Original Article

Adenosine Kinase Deficiency: Report and Review

Alhanouf Alhusani1 Abdulrahman Obaid1 Henk J. Blom2 Anna Wedell3,4,5,6 Majid Alfadhel1

1 Division of Genetics, Department of Pediatrics, King Abdullah Address for correspondence Majid Alfadhel, MD, MHSC, FCCMG,
International Medical Research Centre, King Saud bin Abdulaziz Division of Genetics, Department of Pediatrics, King Saud bin
University for Health Sciences, King Abdulaziz Medical City, Riyadh, Abdulaziz University for Health Sciences, King Abdulaziz Medical City,
Saudi Arabia PO Box 22490, Riyadh 11426, Saudi Arabia
2 Department of Internal Medicine, VU University Medical Center, (e-mail: [email protected]).
Amsterdam, the Netherlands
3 Division of Metabolic Diseases, Department of Laboratory Medicine,
Karolinska Institute, Stockholm, Sweden
4 Department of Molecular Medicine and Surgery, Science for Life
Laboratory, Karolinska Institute, Stockholm, Sweden
5 Centre for Inherited Metabolic Diseases, Karolinska University
Hospital, Stockholm, Sweden
6 Max Planck Institute Biology of Ageing, Karolinska Institute
Laboratory, Stockholm, Sweden

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Abstract Adenosine kinase (ADK) deficiency (OMIM [online mendelian inheritance in man]:
614300) is an autosomal recessive disorder of adenosine and methionine metabolism,
with a unique clinical phenotype, mainly involving the central nervous system and
dysmorphic features. Patients usually present early in life with sepsis-like symptoms,
respiratory difficulties, and neonatal jaundice. Subsequently, patients demonstrate
hypotonia and global developmental delay. Biochemically, methionine is elevated with
normal homocysteine levels and the diagnosis is confirmed through molecular analysis
Keywords of the ADK gene. There is no curative treatment; however, a methionine-restricted diet
► methionine has been tried with variable outcomes. Herein, we report a 4-year-old Saudi female with
► ADK global developmental delay, hypotonia, and dysmorphic features. Interestingly, she has
► adenosine kinase a tall stature, developmental dysplasia of the hip, optic nerve gliosis, and tigroid
deficiency fundus. We found a mutation not reported previously and we compared the current
► adenosine case with previously reported cases. We alert clinicians to consider ADK deficiency in
► inborn errors of any neonate presenting with global developmental delay, hypotonia, dysmorphic
methionine features, and high methionine levels.

Introduction adenosine monophosphate.3 In addition, it removes adeno-

sine which is critical for S-adenosylhomocysteine (AdoHcy)
Adenosine kinase (ADK) deficiency (OMIM [online mende- hydrolase in methylation reactions, as it maintains S-ade-
lian inheritance in man]: 614300) is an autosomal recessive nosylmethionine (AdoMet) in trans methylation-dependent
inborn error of methionine and adenosine metabolism. It paths, where adenosine has to be continually removed.4
was first described by Bjursell et al in 2011 who reported two Under physiological status, adenosine is produced through
Swedish children with global developmental delay, hyper- the transmethylation of methionine, via AdoMet and
methioninemia, and liver impairment.1 It is caused by a AdoHcy. Subsequently, AdoHcy hydrolysis is achieved by S-
homozygous or compound heterozygous mutation in the AdoHcy hydrolase to generate Hcy and adenosine.5 Hcy is
ADK gene which encodes for the ADK enzyme.2 The ADK remethylated again to methionine or irreversibly trans-
enzyme is essential for the phosphorylation of adenosine to sulfurated to cystine by cystathionine β-synthase, while

received © Georg Thieme Verlag KG DOI https://doi.org/

July 1, 2018 Stuttgart · New York 10.1055/s-0038-1676053.
accepted after revision ISSN 0174-304X.
October 15, 2018
Adenosine Kinase Report Alhusani et al.

