Download - Atlantoaxial subluxation with recurrent consciousness disturbance in a boy with Lesch-Nyhan syndrome
Our findings indicate that measurement of the
haemolytic activity of the alternative complement
pathway in addition to total haemolytic complement
activity has to be performed in patients with menin-
gococcal disease, particularly when there is a family
history, or recurrences or infections due to uncom-
mon serogroups. Individuals and affected family
members might be protected from infection by
vaccination.
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Atlantoaxial subluxation with recurrent consciousness disturbance ina boy with Lesch-Nyhan syndrome
JIA-WOEI HOU
Division of Medical Genetics, Department of Paediatrics, Chang Gung Children’s Hospital, Taoyuan, Taiwan
AbstractDeficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) may cause variousclinical entities such as Lesch-Nyhan syndrome (LNS). A 9.5-y-old boy with the phenotypic features of LNS, including
Table I. Concentration of complement proteins in family members.
CH50 AP50 C3 (g/l) C4 (g/l) Properdin (mg/l)
Our patient Normal 0 1.25 0.19 B/0.01
Brother 1 Normal 0 1.29 0.21 B/0.01
Brother 2 Normal 0 1.28 0.13 B/0.01
Mother Normal Normal 0.96 0.22 57%
Father Normal Normal 1.34 0.19 105%
CH50: total haemolytic complement activity; AP50: alternative complement pathway haemolytic activity.
Properdin values for the parents are given as per cent of normal, and the measurements were done by electroimmunoassay. In the brothers,
levels wereB/6% of the normal value, and their samples were then measured by ELISA, giving results in mg/l.
(Received 4 July 2005; revised 2 February 2006; accepted 6 February 2006)
ISSN 0803-5253 print/ISSN 1651-2227 online # 2006 Taylor & Francis
DOI: 10.1080/08035250600617131
Correspondence: Jia-Woei Hou, Division of Medical Genetics, Department of Paediatrics, Chang Gung Children’s Hospital, 5 Fu-Shin St., Kweishan,
Taoyuan, Taiwan. Tel: �/886 3 3281200 ext. 8203. Fax: �/886 3 3278283. E-mail: [email protected]
1500 Clinical observation
hyperuricaemia, choreoathetosis, self-mutilation and profound neurological dysfunction, was found to have HPRTdeficiency. Normocytic anaemia, hyperuricaemia (uric acid 594.8 mmol/l) and microscopic haematuria with uric acidcrystals were noted. Ultrasonography showed bilateral nephrocalcinosis and urinary bladder stones. In addition, hepresented with three episodes of consciousness disturbance with limb paresis, possibly caused by atlantoaxial subluxation(AAS) with compression myelopathy. The diagnosis was made by the amount of residual enzyme activity and a singlenucleotide substitution on the acceptor site region of intron 5 (IVS5�1 G0/C) of the HPRT gene, inherited from hisasymptomatic mother.
Conclusion: Lesch-Nyhan syndrome is a devastating sex-linked recessive disorder resulting from almost completedeficiency of the activity of HPRT. This report highlights the unusual AAS in a boy with LNS presenting recurrentconsciousness change. The mutation described herein is a hitherto unreported splicing error leading to exon 6 skipping ofthe HPRT gene.
Key Words: Atlantoaxial subluxation, HPRT, Lesch-Nyhan syndrome
Inherited hyperuricaemic disorders fall into two major
classes: metabolic overproduction of uric acid and
renal tubular undersecretion [1]. Hyperuricaemia
may result from deficiency of hypoxanthine-guanine
phosphoribosyltransferase (HPRT), overactivity of
phosphoribosylpyrophosphate (PRPP) synthetase
and deficiency of glucose-6-phosphatase [1]. Inher-
ited deficiency of the purine salvage enzyme HPRT
causes various overlapping clinical syndromes with
hyperuricaemia, depending on the amount of residual
enzyme activity. Lesch-Nyhan syndrome (LNS,
OMIM 300323) is a rare X-linked recessive genetic
disorder of purine metabolism caused by a complete
deficiency of HPRT activity, resulting from mutation
in the corresponding gene on the long arm of the X
chromosome (Xq26�27) [1]. Diagnosis can be made
by clinical features and further confirmed by direct
sequencing all nine exons of the HPRT gene [2,3].
