Original Article

Primary Adenosine Monophosphate (AMP)

Deaminase Deficiency in a Hypotonic
Infant

Journal of Child Neurology

26(6) 734-737
The Author(s) 2011
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DOI: 10.1177/0883073810390367
http://jcn.sagepub.com

Manuel Castro-Gago, MD1, Carmen Gomez-Lado, MD1,

Laura Perez-Gay, MD1, Jesus Eirs-Punal, MD1,
Elena Pintos Martnez, MD2, Ines Garca-Consuegra, BSc3, and
Miguel Angel Martn, PhD3

Abstract
The spectrum of the adenosine monophosphate (AMP) deaminase deficiency ranges from asymptomatic carriers to patients who
manifest exercise-induced muscle pain, occasionally rhabdomyolysis, and idiopathic hyperCKemia. However, previous to the
introduction of molecular techniques, rare cases with congenital weakness and hypotonia have also been reported. We report
a 6-month-old girl with the association of congenital muscle weakness and hypotonia, muscle deficiency of adenosine monophosphate deaminase, and the homozygous C to T mutation at nucleotide 34 of the adenosine monophosphate deaminase-1 gene.
This observation indicates the possible existence of a primary adenosine monophosphate deaminase deficiency manifested by
congenital muscle weakness and hypotonia.
Keywords
adenosine monophosphate deaminase deficiency, congenital muscle weakness, hyperCKemia, muscle pain, rhabdomyolysis
Received September 9, 2010. Received revised October 14, 2010. Accepted for publication October 20, 2010.

Adenosine monophosphate (AMP) deaminase deficiency,

described by Fishbein et al in 1978,1 is the most common
metabolic muscle disorder, with a prevalence rate of 1% to
2% in white populations.2-4 Adenosine monophosphate deaminase, the most active enzyme of the purine nucleotide
cycle, deaminates adenosine-5-monophosphate, thereby
maintaining the high adenosine-5-triphosphate/-diphosphate/-monophoshate ratios necessary for a high adenylate
charge or a high energy yield on adenosine-5-triphosphate
hydrolysis, respectively. Inosine-5-monophosphate and
ammonia, formed by adenosine monophosphate deaminase
(AMPD), activate glycogenolysis and glycolysis. In addition,
conversion of inosine-5-monophosphate to adenosine5-monophosphate increases Krebs cycle mediator production
in active muscle. These mechanisms cannot function in adenosine monophosphate deaminase deficiency, leading to a
defective energy supply during work.5,6 The spectrum of this
condition ranges from asymptomatic carriers to patients who
manifest exercise-induced muscle pain and occasionally rhabdomyolysis,7-10 but a few cases with congenital muscle weakness and hypotonia have also been reported.8,11
The adenosine monophosphate deaminase gene (adenosine
monophosphate deaminase-1) has been cloned, sequenced,
and assigned to chromosome 1p13-p21.2,4 After the introduction of molecular techniques, the inherited or primary

form was genetically defined as a homozygous mutant allele.

The acquired or secondary form is defined by a single mutation in 1 allele and a decrease in enzymatic activity, probably
because of its association with other diseases.2,12 A third form
of adenosine monophosphate deaminase deficiency is defined
as double trouble, or coincident adenosine monophosphate
deaminase deficiency, in which genetically proven adenosine
monophosphate deaminase deficiency coexists with another
disorder, generally a metabolic myopathy (glycogenosis V,
glycogenosis VII, partial mitochondrial enzyme defect, or
mitochondrial DNA mutations).13-17

Servicio de Neuropediatra, Hospital Clnico Universitario, Facultad de

Medicina, Universidad de Santiago de Compostela, Santiago de Compostela,
Spain
2
Servicio de Anatoma Patologica, Hospital Clnico Universitario, Facultad de
Medicina, Universidad de Santiago de Compostela, Santiago de Compostela,
Spain
3
Laboratorio de Enfermedades Mitocondriales, Centro de Investigacion,
Instituto de Investigacion Hospital 12 de Octubre (i + 12), Madrid. Centro
de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Spain
Corresponding Author:
Manuel Castro-Gago, MD, Servicio de Neuropediatra, Hospital Clnico
Universitario, La Choupana s/n, 15706 Santiago de Compostela, Spain
Email: manuel.castro.gago@usc.es

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Castro-Gago et al

735

Here we report an additional case, a 6-month-old girl with

clinical association of the primary form of adenosine monophosphate deaminase deficiency, weakness, and hypotonia.

