457
458 Huner et al

errors of metabolism (IEMs). The low protein and amino acid content, protection
against infections, reduction in propionate from the gut and low treatment cost are
some of these benets (Leonard and van Wyk 2002). The principles of breastfeeding
of babies with IEMs are well established for phenylketonuria (PKU, McKusick
2616000) (McCabe et al 1989). This is based on the principle of giving a measured
volume of low-phenylalanine infant formula before breastfeeds, so that sucking
and hence production of breast milk is limited, reducing intake of breast milk and
phenylalanine. Plasma phenylalanine concentrations were used to determine how
much infant formula to give. These principles can be applied to the management
of babies with other IEMs. There are a few absolute contraindications to breast-
feeding, including galactosaemia, long-chain fatty acid oxidation disorders, hyperchy-
lomicronaemia and abetalipoproteinaemia (Leonard and van Wyk 2002). Candidate
disorders for breastfeeding are aminoacidopathies such as maple syrup urine disease
(MSUD, McKusick 248600), organic acidaemias as propionic acidaemia (PA,
McKusick 606054), methylmalonic acidaemia (MMA, McKusick 251000), isovaleric
acidaemia (IVA, McKusick 243500), glutaric acidaemia type I (GA I, McKusick
231670) and mild variants urea cycle disorders such as ornithine carbamoyltransferase
(ornithine transcarbamylase, OTC) deciency (McKusick 311250) and carbamoyl-
phosphate synthetase (CPS) deciency (McKusick 237300) (Leonard and van Wyk
2002). Some IEMs, such as the severe forms of urea cycle disorders as OTC and
CPS (CPS, McKusick 237300), are very dicult to manage, so that breastfeeding
is not likely to be successful.
In this study we tried breastfeeding seven patients with mutase-negative MMA
(n 2), OTC deciency (n 1), PA (n 1), IVA (n 1), MSUD (n 1) and
GA I (n 1) during the rst two years. Our aim was to achieve on-demand
breastfeeding after the stabilization of acute illness, if necessary with the addition
of special amino acids and energy mixtures.

PATIENTS AND METHODS

Seven patients with mutase-negative MMA (n 2), OTC deciency (n 1), PA
(n 1), IVA (n 1), MSUD (n 1) and GA I (n 1) who were prospectively
followed and breastfed were included in the study. Six patients presented with an
acute illness and one patient with MMA was diagnosed soon after birth before
the onset of clinical symptoms because of sibling history (Table 1). Dietary therapy
was planned in two stages as management of acute episodes and long-term
management. During the acute phase, the goals were to maintain biochemical balance
by treating ketoacidosis and hyperammonaemia. After the management of the acute
episode, all of the patients received natural protein intake from a measured volume
of expressed breast milk. After the establishment of good metabolic control, feeding
with expressed breast milk was followed with on-demand breastfeeding. Modular
ingredients such as special amino acids-based feeds developed for IEMs and energy
supplements with glucose polymers and fats were used with expressed breast milk
or prior to on-demand breastfeeding. Clinical parameters such as general wellbeing,
feeding records and body weight and biochemical parameters such as quantitative

J. Inherit. Metab. Dis. 28 (2005)

 Table 1 Study group

Duration of Neurological
Age Clinical breastfeeding Supplements Problems Current developmentd,
Patient (months), Age at symptoms at while during feeding assessment
number Sex Diagnosisa diagnosisb diagnosis Expressed On demand breastfedbc breastfeeding statusb ageb

1 18, M mut  MMA 1 d None 6d 18 mo DAM until None Still Normal,

6 mo, LPWF breastfed 9 and
after 6 mo at 18 mo 18 mo
2 21, F mut  MMA 3 mo Metabolic 1 wk 8 mo DAM, Low plasma Breastfed Normal,
acidosis, LPWF essential until 9 and
encephalopathy, after 5 mo amino acids, 11 mo 15 mo
hyperammonaemia, 2 episodes of
loss of acquired mild acidosis
skills
3 30, F GAI 6 mo Metabolic coma, 5 mo DAM, None Breastfed Retarded,
loss of acquired LPWF after until 6 mo: GDA
skills 7 mo 11 mo 1 mo
Breastfeeding in IEMs other than PKU

