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Cockayne syndrome associated with low CSF 5-hydroxyindole acetic acid levels
  1. C J ELLAWAY*,
  3. V S FUNG,
  4. J W EARL§,
  5. R KAMATH,
  6. P G PARSONS**,
  7. J A ANTONY164,
  8. K N NORTH
  1. * Western Sydney Genetics Program, Royal Alexandra Hospital for Children, NSW, Australia
  2. Department of Paediatrics and Child Health, University of Sydney, NSW, Australia
  3. Department of Neurology, Westmead Hospital, Australia
  4. § Department of Biochemistry, Royal Alexandra Hospital for Children, NSW, Australia
  5. Department of Gastroenterology, Royal Alexandra Hospital for Children, NSW, Australia
  6. ** Queensland Institute of Medical Research, Australia
  7. 164 Department of Neurology, Royal Alexandra Hospital for Children, NSW, Australia
  8. Neurogenetics Research Unit, Royal Alexandra Hospital for Children, NSW, Australia
  1. Dr North, Department of Paediatric and Child Health, Royal Alexandra Hospital for Children, PO Box 3515, Parramatta 2124, NSW, Australia, KathryN{at}

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Editor—Cockayne syndrome is a rare, clinically heterogeneous disorder, characterised by severe growth failure, cognitive impairment, characteristic facies, and photosensitivity. In the older patient the face has a characteristic aged appearance with sunken orbits, a relatively large, “beak-like” nose, and narrow mouth and chin. Both the central and peripheral nervous systems are involved in this neurodegenerative disorder with pigmentary retinopathy, delayed nerve conduction velocities, sensorineural hearing loss, progressive spasticity, and cerebellar involvement with dysarthria, tremor, and ataxia. The cerebral histopathological changes most commonly seen are patchy demyelination of the subcortical white matter and microscopic calcifications throughout the central nervous system. Calcification of the basal ganglia may be visible on CT scan.1-3 The diagnosis of Cockayne syndrome is made on clinical grounds in association with the failure of RNA synthesis in cultured fibroblasts or lymphoblastoid cells to recover to normal rates after UV-C irradiation.2 4 Inheritance is presumed to be autosomal recessive.1

Here we report a patient with Cockayne syndrome in whom cerebrospinal fluid 5-hydroxyindole acetic acid was markedly reduced. To date there are no reports of abnormalities of the cerebrospinal fluid neurotransmitters in association with Cockayne syndrome. This finding may provide insight into the pathogenesis of the central nervous system abnormalities. Furthermore we have described the patient's body composition in terms of resting energy expenditure, total body protein, fat, and bone mineral density which are relevant to management of the progressive cachexia associated with this disorder.

The proband, a 16 year old male, is the third child of consanguineous Sri Lankan parents and was born at term with a birth weight of 2722 g. His early expressive speech development was delayed, but gross and fine motor development were within normal limits. He initially presented at 8 years of age with tremor and poor motor coordination. A cerebral CT scan at that time was normal. He was re-evaluated at the age of 14 years. At this time he had an obvious intention tremor, gait ataxia, mild cognitive impairment, bilateral high tone sensorineural hearing loss, and poor growth. His parents reported extreme sun sensitivity, dry skin, and poor sweating in hot conditions.

On physical examination at 14 years, the proband had slightly sunken eyes, thin hair, and dry skin. His speech was slow and mildly dysarthric. His height, 136 cm, and weight, 32 kg, were both below the 3rd centile (50th centile for 9 years) and head circumference, 52.5 cm, was on the 2nd centile (50th centile for 8 years). He had normal secondary sexual characteristics. Neurological examination showed cerebellar dysfunction with a marked, coarse, irregular intention tremor with overshooting, slow fine finger movements, and heel-shin incoordination. His gait was broad based and unsteady with flexed posture and toe walking. Dystonic posturing of his left arm and fingers were noted intermittently. There was minimal involuntary movement at rest. Muscle tone and power were within normal limits. Deep tendon reflexes were brisk, but his plantar reflexes were downward. There was no clinical evidence of peripheral neuropathy. Examination of his cranial nerves showed saccadic hypermetria, but no nystagmus. The pupils were poorly reactive to light and he was unable to converge. On neuropsychological testing there were specific deficits in short term memory, abstract reasoning, skills of generativity, and mental flexibility.

A repeat CT scan at 14 years of age showed generalised cerebral atrophy and calcification of the globus pallidus, which on MRI scan presented as decreased signal intensity of the globus pallidus (fig 1). In addition, there was atrophy of the cerebellum, temporal lobe structures, hippocampal formation, and brain stem. The pattern of myelination approximated that of a 12 month old child. Nerve conduction studies showed absent sensory action potentials and moderately slowed motor conduction (29 m/sec at the right common peroneal nerve). There was segmental demyelination and onion bulb formation on sural nerve biopsy.

