Original Article

Journal of Child Neurology

26(6) 734-737
Primary Adenosine Monophosphate (AMP) The Author(s) 2011
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Deaminase Deficiency in a Hypotonic DOI: 10.1177/0883073810390367
http://jcn.sagepub.com
Infant

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 monopho-
sphate 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 dea-
minase, the most active enzyme of the purine nucleotide
cycle, deaminates adenosine-5-monophosphate, thereby
maintaining the high adenosine-5-triphosphate/-dipho-
sphate/-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 adenosine-
5-monophosphate increases Krebs cycle mediator production
in active muscle. These mechanisms cannot function in ade-
nosine 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 rhab-
domyolysis,7-10 but a few cases with congenital muscle weak-
ness 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 introduc-
tion 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 muta-
tion 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
1
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 monopho-
sphate 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 weak-
ness 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. Electro-
myogram recorded from biceps brachii, deltoids, gluteus, quad-
riceps, 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 immunohisto-
chemistry for dystrophin, sarcoglycans (a, , g, d), a and
dytroglycans, dysferlin, utrophin, merosin, caveolin-3, col-
lagen VI, desmin, emerin, lamin A/C, myotilin, titin, teletho-
nin, and calpain-3 were normal. Histoenzymatic staining for
adenosine monophosphate deaminase showed loss of enzy-
Figure 1. Loss of histoenzymatic staining for adenosine
matic activity in comparison with normal muscle control monophosphate deaminase (top) in comparison with normal muscle
(Figure 1), and histoenzymatic staining for myophosphory- control (bottom).
lase, phosphofructokinase, and lactate dehydrogenase were
normal. Staining with the oxidative enzymes reduced nicoti-
namide adenine dinucleotide-tetrazolium reductase, succinate
dehydrogenase, and cytochrome oxidase was normal. The introduction, adenosine monophosphate deaminase deficiency
mitochondrial respiratory chain complexes in muscle homo- has also been noted in patients with other neuromuscular
genate and the relation in muscle of mtDNA/nDNA were nor- diseases and appears to be secondary or coincident double trou-
mal. Genetic testing showed a homozygous C to T mutation at ble, but whether it contributes to these patients symptoms is
nucleotide 34 of the adenosine monophosphate deaminase-1 not clear.2,12-17 Myalgia upon exertion was the main clinical
gene, and her mother was heterozygous for this particular symptom in 93% of primary adenosine monophosphate deami-
mutation (Figure 2). nase deficiency cases reported. Other manifestations include
At this time, 12 months after the initial clinical exploration myoglobinuria, which has been reported in a small fraction of
and diagnosis (18 months of life), she was unable to sit and patients, and occasional idiopathic hyperCKemia.9,18
muscular weakness and hypotonia of trunk and upper limbs In almost 80% of patients, the onset of the symptoms is
persist, with absence of deep tendon reflexes. 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 non-
Discussion progressive and approximately one-half experience their initial
Primary adenosine monophosphate deaminase deficiency is difficulties in childhood.19
characterized by dynamic symptoms related to exertion, con- The presenting complaints in children with primary adeno-
sisting primarily of muscle aches and cramps that are some- sine monophosphate deaminase deficiency include stiffness,
times very mild and poorly defined.18 As discussed in the muscle cramps, and postexercise myalgia and weakness.18,19