the adenosine is removed by deamination into inosine via labor and a previous caesarean section with an Apgar’s
adenosine deaminase (prenatally) and into adenosine mono- score 7 and 8 at 1 and 5 minutes, respectively. Her birth
phosphate via phosphorylation (postnatally) by ADK.6,7 weight was 2.9 kg (75–90th percentile), length: 49 cm (75–
Accumulation of adenosine will cause elevated S-AdoHcy 90th percentile), and head circumference (HC): 33.5 cm
which is a strong inhibitor of most methylation reactions. (75–90th percentile). A few hours after birth, she developed
Consequently, levels of S-AdoMet and methionine can tachypnoea, respiratory distress, and hypoactivity, and
become increased. therefore was transferred to an Intermediate Care Nursery
The clinical features of ADK deficiency include global and was connected to a nasal cannula and treated using
psychomotor retardation/delay, muscular hypotonia, dys- antibiotics and other supportive measures. On examination,
morphic features (especially frontal bossing), mild to severe she was found to be hypotonic with poor sucking and she
hepatic dysfunction, and epilepsy.1,2 Laboratory findings developed jaundice. Therefore, the neurology department
include high levels of liver enzymes, hyperbilirubinemia, became involved and magnetic resonance imaging (MRI) of
hypermethioninemia, and elevated plasma AdoHcy and the brain showed delayed myelination and a left subepen-
AdoMet. Neuroradiological abnormalities include brain atro- dymal cyst. At this time, a metabolic genetics service
phy, hydrocephalus, nonspecific white matter changes, and became involved and the review for initial newborn screen-
delayed myelination. Diagnosis requires the aforementioned ing was unremarkable. However, plasma amino acid levels
clinical and biochemical abnormalities and confirmation at 18 days of life showed a high methionine level of 123
through molecular analysis of the ADK gene.1,2,5 There is µmol/L (normal range 11–27 µmol/L) with a normal homo-
no curative treatment. However, some previously reported cysteine level. The patient improved, and demonstrated
cases were treated through a methionine-restricted diet and spontaneous breathing, good sucking, weight gain, and

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in addition to support the treatment, it included periodic tolerated feeding, and therefore was discharged after
monitoring of neurological and hepatic function, physiother- 1 month, with follow-up occurring in a clinic. At the age
apy, occupational therapies, and long-term rehabilitation. of 12 months, the patient was readmitted with poor feed-
These treatments resulted in variable outcomes.2,5 ADK ing, decreased activity, fever (38.9°C), symptoms of an
deficiency has been reported in different countries including upper respiratory tract infection, and vomiting. Develop-
Sweden, Malaysia, Germany, and Iran. In the current report, mentally, she was bed-bound, with no head support. She
we describe the first Saudi case of ADK deficiency, with optic was unable to sit or crawl (functioning as 2 months). Her
nerve gliosis, tigroid fundus, and a tall stature that has not weight was 9.5 kg (25th percentile), length 79 cm (95th
yet been associated with ADK deficiency. A novel frameshift percentile), and HC was 49 cm (> 95th percentile). She
duplication was found. We compare the presented case with demonstrated subtle dysmorphic features (frontal bossing,
the previously reported cases. high forehead, deep-seated eyes, and depressed nasal
bridge; (►Fig. 1). A neurological examination showed gen-
eralized hypotonia. The investigation also revealed persis-
Case Report
tent hypermethioninemia (methionine levels at
The case concerns a 4-year-old female who is the fifth child approximately 1,500 µmol/L). The diagnosis of ADK defi-
of parents who are first cousins. She was born at 35 weeks ciency was confirmed through whole-exome sequencing,
of gestation through caesarean section because of preterm (WES) which revealed a novel homozygous duplication in

Fig. 1 Dysmorphic features and brain MRI features of ADK deficiency. (A) An axial T2-weighted image shows delayed myelination. (B) Frontal
bossing, high forehead, deep-seated eyes, and depressed nasal bridge. (C) An axial FLAIR image shows a small subependymal cyst at the left
lateral ventricle. ADK, adenosine kinase; MRI, magnetic resonance imaging; FLAIR, fluid attenuated inversion recovery.