Many different mutations on the HPRT coding
region of LNS patients have been described, including
single base substitutions, partial or entire gene
deletions, gene insertions, or endoduplication of
exons [2�4].
Atlantoaxial subluxation (AAS) is a rare condition
in children and is predominantly found in Down
syndrome [5]. AAS is difficult to diagnose and, if
improperly treated, it may lead to permanent neck
deformity or cervical myelopathy. Children present
with neck pain, head tilt, and reduction in neck
mobility or even limb paresis. Early detection and
intensive conservative treatment constitute the main-
stay of management of AAS. This is the first report on
a patient with LNS coincident with AAS which was
corrected after cervical fixation and physiotherapy.
Case report
A 9.5-y-old male patient was observed to have
psychomotor retardation since the age of 1 y, and
was considered to have cerebral palsy. No other
special findings could be noted from previous medical
records.
He is the only son born to 25-y-old healthy parents.
Self-mutilation (mouth and finger biting) developed
from 6 y old. Abnormal behaviour or movement such
as choreoathetosis was noted at the age of 7 y. No
family members have a similar phenotype.
Diagnosis of LNS was made at 9 y when hyperur-
icaemia (uric acid 594.8 mmol/l) and microscopic
haematuria were present, in addition to the clinical
features. Three episodes of neck pain, head tilt and
sudden onset of consciousness disturbance for 30 to
60 min with lower-limb weakness occurred at the ages
of 6, 9 and 9.5 y, respectively. At this time, the coma
last for 45 min, associated hypothermia and CO2
retention, and he recovered after tracheostomy and
intubation.
Physical examination revealed a bed-ridden boy
with generalized spasticity and mental retardation.
His neck was mildly stiff and coma scale was
E1M3Ve. Patches of hypopigmented hair (golden
yellowish, as seen in the mother and maternal grand-
mother) and several ulcers and scars were seen over
the upper and lower lips. Diffuse rhonchi and rales
were auscultated over the chest. Paresis of four
extremities but moderate spasticity was noted. Ankle
clonus and bilateral Babinski signs were positive.
Laboratory findings showed normocytic anaemia
(haemoglobin 1.28 mmol/l), hypoalbuminaemia (36 g/
l), elevated levels of lactate/pyruvate (3.8/0.13 mmol/
l), and microscopic haematuria (RBC 52/ml). Thyr-
oid, hepatic and renal functions were all normal.
Chest films showed diffusely increased lung infiltrates,
thin cortical bones and an old fracture at the
left proximal humerus. Bone mineral density
showed osteopenia (0.474 g/cm2, z score �/2.0).
Ultrasonography showed bilateral moderate medul-
lary nephrocalcinosis and urinary bladder stones.
Electroencephalography showed diffuse cortical dys-
function. Magnetic resonance imaging (MRI) of the
brain showed diffuse cortical atrophy with lacunar
infarcts or microvascular disease at the right frontal
lobe. In addition, bilateral mastoiditis with left otitis
media, and compression of the upper cervical spinal
cord with myelomalacia (Figure 1), were also noted.
Clinical observation 1501
The diagnosis of AAS was established by a three-
dimensional computerized tomography (CT) scan,
which showed anterior displacement of the C2 tip
with separate dens, suggesting C1-C2 subluxation
and dens fracture over the C-spine (Figure 2).
Intraoperative C1-C2 reduction and a subsequent
posterior transarticular fixation with a soft wire with
allograft bone fusion were done smoothly (Figure 3).
There was no more choreoathetosis and self-biting
after 6-mo treatment with allopurinol. He was often
ventilator dependent, and a tracheostomy was needed
because of CO2 retention (low spontaneous tidal
volume) with respiratory failure. Gastrointestinal
problems such as chronic constipation and meteorism
were noted. He was able to follow orders but did not
sit or walk alone, with only some simple but dysarthric
words. Treatment with allopurinol continues.
His karyotype was 46, XY. The activities of HPRT
in the erythrocyte lysates of the parents were both
within normal limits, but that of the patient was very
low (0.0358 nm/min/mg protein,B/0.05% of control).
Direct genomic DNA sequencing of the HPRT gene
after the amplification of all its nine exons by
polymerase chain reaction (PCR) [2,6] revealed a
single nucleotide substitution from guanine to cyto-
sine on the acceptor site region of intron 5 of the
Figure 1. Brain MRI showing compression of the upper cervical spinal cord with myelomalacia: A) sagittal view, B) transverse view.