Case Report
A 6-month-old girl, without relevant family or personal history,
was referred for weakness and hypotonia. She was born to a
37-year-old gravida 1, following a normal pregnancy by in
vitro fertilization with sperm donation. Birth weight was
3.80 kg, and delivery was by cesarean section. Apgar scores
at 1 and 5 minutes were 6 and 10, respectively. Neonatal
screening for congenital metabolic diseases, including blood
acyl-carnitines was normal. Hypotonia was detected by the
mother during the first month of life. Clinical examination
showed macrocephaly (45.5 cm > 2 SD), severe muscle weakness and hypotonia of trunk and upper limbs, and tendency to
slip through the hands when held, without muscle atrophy, and
with absence of deep tendon reflexes. Ocular movements were
normal.
Blood biochemistry, including creatine kinase, carnitine,
basal lactic acid, and pyruvic acid levels, was normal. Electromyogram recorded from biceps brachii, deltoids, gluteus, quadriceps, and anterior tibialis was myopathic with a full
recruitment pattern of reduced amplitude and polyphasic
potentials. Motor nerve conduction velocity and brain magnetic
resonance were normal. Histological examination (optic and
electron microscope) of the deltoid muscle and immunohistochemistry for dystrophin, sarcoglycans (a, , g, d), a and
dytroglycans, dysferlin, utrophin, merosin, caveolin-3, collagen VI, desmin, emerin, lamin A/C, myotilin, titin, telethonin, and calpain-3 were normal. Histoenzymatic staining for
adenosine monophosphate deaminase showed loss of enzymatic activity in comparison with normal muscle control
(Figure 1), and histoenzymatic staining for myophosphorylase, phosphofructokinase, and lactate dehydrogenase were
normal. Staining with the oxidative enzymes reduced nicotinamide adenine dinucleotide-tetrazolium reductase, succinate
dehydrogenase, and cytochrome oxidase was normal. The
mitochondrial respiratory chain complexes in muscle homogenate and the relation in muscle of mtDNA/nDNA were normal. Genetic testing showed a homozygous C to T mutation at
nucleotide 34 of the adenosine monophosphate deaminase-1
gene, and her mother was heterozygous for this particular
mutation (Figure 2).
At this time, 12 months after the initial clinical exploration
and diagnosis (18 months of life), she was unable to sit and
muscular weakness and hypotonia of trunk and upper limbs
persist, with absence of deep tendon reflexes.

Discussion
Primary adenosine monophosphate deaminase deficiency is
characterized by dynamic symptoms related to exertion, consisting primarily of muscle aches and cramps that are sometimes very mild and poorly defined.18 As discussed in the

Figure 1. Loss of histoenzymatic staining for adenosine

monophosphate deaminase (top) in comparison with normal muscle
control (bottom).

introduction, adenosine monophosphate deaminase deficiency

has also been noted in patients with other neuromuscular
diseases and appears to be secondary or coincident double trouble, but whether it contributes to these patients symptoms is
not clear.2,12-17 Myalgia upon exertion was the main clinical
symptom in 93% of primary adenosine monophosphate deaminase deficiency cases reported. Other manifestations include
myoglobinuria, which has been reported in a small fraction of
patients, and occasional idiopathic hyperCKemia.9,18
In almost 80% of patients, the onset of the symptoms is
noted in late childhood to the early adult years; the median age
at the time of diagnosis is 37 years, with onset as early as 12
years and as late as 76 years.18 The symptoms are usually nonprogressive and approximately one-half experience their initial
difficulties in childhood.19
The presenting complaints in children with primary adenosine monophosphate deaminase deficiency include stiffness,
muscle cramps, and postexercise myalgia and weakness.18,19