7 mo: GDA 3 mo
10 mo: 5 mo
4 4, M OTC 5d Severe metabolic 1 mo 2 wk DAM with Inadequate Breastfed Lost in a later
coma, expressed metabolic until metabolic
hyperammonaemia breast milk control 1.5 mo coma at
age 4 mo
5 24, M MSUD 10 d Metabolic 55 d 5 wk DAM Elevated Breastfed Normal,
encephalopathy, branched-chain until 12 and 16 mo
ketosis amino acids 4 mo
6 14, M PA 6d Metabolic 2 wk 3 mo DAM 2 episodes of Breastfed Normal, 1 y
acidosis, vomiting, until
encephalopathy, encephalopathy 4 mo
hyperammonaemia
7 18, F IVA 8d Metabolic 13 d 1 mo DAM Breast milk Breastfed Normal, 1 y
acidosis, insuciency, until
encephalopathy, poor weight 1.5 mo
hyperammonaemia gain
a
mut  MMA, mutase-negative methylmalonic acidaemia; GAI, glutaric acidaemia type I; OTC, ornithine carbamoyltransferase deciency; MSUD, maple
459

J. Inherit. Metab. Dis. 28 (2005)

syrup urine disease; PA, propionic acidemia; IVA, isovaleric acidemia
b
d, day(s); wk, week(s); mo, month(s) y, year(s)
c
DAM, disease-specic amino acid mixture; LPWF, low-protein weaning foods
d
Neurological development assessed with Denver Developmental Screening Test II (DDST II); GDA, global developmental age assessed with DDST II
460 Huner et al

plasma amino acids, serum ammonia and urinary ketones and organic acids analysis
by gas chromatography^mass spectrometry (GC-MS) were monitored on a weekly
or biweekly basis after discharge from the hospital. Developmental assessment
was performed with the Denver Developmental Screening Test II (DDST II).
The characteristics of the study group such as age, sex, diagnosis, age at diagnosis,
duration of expressed and on-demand breastfeeding, supplements given during
breastfeeding, problems encountered during breastfeeding, current status of the
patient and the results of developmental assessment are summarized in Table 1.
Patient 1: A 112-year-old boy with mutase-negative MMA was diagnosed on the rst
day of life from sibling history before the onset of acute symptoms. On day 1 he
received 1.0 g protein/kg per day form a special methionine-, valine-, isoleucine-
and threonine-free amino acid mixture, energy from glucose polymer and fat mixture
with a caloric content 314/kJ/kg per day, and 0.25 g natural protein/kg per day from
expressed breast milk. After day 2 the amount of expressed breast milk was increased,
and after day 7 breastfeeding on demand was initiated. Details of dietary records,
body weight z-scores and methylmalonic acid excretion are given in Table 2. Protein
intake from the special essential amino acid mixture was decreased after 4 months
and low-protein weaning foods were started on the 6th month. The feeding plan after
6 months was on-demand breastfeeding with the addition of low-protein weaning
foods. The low plasma levels of methionine, valine, isoleucine and threonine in quan-
titative amino acid analyses and the low levels of urinary methylmalonic acid
excretion measured with GC-MS permitted us to exclude the special amino acid
mixture from the diet after the age of 6 months. Body weight z-scores increased during
the rst year from 0.05 to 0.6. The high MMA excretion at month 9 corresponds

Table 2 Follow-up records of patient 1 with mutase-negative methylmalonic acidaemia

Protein intake Urinary
Breastfeeding (g/kg per day) methylmalonate
Body excretion
weight Expressed On Special amino Weaning (mmol/mol
Agea z-scores (g protein/kg per day) demand acid mixture foods creatinine)

1d  0.05 0.25  1.0 846

2d  0.06 0.5  1.25
4d  0.07 0.75  1.25
6d  0.09 1.0  1.25 786
7d  0.09 ^ 0.75
14 d  0.07 ^ 0.75 110^17
1 mo  0.09 ^ 0.75 253
2 mo  1.1 ^ 0.75 150
4 mo  1.2 ^ 0.6 242^302
6 mo  0.9 ^ 0.3 0.3 292^414
9 mo 0.5 ^ ^ 0.4 4809b^199
ly 0.6 ^ ^ 0.5 595
a
d, day(s); mo, month(s); y, year(s)
b
Corresponds to the time of eruption of teeth