Figure 1

Spin echo T2 weighted image and axial fast field sequence (A) shows decreased signal intensity foci in the globus pallidus, consistent with calcification. There is global cerebral atrophy with thinning of the white matter and ventricular dilatation. The pattern of myelination (B) approximates that of a 12 month old child.

Other investigations at this time included a full blood count, serum electrolytes, liver function tests, calcium, phosphorus, glucose, parathyroid hormone, copper, caeruloplasmin, 25-hydroxycalciferol, uric acid, cholesterol, triglycerides, thyroid function tests, vitamin A, vitamin D, vitamin E, vitamin B12, α-fetoprotein, urinary amino and organic acid analyses, very long chain fatty acids, phytanic acid, lysosomal enzymes, transferrin isoforms, trinucleotide repeat expansion studies for spinocerebellar ataxia types 1, 2, and 3, Friedrich's ataxia, Machado-Joseph disease, dentatorubropallidoluysian atrophy, and a karyotype. All investigations were normal. Analysis of mitochondrial respiratory chain enzymes in skeletal muscle showed a borderline low complex III activity relative to protein (36% relative to control mean), but normal relative to citrate synthase (74% of control mean). The common mitochondrial DNA point mutations for MELAS, MERFF, NARP, and Leigh syndrome were not detected in skeletal muscle DNA.

Cerebrospinal fluid protein was raised above the normal range on two occasions, 0.76 g/l and 0.65 g/l (normal range <0.3 g/l). Cerebrospinal fluid and plasma lactates were normal. On analysis of cerebrospinal fluid neurotransmitters, there was a low 5-hydroxyindole acetic acid level, 0.03 μmol/l (normal range 0.13-0.21 μmol/l) and a normal homovanillic acid level with a ratio of 5-hydroxyindole acetic acid:homovanillic acid of 0.1 (normal 0.3-0.8).5Cerebrospinal fluid amino acid levels including tryptophan were normal.6 Peripheral serotonin levels, urinary 5-hydroxyindole acetic acid, and platelet serotonin were also normal, as were plasma phenylalanine levels and dihydropteridine reductase activity. In view of these findings a primary disorder of central serotonin metabolism was considered and the proband started treatment with 5-hydroxytryptophan, 1 mg/kg/day.

Over a two year period the dose of 5-hydroxytryptophan was gradually increased to 5 mg/kg/day. There was no obvious clinical improvement, but on the other hand, his cognitive function, tremor, and gait have not deteriorated and cerebral MRI scan showed no change. During this period, however, he developed a pigmentary retinopathy, lost 3 kg in weight, and his facial appearance came to resemble a “cachectic bird-nose dwarf”1 with sunken eyes (fig 2). Despite continued treatment with 5-hydroxytryptophan, cerebrospinal fluid levels of 5-hydroxyindole acetic on two further occasions have remained markedly low (0.02 and 0.03 μmol/l).

Figure 2

The proband at 16 years of age with the characteristic facial features of Cockayne syndrome with sunken eyes, “bird-like nose”, and aged appearance.

The clinical diagnosis of Cockayne syndrome was confirmed by survival studies of Epstein-Barr virus transformed B cells after irradiation with UVB7 (fig 3). These studies show that the proband's cells were very sensitive to irradiation, with only 1% of cells surviving a dose of 100 J/sq m UVB. In comparison, the normal controls' cells did not approach 1% survival until irradiated with doses of 250 J/sq m and over. To confirm the Cockayne phenotype further, the rate of RNA polymerase II transcription in the lymphoblastoid cells was compared with control lymphoblastoid cells. The constitutive incorporation of 14C-uridine over 90 minutes was found to be 64 ± 2% (n=4) of the control lymphoblastoid cells (after normalisation against thymidine incorporation). This is within the 40-70% range for Cockayne syndrome lines reported by Balajeeet al,4 who also found that xeroderma pigmentosa cells had the same rate of RNA synthesis as controls.

Figure 3

Survival of Epstein-Barr virus transformed B cells after irradiation with UVB. Results are expressed as % of the incorporation of 3H-thymidine three days after irradiation. The results of our patient are shown together with those from cell strains from three normal controls (WW2, SS, 11224). These results illustrate the marked sensitivity to UVB light, with only 1% of cells surviving 100 J/sq m as compared to doses of 250 J/sq m and over required to achieve similar survival rates in the control cells.

Because of progressive weight loss, the proband was referred for nutritional assessment. The resting energy expenditure measured by indirect calorimetry was 75% of the predicted value, 3856 kJ/24 h, with a predicted resting energy expenditure based on age, sex, height, and weight for healthy children of 5135 kJ/24 h.8 The respiratory quotient was 0.89, indicative of appropriate nutritional intake. Total body protein measured by neutron capture analysis9 was low for age (65%) but above predicted for weight (112%), height (112%), and lean body mass (108%). Total body bone mineral density measured by dual energyx ray absorptiometry10 was on the 50th centile for age, 1.141 g/cm3. Total body fat tissue measured by dual energy x ray absorptiometry was 31.2%.