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 Adenosine Kinase Report Alhusani et al.

exon 9 of the ADK gene; NM_006721.3 [c.813dup (p. cystathionine β-synthase (CBS) deficiency. And secondary
Asn272Glufs
16)]. This variant was detected in the hetero- due to, fumarylacetoacetate hydrolase (FAH) deficiency,
zygous state in both parents and was not detected in a citrin deficiency, and mitochondrial depletion syndrome
healthy brother of the patient. The patient stabilized fol- caused by mutations in the MPV17 and DGUOK genes.8,9
lowing supportive measures and was discharged. An MRI The most common cause of hypermethioninemia is liver
scan of the brain, repeated at 22 months of age, showed disease, next to low birth weight and prematurity.9
cerebral atrophy, delayed myelination, and a left subepen- ►Table 1 summarizes the clinical characteristic of pre-
dymal cyst (►Fig. 1). Subsequently, the patient continued to viously reported patients with ADK deficiency, including the
demonstrate global developmental delay, dysmorphic fea- current case. To date, 19 cases have been reported in the
tures, no history of seizure, and was admitted to hospital literature. ADK deficiency is pan-ethnic. Patients from Swe-
several times because of recurrent chest infections. Addi- den, Malaysia, Turkey, Kuwait, Italy, Morocco, Germany, and
tionally, the patient demonstrated a mild elevation in Iran have been reported. The current report details the first
transaminases: aspartate aminotransferase levels (AST) ran- Saudi patient to date. A total of 90% of cases present in the
ged between 47 and 200 U/L (normahealthy: 5–34 U/L) neonatal period, indicating an early onset with sepsis-like
while alanine aminotransferase (ALT) ranged between 77 symptoms, hypoglycemia, and neonatal jaundice in 84% of
and 194 U/L (normal 5–55 U/L). However, there was no patients. All patients demonstrate global developmental
hepatomegaly and the synthetic function of the liver was delay, frontal bossing, and hypotonia. The most common
normal. phenotype includes dysmorphic features in the form of
Currently, at 48 months of age, she is wheelchair-bound frontal bossing, deep-seated eyes, hypertelorism, a high
with severe hypotonia and global developmental delay, she forehead, a depressed nasal bridge, thin sparse hair, and