J. Inherit. Metab. Dis. 28 (2005)

Breastfeeding in IEMs other than PKU 461

to eruption of teeth. This patient did not encounter any metabolic problems. Growth
and development are normal and he was still breastfed on demand at the age of
18 months.
Patient 2: A 21-month-old girl with mutase-negative MMA was diagnosed at the
age of 3 months during an episode of acute encephalopathy, metabolic acidosis and
hyperammonaemia. This episode had caused loss of acquired skills. She was exclu-
sively breastfed at the time of diagnosis. After the management of the acute episode,
breastfeeding on demand was recommended, with the addition of 1.0 g protein/kg
per day from a special amino acid mixture. The protein intake from this essential
amino acid mixture was lowered to 0.75 g protein/kg per day because of low plasma
levels of methionine, valine, isoleucine and threonine at follow-up. During the rst
year of life, she had two more acute episodes with vomiting and mild acidosis nece-
ssitating hospitalization. She received additional intravenous glucose and bicarbonate
treatment during these episodes while she was breastfed. Low-protein weaning foods,
mostly vegetables and fruits, were given after 5 months. She was breastfed on demand
successfully until 11 months and has attained normal growth rate and developmental
milestones (Table 1).
Patient 3: A 212-year-old girl with GA I was diagnosed at the age of 6 months with
acute encephalopathy. After this episode, her global developmental age with DDST
II was assessed as 1 month in all developmental areas. Breastfeeding on demand,
with the addition of essential amino acid mixture free of lysine and containing a
reduced amount of tryptophan, was continued. Her developmental age was not appro-
priate for weaning. On follow-up, plasma lysine and tryptophan levels were within the
normal range and there was no urinary excretion of 3-hydroxyglutaric acid. We
observed developmental catch-up while she was breastfed, although she was still
developmentally retarded at the age of 11 months (Table 1).
Patient 4: A boy with severe OTC deciency was diagnosed at the age of 5 days with
encephalopathy and hyperammonaemia. After the management of the initial acute
episode, he received expressed breast milk for about a month. He was breastfed
on demand after day 40 for nearly two weeks. He was still at the hospital when
he had a respiratory infection and hyperammonaemia. Breastfeeding on demand
was terminated owing to poor metabolic control during this episode and was never
tried again. This patient had a severe case of OTC deciency and died later during
another acute episode in follow-up at the age of 4 months.
Patient 5: A 2-year-old boy with MSUD was diagnosed at day 10 with encephalo-
pathy and ketosis. After the management of the acute episode, expressed breast milk
was introduced at 1.0 g protein/kg per day and with the addition 1.5 g protein/kg
per day from a special essential amino acid mixture free of leucine, valine and iso-
leucine. By 2 months, breastfeeding on demand was recommended with acceptable
levels of plasma branched-chain amino acids (BCAA) (leucine 35 mmol/L, normal
range 47^155; isoleucine 195 mmol/L, normal range 31^86; valine 180 mmol/L,
normal range 64^294). After on-demand breastfeeding for a week, very high levels
of BCAA (leucine 1726 mmol/L, isoleucine 692 mmol/L, valine 298 mmol/L)

