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.

References

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Methods 2005;/296:/187�98.

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: houjw741@cgmh.org.tw

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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Nephrol 2005;/147:/22�34.

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The spectrum of inherited mutations causing HPRT deficiency:

75 new cases and a review of 196 previously reported cases.

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1504 Clinical observation