American Journal of Medical Genetics 79:373–375 (1998)
Methylmalonic Aciduria (cblF): Case Report and
Response to Therapy
D.J. Waggoner,1* K. Ueda,1 C. Mantia,1 and S.B. Dowton2
1
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
2
University of New South Wales, Office of the Dean, Sydney, Australia
Methylmalonic acidemia can be secondary
to a deficiency of methylmalonyl CoA mu-
tase or to a defect of cobalamin metabolism
that is classified by complementation group.
We report on a new patient with cblF
complementation group that is associated
with an elevation of both methylmalonic
acid and homocysteine, and her outcome in
response to routine therapy and a dietary
restriction. Am. J. Med. Genet. 79:373–375,
1998. © 1998 Wiley-Liss, Inc.
KEY WORDS: cobalamin; propionate; de-
velopment
INTRODUCTION
The methylmalonic acidemias (MMAs) are a hetero-
geneous group of autosomal recessive inborn errors of
propionate metabolism. They are characterized by im-
paired conversion of methymalonyl CoA to succinyl
CoA by the enzyme methylmalonyl CoA mutase, which
requires adenosylcobalamin as a cofactor. Several de-
fects of the metabolism of cobalamin (vitamin B12) to
adenosylcobalamin (Ado-B12) have been described and
are associated with MMA. The cobalamin disorders are
categorized into complementation groups and have
variable clinical presentation and outcome [Cooper and
Rosenblatt, 1987; Fenton and Rosenberg, 1995]. The
cobalamin F complementation group has elevation of
both methylmalonic acid and homocysteine secondary
to the lack of synthesis of adenosylcobalamin and
methylcobalamin respectively. We report on a new pa-
tient with cobalamin F mutation and describe her
treatment and course.
CLINICAL REPORT
The patient was born to an 18-year-old G1 woman by
spontaneous vaginal delivery. The parents denied con-
*Correspondence to: Darrel J. Waggoner, M.D., Department of
Pediatrics, St. Louis Children’s Hospital, One Children’s Place,
St. Louis, Missouri 63130. E-mail: waggoner_d@a1.kids.wustl.edu
Received 4 March 1998; Accepted 16 June 1998
© 1998 Wiley-Liss, Inc.
sanguinity. Birth weight was 2.8 kg (10th centile). The
infant experienced inadequate weight gain, difficulties
in feeding, and gastroesophageal reflux. She was hos-
pitalized at 4 weeks of age for failure to thrive. Her
weight was 2.8 kg (5th centile), length 52.5 cm (25th
centile), and occipital frontal circumference 34.5 cm
(10th centile). She had no minor anomalies. She had
oropharyngeal candidiasis and a soft systolic murmur.
Abdomen was soft and there was no hepatic or splenic
enlargement. Tone, reflexes, and eye findings were nor-
mal.
Initial laboratory evaluations included urinalysis,
sweat test, ammonia level, thyroid function tests, and
liver enzymes, which were all within reference ranges.
Results of other laboratory studies included white
blood cell count 13,600/mm3, hemoglobin 14.7 g/dl,
mean corpuscular volume 91.7 ␮m3, platelet count 417
103/mm3, serum sodium 136 mEq/liter, potassium 5.2
mEq/liter, chloride 103 mEq/liter, bicarbonate 18 mEq/
liter, BUN 17 mg/dl, and creatinine 0.5 mg/dl. Lactate
was 2.5 mEq/liter (reference range 0.5 to 1.5 mmol/
liter) and pyruvate was 1.3 mg/dL (reference range 30
to 80 ␮mol/liter). Total carnitine was 27 nmol/ml (ref-
erence range 36 to 58), free carnitine was 16 nmol/ml
(reference range 27 to 49), short-chain acylcarnitine
was 11 nmol/ml (reference range 4 to 14), and acylcar-
nitine profile showed elevated propionyl carnitine (per-
formed at Duke University Mass Spectrometry Facil-
ity).
Organic acids were extracted by standard protocol
using ether and derivatization with BSTFA Bis(tri-
methylsilyl)trifluoroacetamide followed by separation
on an XP-1 column (Cobert Associates, Inc., St. Louis,
MO); initial temperature was 80°C and final tempera-
ture was 26°C with a temperature increase rate of 6°C.
Gas chromatography (Varian 3700, Palo Alto, CA) was
interfaced with a Finnigan ITD mass detector (Finni-
gan Mat, San Jose, CA). Amino acids were analyzed
using high performance liquid chromatography on a
Beckman System 7300 Analyzer (Beckman Instru-
ments Inc., Palo Alto, CA).
Urine organic analysis detected 290 ␮g/mg of creat-
inine of methylmalonic acid. Serum amino acid levels
were normal; urine amino acid quantitation showed a
homocystine level of 32 ␮mol/mmol creatinine. Vitamin
B12 level was 221 pg/ml (normal 艌200).
An echocardiogram showed a patent foramen ovale
374 Waggoner et al.