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is unable to sit unsupported and reach or transfer objects, slender hands and feet. Macrocephaly is found in at least half
babbles, she is friendly with family and strangers, still wears of patients. Seizure presents in approximately 68% of cases,
diapers, and demonstrates good vision and hearing (func- and the type is nonspecific consisting of both partial and
tioning at 5–6 months of age). Her current weight is 13.7 kg generalized epilepsy with a variable age of onset. Hepatolo-
(25–50th percentile), length 112 cm (> 95th percentile), gical signs consist of elevated transaminases (90%) and
HC: 52.5 cm (> 95th percentile), and she is macrocephalic hepatic fibrosis (32%), while hepatomegaly was found only
with the same subtle dysmorphic features. She has a squint in one patient. Cardiac defects, including pulmonary steno-
and an ophthalmological evaluation revealed optic nerve sis, atrial septal defects, coarctation of the aorta, ventricular
gliosis and tigroid fundus with normal pupil size. A neuro- septal defects, and patent ductus arteriosus, have been
logical examination showed head lag, generalized hypoto- reported. Interestingly, the current case showed no hepato-
nia, and normal reflexes. A respiratory, cardiovascular, and megaly, hepatic fibrosis, or seizures. Approximately 60% of
gastrointestinal examination were unremarkable and the patients suffer from failure to thrive and short stature but the
patient has normal female external genitalia. A skeletal presented case demonstrates tall stature. Other features
survey showed bilateral dysplasia of the hip with subluxa- present in a few cases include strabismus, undescended
tion without shorting or contractures. An auditory brain- testis, retinal dystrophy, abnormal dentition, cholelithiasis,
stem response assessment, echocardiogram, and abdominal neurogenic bladder, and megaloblastic anemia. The present
ultrasound were normal. Of note, all the following biochem- patient differs from the previously reported cohort through
ical and genetic investigations were unremarkable: acylcar- the findings of developmental dysplasia of the hip, optic
nitine profile, ammonia, lactic acid, creatine kinase levels, nerve gliosis, and tigroid fundus. These findings expand the
total homocysteine, urine amino acids, urine organic acids, phenotype of ADK deficiency.
liver enzymes, coagulation profile, lipid profile, chromoso- The ADK gene has been mapped to chromosome 10q22.2,
mal analysis, comparative genomic hybridization (CGH) spans approximately 550 kb of genomic DNA, and consists of
microarray, and DNA (deoxyribonucleic acid) molecular 11 exons. The mutation spectrum of ADK deficiency is
testing for the MAT1A gene. Unfortunately, we were unable extremely heterogeneous. The most common type is mis-
to measure AdoHcy levels or AdoMet levels because of sense mutation (50%). Other variations include deletion,
difficulty in finding a laboratory performing such tests nonsense, and deletion–insertion mutations. This is the first
and poor parental compliance. In addition, a methionine- report of a duplication creating a frameshift starting at
restricted formula was refused by the parents. Interestingly, codon Asn272 and ending in a stop codon 15bp downstream.
methionine levels over the past 2 years became lower This variant is not described in the Exome Aggregation
spontaneously without any intervention (59–68, 68–77 Consortium, Exome Sequencing Project, or 1,000 genomes
µmol/L respectively). browser, as well as a database of 2000 in-house ethnically
matched xomes supports its pathogenicity. In ADK defi-
ciency, there appears to be no clear genotype–phenotype
Discussion
correlation.
Hypermethioninemia is a biochemical marker of inherited Since methionine is elevated in this disorder, substrate
inborn errors of metabolism in the methylation pathway, reduction therapy through a methionine-restricted diet
such as methionine adenosyltransferase I/III (MAT I/III) (MRD) may be reasonable and 42% of the cohort was treated
deficiency, S-AdoHcy hydrolase (SAHH) deficiency, and through an MRD with variable efficacy. In several patients, an

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Adenosine Kinase Report Alhusani et al.

Table 1 Summary of the clinical characteristics of previously reported patients with ADK deficiency compared with the current
case

Authors Bjursell et al, Staufner et al, Shakiba et al, Current study, Total (%)
2011 2016 2016 2018
Number of cases 6 11 1 1 19
Male:female 4:2 4:7 0:1 0:1 8:11
Ethnicity Two Swedish and Four Turkish, Iranian Saudi
four Malaysian two Kuwaiti, one
Italian, one
Moroccan, one
German, two
Iranian
Age at diagnosis (y 8–24 1.9–29 3 1 1–24
Neonatal onset 6/6 9/11 þ þ 17/19 (90)
Developmental 6/6 11/11 þ þ 19/19 (100)
delay
Frontal bossing 6/6 11/11 þ þ 19/19 (100)
Hypotonia 6/6 11/11 þ þ 19/19 (100)

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Seizure 6/6 7/11   13/19 (68)
Neonatal jaundice 5/6 9/11 þ þ 16/19 (84)
Elevated 6/6 9/11 þ þ 17/19 (90)
transaminases
Hepatic fibrosis 1/6 4/11 þ  6/19 (32)
Hepatomegaly – – þ  1/19 (5)
Hypertelorism 6/6 7/11 þ þ 17/19 (90)
Sparse, thin hair – 4/11 þ  5/19 (26)
Short stature and 6/6 5/11   11/19 (58)
FTT
Cardiac defect 3/6 5/11 þ  9/19 (47)
Sensorineural 2/6 –   2/19 (10)
hearing loss
Methionine – 7/11 þ  8/19 (42)
restricted diet
Prognosis One patient died One patient died Global develop- Global develop-
at 10 y after a at 15 mo. The mental delay mental delay
refractory seizure. others survived
The others sur- and some reached
vived until adult- adulthood with
hood with global global develop-
developmental mental delay
delay
Other features Macrocephaly in Undescended tes- Recurrent infec- Macrocephaly, tall
5/6. Slender hands tis, strabismus, ret- tion, neurogenic stature, optic nerve
and feet inal dystrophy, bladder, megalo- glioma, tigroid
abnormal denti- blastic anemia fundus, develop-
tion, cholelithiasis, mental dysplasia of
MA, slender hands the hips, lax joint,
and feet slender hands and
feet