J. Inherit. Metab. Dis. 28 (2005)

462 Huner et al

were recorded. There was no observable clinical problem and the patient was
gaining weight, but we had to terminate breastfeeding and urgently hospitalize
the patient. On-demand breastfeeding was introduced again at 3 months (leucine
282 mmol/L, isoleucine 89 mmol/L, valine 285 mmol/L). Because of the stress of
this trial, frequent checks led to cessation of breastfeeding after a month in spite
of normal levels of plasma BCAA. This patient has attained normal growth
and developmental milestones (Table 1).
Patient 6: A 14-month-old boy with PA was diagnosed at the age of 6 days with
metabolic acidosis, encephalopathy, hypotonia and hyperammonaemia. Expressed
breast milk was introduced when he was 10 days old and on-demand breastfeeding
after he was 20 days old, with the addition of special amino acid mixture free of
methionine, valine, isoleucine and threonine. On follow-up he had a metabolic attack
with vomiting and mild acidosis and was hospitalized for 8 days. At discharge he
was still breastfed. A week later he had a similar episode with hypotonia and mild
encephalopathy requiring hospitalization for another two weeks. Breastfeeding on
demand was not recommended after these two acute episodes. Expressed breast
milk feeding and breastfeeding on demand were continued for a total period of
3.5 months. Developmental assessment with DDST II was normal at the age of
12 months (Table 1).
Patient 7: A 19-month-old girl with IVA was diagnosed at the age of 8 days with
metabolic coma. Expressed breast milk was given after the management of the initial
acute episode, with the addition of special amino acid mixture. Breastfeeding on
demand was recommended at the age of 21 days. She was not gaining good body
weight, essential plasma amino acid levels were below the normal range, and breast
milk was insucient. Formula supplementation was necessary, and breastfeeding
failed after a trial of two weeks. She has attained normal growth and development
(Table 1).

RESULTS
The results of breastfeeding experience are summarized in Table 1. Breastfeeding on
demand was very well tolerated in patients with mutase-negative MMA and GA I,
with good growth and metabolic control (Table 1). The patient with MMA diagnosed
during the rst day of life had the best outcome with respect to tolerance and
development. The other patient with MMA was exclusively breastfed at diagnosis
at the age of 3 months. After attainment of metabolic control, we could continue
on-demand breastfeeding successfully and neurological catch-up was complete at
the age of 9 months. In the patient with PA, breastfeeding on demand could be con-
tinued for 3 months, but was stopped after two metabolic decompensations requiring
hospitalization (Table 1). The patient with IVA had a shortage of breast milk after a
month, and formula supplementation ended with breast milk cessation. Breastfeeding
on demand in the male patient with severe OTC deciency was terminated owing to
poor metabolic control. The patient with MSUD encountered problems in metabolic
control while he was breastfed on demand.

J. Inherit. Metab. Dis. 28 (2005)

Breastfeeding in IEMs other than PKU 463

DISCUSSION
Our interest in breastfeeding infants with IEMs started with phenylketonuria (PKU).
In a pilot study, 13 infants with PKU were breastfed on demand after receiving a
measured volume of phenylalanine-free infant formula, and the results were compared
with those of 7 infants with PKU fed with a measured volume of phenylalanine-free
formula and infant formula instead of breast milk (Hner and Demirkol 1994).
The breastfed group had normal growth and cognitive development and serum
phenylalanine levels were within the desired range. From 1994 to 2000 we breastfed
86 infants with PKU on demand and we have recorded similar results (Demirkol
et al 2001). The same principles can be applied to some other IEMs with protein
catabolism.
The most important part of the breastfeeding of infants with IEMs is to have a
well-dened protocol, including dietetic management and clinical and biochemical
monitoring. It is important to remember the general principles of breastfeeding when
feeding plans are made. The quantity of milk produced by the mother is dependent on
stimulation by sucking. If complementary feeds are introduced, there will be less
stimulation and hence less milk will be produced (Leonard and van Wyk 2002).
Giving an amount of protein-free or amino acid-restricted mixture reduces the
amount of breast milk taken. It is necessary to vary feeding plans depending on
the disorder and clinical severity. The best-tolerated and easiest to control approach
involves feeds that contain expressed breast milk mixed with other modular
ingredients. Breastfeeding on demand with protein-free/amino acid-restricted
mixtures given prior to some breastfeeds is also tolerated in most cases. Breastfeeding
on demand without any supplemental feeds is also possible in mild cases of inborn
errors of protein catabolism.
In the literature, breastfeeding was well tolerated in one patient with urea cycle
disorder and in two patients with organic acidaemias (White 2000). However, in
one case of MMA, breastfeeds had to be discontinued owing to poor weight gain
and diculties in achieving adequate metabolic control. Successful exclusive
breastfeeding management of a patient with neonatal-onset methylmalonyl-CoA
mutase deciency who presented at the age of 2 days with metabolic acidosis and
hypoglycaemia was reported (Dixon 2000).
We did not observe any problems while the infants were fed with measured volumes
of expressed breast milk, but on-demand breastfeeding caused problems in the man-
agement of patients with MSUD, OTC deciency and PA. If patients with MSUD
are breastfed, amino acid levels should be determined at least weekly. In our case,
during on-demand breastfeeding plasma leucine, isoleucine and valine levels were
elevated during a very short interval without any clinical signs. The infant was gaining
weight and there were no signs of catabolism. This elevation was probably the result of
intake of too much breast milk. In MSUD there is a good biochemical marker in terms
of plasma amino acids for monitoring treatment, but in organic acidaemias organic
acids and amino acids are less reliable biochemical markers (Dixon 2000). The patient
with PA is an example of problems that can be faced in metabolic control with severe
forms. In the patient with PA, breastfeeding was successful for about three months but