TABLE I. Findings in Patients With cblF Complementation Group Methylmalonic Acidemia Including the Subject of This Report
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
(Rosenblatt et al. (Shih et al. (Wong et al. (MacDonald et al. (MacDonald et al. (subject of
Findings [1992]) [1989]) [1992]) [1992]) [1992]) this report)
Sex Female Female Female Male Male Female
Age at presentation 12 days 18 days 6 months 11 years Birth 1 month
Birth weight (g) 2,500 2,300 2,800
Stomatitis + + +
Skin rash + +
Developmental delay + + + + +
Feeding difficulties + + +
Seizures +
Hypotonia + + +
Recurrent infections +
Megaloblastic anemia + + +

and small apical muscular ventricular septal defect. A Review of the previously reported patients [Rosenb-
fibroblast culture was obtained from a skin biopsy and latt et al., 1986; Shih et al., 1989; MacDonald et al.,
cells were sent to David S. Rosenblatt, M.D. at McGill 1992; Wong et al., 1992] shows that there is variability
University for measurement of cobalamin metabolism in the age of presentation, clinical symptoms at diag-
[Rosenblatt et al., 1985; Shih et al., 1989] and comple- nosis, and complications (see Table I). There are no
mentation analysis [Watkins and Rosenblatt, 1986]. unique clinical aspects of these patients that permit
The uptake of (14C)propionate and (14C)methyltetrahy- prediction of their complementation groups. All of the
drofolate was low and there was good response to the patients responded to hydroxycobalamin with de-
presence of OHCbl. There was little synthesis of creased methylmalonic acid excretion and either de-
AdoCbl or MeCbl. Complementation analysis showed creased megaloblastic anemia, increased growth, or im-
the patient to be in the cblF complementation class. provement in the neurological symptoms.
The patient was treated with hydroxycobalamin The patient reported on here was treated with hy-
1,000 ␮g i.m. twice weekly for 2 weeks then once per droxycobalamin weekly. In addition, her diet was re-
week. Carnitine was started orally at 100 mg/kg/day stricted in valine, threonine, methionine, and isoleu-
immediately following diagnosis. The patient’s diet was
altered to include Propimex-1 and Similac formula to
provide 80 mg/kg/day of valine, 3 g/kg/day of protein
equivalents, and 120 kcal/kg/day. Her diet was moni-
tored closely and her dietary valine intake was ad-
justed to maintain all amino acid values within the
reference range, if possible.
At age 20 months her weight was 9.5 kg (10th cen-
tile) and length was 81.8 cm (25th centile). Her evalu-
ation at that time included a neurodevelopmental as-
sessment. The Bayley Scales of Infant Development
(Revised) were administered and her mental and psy-
chomotor development fell within the average range
with index scores of 98 and 94, respectively. The results
of the Behavior Rating Scale from the Bayley and the
parents’ response to the Vineland Adaptive Behavior
Scale showed appropriate social and emotional devel-
opment. Standard scores were 90 for communication,
96 for daily living skills, 93 for socialization, and 93 for
motor skills.

DISCUSSION
The clinical presentation and response to therapy is
variable among the several types of methylmalonic aci-
demia [Fenton et al., 1995]. Some of these differences
are related to the underlying cause of MMA from either
methylmalonic CoA mutase deficiency or vitamin B12
metabolism. Patients with MMA from the cblF group
have a defect in release of vitamin B12 from lysosomes Fig. 1. A: Methylmalonic acid levels (left axis, solid line) and urine
[Rosenblatt et al., 1985; Vassiliadis et al., 1991]. Our homocystine levels (right axis, triangles). B: Each section shows the re-
sponse of plasma amino acid concentrations (dotted line) to changes in
patient is the sixth report of a patient with the cblF dietary intake for respective amino acids (solid line). Reference ranges in
mutation. ␮mol/liter for each amino acid are listed in parentheses.

cine by use of Propimex-1 (Ross Laboratories, Colum-
bus, OH). Her plasma amino acid concentrations and
growth were monitored frequently and the diet was
adjusted to maintain levels in the reference ranges
(Fig. 1). At age 10 months her restriction was relaxed
and her intake of formula decreased. She tolerated the
decreased formula and increase in protein from food
without difficulty. Her development to date has been
normal and she has had no adverse neurological symp-
toms.
All patients, including the subject of this report, with
cblF, respond to hydroxycobalamin. In addition, pa-
tients who are diagnosed at an early age may benefit
from dietary restriction of the amino acids metabolized
via the propionate pathway. Long-term follow-up of the
first five patients reported with cblF is not available,
but they all showed some neurological symptoms early
on. Although developmental concerns are not clearly
established as a major component of this disease, it is
of interest to note that our patient does not exhibit any
neurological findings. Thus, the modified diet may not
be needed for life, but is potentially beneficial during
the first few years of growth and development.
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