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736

Journal of Child Neurology 26(6)

G
AATACTCACATA TCTC TTC

3
226 bp
200 bp

a)

b)
26 bp

deaminase deficiency is not always the primary cause of

symptoms in symptomatic patients.18
In conclusion, our observations indicate the possible existence of a primary adenosine monophosphate deaminase deficiency manifested by congenital weakness and hypotonia, and
that routine histochemical analysis of adenosine monophosphate
deaminase should be performed in all muscle biopsies, followed
by molecular analysis in each adenosine monophosphate
deaminase-negative case.

c)

Author Contributions
Figure 2. Molecular analysis of c.34C>T (p.Q12X) mutation in the
adenosine monophosphate deaminase-1 gene. Left panel: polymerase
chain reaction (PCR) and restriction length polymorphism. Lane 1,
healthy control; lane 2, proband homozygous for the mutation; lane
3, heterozygous probands mother. Right panel: direct sequencing in
the reverse direction of exon 2 in the adenosine monophosphate
deaminase-1 genes showing (a) homozygous proband, (b) heterozygous patients mother, and (c) wild-type control. Electropherogram
shows the mutated nucleotide position (G >A in reverse) and a mismatched nucleotide belonging to the forward primer (underlined).

Cardiomyopathy has also been described, but most of these

patients probably have an acquired or coincidental form
of adenosine monophosphate deaminase deficiency, because
the adenosine monophosphate deaminase deficiency was primary in only 1 patient with this association.6,18 The severe
congenital muscle weakness and hypotonia observed in our
patient is an uncommon finding, reported in some rare cases
prior to the introduction of molecular techniques.8,11,19 In this
sense, because the patient was homozygous for the most common mutation and other known myopathies were excluded,
we think that our observation probably represents a primary
deficiency in adenosine monophosphate deaminase, without
excluding the possibility of a coincidental form of adenosine
monophosphate deaminase deficiency with an uncharacterized associated disease.
The absence of symptoms in many individuals with inherited adenosine monophosphate deaminase deficiency suggests a biochemical or genetic compensatory mechanism,
although it is not reflected in the expression of adenosine
monophosphate deaminase in muscle, in which a total
absence of the enzyme was invariably demonstrated.9,10 The
hypothesis that compensatory overexpression of 2 nonmuscle isoforms (adenosine monophosphate deaminase-2 and
adenosine monophosphate deaminase-3) leads to asymptomatic cases has been discarded, because increases in
expression of these genes has not been demonstrated.9,18
Alternative splicing of exon 2 has been proposed as a possible explanation for the absence of clinical manifestations.
However, the absence of enzyme activity in muscle biopsies
argues against this possibility.9 Other authors have stated
that adenosine monophosphate deaminase deficiency is not
a disease but instead represents a harmless polymorphism,20
and perhaps an inherited adenosine monophosphate

MC-G, CG-L, LP-G and JE-P were responsible for the clinical diagnosis and collaborated on the writing of the text. EP-M was responsible
for the histological examination of the deltoid muscle and collaborated
on the writing of the text. IG-C and MAM were responsible for the
determination of the mitochondrial respiratory chain complexes in muscle homogenate, the ratio in muscle of mtDNA/nDNA, and the genetic
testing of the adenosine monophosphate deaminase-1 gene and collaborated on the writing of the text. MC-G was the director of the investigation and was responsible for the final version of the text.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interests with respect to
the authorship and/or publication of this article.

Financial Disclosure/Funding
The authors disclosed receipt of the following financial support for the
research and/or authorship of this article: This work was supported by
a Grant from Instituto de Salud Carlos III (ISCIII), Ministry of Science
and Innovation, Spain (Number PS 09-1359). IG-C is supported by a
research contract from ISCIII.

Ethical Approval
No ethical approval was necessary.

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