J. Inherit. Metab. Dis. 28 (2005)

464 Huner et al

two episodes, starting with vomiting, that required hospitalization with prolonged
encephalopathy and hypotonia forced us to terminate breastfeeding. The episodes
were probably related to minor infections and there was not much hint from biochem-
istry with respect to organic acids, ammonia and amino acids to guide us to the
biochemical cause as in the MSUD case.
We were not successful in breastfeeding on demand in some of the patients with
IEMs. Diculties were encountered in both metabolic control and suciency of
breast milk. To achieve success, it is important to underline the problems that clini-
cians may meet in the breastfeeding of infants with IEMs. In IVA the patient showed
signs of breast milk insuciency, such as poor weight gain and irritability. Because of
the potential risk of catabolism, we supplemented the diet with an infant formula. As
may be observed in a healthy infant, formula supplementation caused reduction and
cessation of breast milk production.
Special attention should be given to the mother with respect to breastfeeding while
the team is busy with the acutely ill child. This should include breast milk pumping
and education about breastfeeding of infants with IEMs. Support of breastfeeding
is essential, and many mothers will benet from specialist nurse advice. The mother
needs reassurance in expressing breast milk until a diagnosis is established. Condence
should be encouraged that re-establishment of breastfeeding is possible (Leonard and
van Wyk 2002). A good mother^infant bond is very important, especially in the
management of IEMs, and breastfeeding may help to develop this.
Protein requirements change, in particular with severity of disease and growth rate.
This will obviously aect the feeding plan, which must also ensure an adequate intake
of all other nutrients. Many patients will present with an acute illness, and while the
child is being treated it is necessary for the mother to express her milk. Once the
baby improves, the expressed breast milk can be introduced into the diet gradually.
When the child is better and the condition is stabilized, the baby may be breastfed
on demand. It is traditional to give supplementary amino acids before a feed, but
this may not always be necessary, especially in milder cases as in patient 1 (Table 2).
This may represent an additional advantage of breast milk due to its special ingre-
dients. Infants with IEMs should be evaluated for breastfeeding under close medical
and dietetic management to maintain good metabolic control.

CONCLUSION
The breastfeeding of patients with IEMs was successful in mutase-negative MMA and
GA I patients. We recommend that patients with PA, IVA and MSUD are also can-
didates for breastfeeding. In our experience, severe OTC deciency is prone to easy
metabolic decompensation during breastfeeding. Breastfeeding in IEMs has import-
ant advantages and should be encouraged. Infants with IEMs need close monitoring
with attention to clinical parameters such as growth, development and biochemistry
while they are being breastfed. The principles of breastfeeding babies with IEMs
are well established and, provided these are understood, the management of such
children once they have been stabilized is often feasible.

J. Inherit. Metab. Dis. 28 (2005)

Breastfeeding in IEMs other than PKU 465

ACKNOWLEDGEMENT
This work was supported by the Research Fund of the University of Istanbul. Project
number: UDP 176.

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Dixon M (2000) Breastfeeding in metabolic disease: how successful is this? Dietitians Meeting.
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Hner G, Demirkol M (1996) Breastfeeding and phenylketonuria. In Demirkol M, Shin YS,
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Leonard J, van Wyk K (2002) Breastfeeding in IEOM other than PKU. 34th EMG Meeting
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J. Inherit. Metab. Dis. 28 (2005)