Figure 2. Three-dimensional CT scan of the C-spine showing
anterior displacement of the C2 tip, suggesting separate dens with
C1-C2 subluxation.
Figure 3. The C1-C2 subluxation is corrected by a transarticular
screw fixation.
1502 Clinical observation
HPRT gene (IVS5�1 G0/C) (Figure 4). His mother
has the heterozygous G/C change. The HPRT cDNA,
amplified from total RNA of the patient’s peripheral
blood by reverse-transcription PCR study, showed the
absence of exon 6. This mutation was also detected in
his heterozygous, asymptomatic maternal grand-
mother and maternal aunts. This transversion puta-
tively caused an alternatively spliced transcript leading
to an abnormal translated protein. The family study
revealed that the patient’s mother was a heterozygous
carrier, and the mutation comes from the maternal
grandmother.
Discussion
In this Taiwanese family, the male proband has
clinical features of LNS including spasticity, involun-
tary movements (choreoathetosis and a compulsive
form of self-mutilation), developmental disability and
self-injurious behaviour, while the heterozygous fe-
males are clinically normal. A hitherto unreported
new mutation has been identified in this boy mani-
festing LNS and AAS, by the analysis of all nine exons
of HPRT from the genomic DNA and a skipping of
exon 6 from the reverse-transcribed mRNA using the
PCR technique coupled with direct sequencing.
Thus, correct diagnosis can be made, allowing appro-
priate treatment as well as informed genetic counsel-
ling. In addition, the patient had unusual
presentations of recurrent consciousness disturbance
and limb weakness, resulting from a recurrent com-
pression effect by AAS. Both the mother and grand-
mother were carriers with normal phenotypes, except
for patches of yellowish hair. These findings may
present one of the signs of LNS patient or carrier.
Atlantoaxial instability or subluxation (AAS) is a
relatively frequent finding in Down syndrome with
syringomyelia [5] or after neck trauma. The initial
presentations include torticollis and progressive motor
deterioration presenting with abnormal gait, ataxia or
quadriparesis. AAS may be confirmed by X-ray films
of the cervical spine which show widening between
the joint space of the atlas and odontoid processes.
Three-dimensioanl CT and MRI will reveal C1-C2
subluxation with syringomyelia or myelopathy. In
cases of LNS, the involvement of the cervical spinal
cord may result directly from the metabolic defect or
indirectly from the chronic opisthotonus and some-
times forcible involuntary neck movements [7,8].
Treatment strategies are limited to protective physical
devices and behaviour therapy. Treatment with
xanthine oxidase inhibitors (allopurinol) is effective
for the control of the elevated renal excretion of uric
acid, but there is only merely symptomatic treatment
for the neurological symptoms. Surgery is reserved for
cases with irreducible or recurrent subluxation [9].
HPRT mutations are associated with a spectrum of
diseases that ranges from hyperuricaemia alone to
hyperuricaemia with profound neurological and be-
havioural dysfunction. More than 2000 mutations
throughout the HPRT gene coding region and muta-
tions causing alternative mRNA splicing have been
reported [2�4,6]. A mechanism by which the muta-
tion-induced structural alteration of HPRT reduces
the affinity of the enzyme for PRPP has been
suggested. Most of the mutations are explainable by
the predicted effect on protein structure and function
[6]. The partial phenotypes are more likely to have
mutations predicted to allow some residual enzyme
activities; however, the differences between LNS and
the partial phenotypes cannot be explained by differ-
ences in the locations of mutations [2�4,6]. The novel
HPRT transcript lacking exon 6 of the HPRT gene in
this patient may explain both LNS and the associated
Figure 4. DNA study showing a mutation in the acceptor site
region of intron 5 of the HPRT gene (IVS5�1 G0/C) from a reverse
primer (C0/G). His mother has heterozygous G/C change.
Clinical observation 1503
AAS, which has broadened the clinical spectrum of
LNS.
In conclusion, this report highlights the unusual
anomalies, including AAS and cervical myelopathy, in
a boy with LNS presenting recurrent consciousness
change. Regular monitoring of C-spine images and
special devices to prevent self-injury are recom-
mended in LNS patients. The hitherto unreported
splicing error leading to exon 6 skipping of the HPRT
gene may explain his unusual phenotype.
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1504 Clinical observation