Abbreviation: ADK, adenosine kinase; FTT, failure to thrive; MA, megaloblastic anemia.

improvement in cognitive function, developmental delays, over the past 2 years. The early onset of ADK deficiency in the
and speech were reported while in others treatment was first few days of life indicates that the pathology may start in
ineffective. The current patient was not treated through an utero and this may explain why MRD has been largely
MRD. However, methionine levels decreased spontaneously ineffective in this disorder.

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 Adenosine Kinase Report Alhusani et al.

Two patients died in the reported cohort, while the others Funding Sources
survived into the third decade, demonstrating that this No funding for this article from any institution or agency.
disorder is generally not lethal and patients can live but
with global developmental delay. Ethics Approval and Consent to Participate
This study was approved by the institutional review board
office at King Abdullah International Medical Research
Conclusion
Centre (KIMARC; study number: RC16/113/R).
We expand the phenotype of ADK deficiency to include tall
stature, developmental dysplasia of the hip, optic nerve gliosis, Consent for Publication
and tigroid fundus. We have reported a novel mutation, and we Written consent was obtained from the parents.
compared the current case with previously reported cases.
ADK deficiency consists of a triad of global developmental Acknowledgments
delay, hypotonia, and frontal bossing. Macrocephaly and We are grateful to the patient and her family for their
hypertelorism are common findings; and this disease has a genuine support.
variable degree of hepatic and cardiac features, and early onset
of the disease is characteristic. Moreover, international regis-
tries such as E-HOD (European Network and Registry for References
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hod.org/), which document more cases of the ADK gene defect, ciency disrupts the methionine cycle and causes hypermethioni-
nemia, encephalopathy, and abnormal liver function. Am J Hum
will lead to a better understanding of the natural history of this

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Genet 2011;89(04):507–515
inborn error of metabolism and facilitate well-designed, large- 2 Staufner C, Lindner M, Dionisi-Vici C, et al. Adenosine kinase
sample clinical trials which may aid in improving the manage- deficiency: expanding the clinical spectrum and evaluating ther-
ment of this genetic disorder. apeutic options. J Inherit Metab Dis 2016;39(02):273–283
3 Spychala J, Datta NS, Takabayashi K, et al. Cloning of human
adenosine kinase cDNA: sequence similarity to microbial riboki-
Author Contributions
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A.A.: wrote the first draft and edited the subsequent
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data. homocysteine. J Inherit Metab Dis 2009;32(04):459–471
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H.J.B.: edited the manuscript and reviewed the clinical
deficiency in a human: a genetic disorder of methionine meta-
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M.A.: supervised the work associated with preparing, 7 Boison D, Scheurer L, Zumsteg V, et al. Neonatal hepatic steatosis
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to the clinical diagnosis and management of the patient. A 2002;99(10):6985–6990
All authors have read and approve the final draft of the 8 Shakiba M, Mahjoub F, Fazilaty H, et al. Adenosine kinase defi-
ciency with neurodevelopemental delay and recurrent hepatic
manuscript.
dysfunction: A case report. Adv Rare Dis 2016;3:3
9 Mudd SH. Hypermethioninemias of genetic and non-genetic
Conflict of Interests origin: A review. Am J Med Genet C Semin Med Genet 2011;
None. 157C(01):3–32

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