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736
1 2 3 G
AATACTCACATA TCTC TTC
226 bp a)
200 bp
b)
26 bp
c)
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) heterozy-
gous patients mother, and (c) wild-type control. Electropherogram
shows the mutated nucleotide position (G >A in reverse) and a mis-
matched 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 pri-
mary 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 com-
mon 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 uncharacter-
ized associated disease.
The absence of symptoms in many individuals with inher-
ited adenosine monophosphate deaminase deficiency sug-
gests 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 nonmus-
cle isoforms (adenosine monophosphate deaminase-2 and
adenosine monophosphate deaminase-3) leads to asymp-
tomatic 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 possi-
ble 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
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Journal of Child Neurology 26(6)
deaminase deficiency is not always the primary cause of
symptoms in symptomatic patients.18
In conclusion, our observations indicate the possible exis-
tence of a primary adenosine monophosphate deaminase defi-
ciency 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.
Author Contributions
MC-G, CG-L, LP-G and JE-P were responsible for the clinical diag-
nosis 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 mus-
cle homogenate, the ratio in muscle of mtDNA/nDNA, and the genetic
testing of the adenosine monophosphate deaminase-1 gene and collabo-
rated on the writing of the text. MC-G was the director of the investiga-
tion 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.
References
1. Fishbein WN, Armbrustmacher VM, Griffin JL. Myoadenylate
deaminase deficiency: A new disease of muscle. Science. 1978;
200:545-548.
2. Morisaki T, Gross M, Morisaki H, Pongratz D, Zollner N,
Holmes EW. Molecular basis of AMP deaminase deficiency in ske-
letal muscle. Proc Natl Acad Sci U S A. 1992;89:6457-6461.
3. Norman B, Glenmark B, Jansson E. Muscle AMP deaminase defi-
ciency in 2% of healthy population. Muscle Nerve. 1995;18:
239-241.
4. Norman B, Mahnke-Zizelman DK, Vallis A, Sabina RL. Genetic
and other determinants of AMP deaminase activity in healthy adult
skeletal muscle. J Appl Physiol. 1998;85:1273-1278.
5. Zollner N, Reiter S, Gross M, et al. Myoadenylate deaminase defi-
ciency: Successful symptomatic therapy by high dose oral admin-
istration of ribose. Klin Wochenschr. 1986;64:1281-1290.
6. Skyllouriotis MI, Marx M, Bittner RE, Skyllouriotis P, Gross M,
Wimmer M. Myoadenylate deaminase deficiency, hypertrophic
cardiomyopathy and gigantism syndrome. Pediatr Neurol. 1997;
17:61-66.
Castro-Gago et al
7. DiMauro S, Miranda AF, Hays AP, et al. Myoadenylate deaminase
deficiency. Muscle biopsy and muscle culture in a patient with
gout. J Neurol Sci. 1980;47:191-202.
8. Kelemen J, Rice DR, Bradley WG, Munsat TL, DiMauro S,
Hogan EL. Familial myoadenylate deaminase deficiency and
exertional mylagia. Neurology. 1982;32:857-863.
9. Teijeira S, San Millan B, Fernandez JM, et al. Myoadenylate dea-
minase deficiency: clinico-pathological and molecular study of a
series of 27 Spanish cases. Clin Neuropathol. 2009;28:136-142.
10. Hanish F, Joshi P, Zierz S. AMP deaminase deficiency in skeletal
muscle is unlikely to be of clinical relevance. J Neurol. 2008;255:
318-322.
11. Shumate JB, Kaiser KK, Carrol JE, Brooke MH. Adenylate dea-
minase deficiency in a hypotonic infant. J Pediatr. 1980;96:
885-887.
12. Fishbein WN. Primary, secondary, and coincidental types of
myoadenylate deaminase deficiency. Ann Neurol. 1999;45:
547-548.
13. Tsujino S, Shanske S, Carroll JE, Sabina RL, DiMauro S. Double
trouble: combined myophosphorylase and AMP deaminase defi-
ciency in a child homozygous for nonsense mutations at both loci.
Neuromuscul Disord. 1995;5:263-266.
Downloaded from jcn.sagepub.com at Hoffmann-La Roche on September 20, 2016
737
14. Rubio JC, Martn MA, Bautista J, Campos Y, Segura D, Arenas J.
Association of genetically proven deficiencias of myophosphory-
lase and AMP deaminase: a second case of double trouble.
Neuromuscul Disord. 1997;7:387-389.
15. Bruno C, Minetti C, Shanske S, et al. Combined defects of muscle
phosphofructokinase and AMP deaminase in a child with myoglo-
binuria. Neurology. 1998;50:296-298.
16. Rubio JC, Martn MA, Del Hoyo P, et al. Molecular analysis of
Spanish patients with AMP deaminase deficiency. Muscle Nerve.
2000;23:1175-1178.
17. Tsao CY, McCombo RD. Myalgia with parcial defects of mito-
chondrial enzyme and myoadenylate deaminase. Pediatr Neurol.
1999;6:65.
18. Darras BT. Myoadenylate deaminase deficiency. In: Jones HR Jr,
De Vivo DC, Darras BT, eds. Neuromuscular Disorders of Infancy,
Childhood, and Adolescence. A Clinicans Approach. Amsterdam:
Butterwordth Heinemann; 2003:861-866.
19. Ashwal S, Peckham N. Myoadenylate deaminase deficiency in
children. Pediatr Neurol. 1985;1:185-191.
20. Verzijl HT, van Engelen BG, Luyten JA, et al. Genetic character-
istics of myoadenylate deaminase deficiency. Ann Neurol. 1998;
44:140-143.