Our patient's clinical features are consistent with the diagnosis of Cockayne syndrome (table 1). Diagnostic criteria include growth failure after normal or slightly low birth weight, neurological dysfunction with cerebral white matter involvement plus at least three of the following features: cutaneous photosensitivity, progressive pigmentary retinopathy/cataracts, optic disc atrophy, miotic pupils or decreased lacrimation, sensorineural hearing loss, dental caries, short stature, and a characteristic physical appearance of “cachectic dwarfism”.1 Atypical features in our patient include later age of onset of neurological signs, absence of dental caries, and only mild cognitive impairment. The diagnosis of Cockayne syndrome was supported by finding hypersensitivity to UV light in Epstein-Barr virus transformed lymphoblasts. The pathogenesis of Cockayne syndrome is poorly understood. The cells of patients with Cockayne syndrome are hypersensitive to the lethal effects of UV light because they have a defective subpathway of nucleotide excision repair known as “transcription coupled repair”.11 Cockayne syndrome is genetically heterogeneous. Two disease genes have been identified,CSB on chromosome 10q11 and theCSA gene maps to chromosome 5.12 13 Both proteins play an essential role in preferential repair of transcription blocking lesions from active genes.14 The CSB protein is a member of the SW12/SNF2 family of ATPases whose function is thought to involve remodelling of protein-DNA interactions, such as chromatin structure in different situations. The CSA gene encodes a “WD repeat” protein.13

Table 1

Clinical features previously reported in Cockayne syndrome and those seen in our patient

A unique finding in our patient was very low cerebrospinal 5-hydroxyindole acetic acid and normal homovanillic acid levels on three separate occasions. The peripheral serotonin levels were normal. The metabolic pathways of 5-hydroxyindole acetic acid and homovanillic acid are shown in fig 4. The concentrations of 5-hydroxyindole acetic acid and homovanillic acid in the cerebrospinal fluid are thought accurately to reflect the turnover of catecholamine neurotransmitters.15 The low 5-hydroxyindole acetic acid, in association with normal tryptophan and homovanillic acid in the cerebrospinal fluid and normal peripheral serotonin, is suggestive of low brain serotonin turnover with normal dopamine turnover and may suggest a primary central serotonin deficiency, a selective serotoninergic tract degeneration, or an isolated central nervous system tryptophan hydroxylase deficiency. This finding in our patient may provide some insight into the mechanism of the neurological complications and the inanition of Cockayne syndrome given the putative roles of serotonin in control of movement and appetite. We treated our patient with 5-hydroxytryptophan (5 mg/kg/day) in an attempt to increase his cerebrospinal fluid 5-hydroxyindole acetic acid levels, with no change in levels observed. However, from a clinical point of view, he has had no further deterioration in cognitive or neurological function.

Figure 4

Synthetic and catabolic pathway of serotonin and dopamine. 5-hydroxyindole acetic acid is formed initially from tryptophan in a reaction catalysed by tryptophan hydroxylase○2 to form 5-hydroxytryptophan (5HTP), which requires molecular oxygen and tetrahydrobiopterin (BH4) for its activity. 5-hydroxytryptophan is decarboxylated by pyrimidine dependent aromatic L-amino acid decarboxylase○3 to form the active neurotransmitter serotonin. Serotonin is catabolised by monoamine oxidase○4 to form 5-hydroxyindole acetic acid (5HIAA). Tyrosine is metabolised by tyrosine hydroxylase○1 to L-dopa. Aromatic L-amino acid decarboxylase○3 is also required for the decarboxylation of L-dopa to dopamine, which is then catabolised to homovanillic acid by monoamine oxidase and catechol O-methyl-transferase○5.

The cause of death in the majority of cases of Cockayne syndrome has been secondary to inanition and thus attention to nutrition is essential to patient care and well being.1 Although our patient was always small for his age, he recently showed accelerated weight loss. In the setting of premature aging we predicted an increased metabolic rate, but, surprisingly, detailed energy expenditure studies indicated a lowered metabolic rate. This is similar in subjects with anorexia nervosa, whose resting energy expenditure is reduced when compared to healthy, aged matched controls.16With re-feeding, however, the resting energy expenditure in anorexia nervosa subjects normalises, with concomitant increases in body weight. It would therefore appear possible to manage Cockayne syndrome patients with programmes that correct the energy deficits, documented by energy expenditure studies. Whether such strategies will prevent deterioration in nutritional status remains to be shown.


We would like to thank Dr P McVeagh, Department of Paediatrics, Royal Alexandra Hospital for Children, for referring this patient to the Neurogenetic Service. We would also like to thank Ms Jane Allen, Department of Nutrition and Dietetics, Royal Alexandra Hospital for Children, for performing the energy expenditure studies, Mr Nick Hayward for transforming our patient's B cells, and Dr Adam Steinberg, Department of Radiology, Royal Alexandra Hospital for Children for interpreting the MRI findings.