A population study of Lesch Nyhan disease in the UK

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1 DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE A population study of Lesch Nyhan disease in the UK GILLIAN T MCCARTHY 1 ELIZABETH M GREEN 1 OLUWAFEMI OGUNBONA 2 H ANNE SIMMONDS 3 LYNETTE FAIRBANKS 3 TERRY POUNTNEY 1 ELIZABETH BRYANT 1 1 South Downs Health NHS Trust, Chailey Heritage Clinical Services, East Sussex, UK. 2 East Kent Hospitals University NHS Foundation Trust, Canterbury, Kent, UK. 3 Purine Research Laboratory, St Thomas' Hospital, London, UK. Correspondence to Dr Gillian T McCarthy at Chailey Heritage Clinical Services, Beggars Wood Road, North Chailey, Near Lewes, East Sussex BN8 4JN, UK. gramsay39@tiscali.co.uk. This article is commented on by Jinnah on pages 6 7 of this issue. PUBLICATION DATA Accepted for publication 7th July Published online 24 September ABBREVIATIONS HPRT Hypoxanthine-guanine phosphoribosyl transferase LND Lesch Nyhan disease AIM The aims of this study were to identify all people with Lesch Nyhan disease (LND) born in the UK between 1988 and 2008, and to obtain a clinical profile including age at diagnosis, genetic background, family history, neurological signs, and medications. METHOD Potential participants were contacted through the British Paediatric Neurology Surveillance Unit. Questionnaires were sent to each child s paediatric neurologist or primary consultant. Two purine laboratories provided metabolic information. RESULTS Twenty-three live males with LND in the 0- to 20-year age band and eight live males over the age of 20 years were identified. Thirty-one live people with LND were identified in the UK in 2008, giving a prevalence of 1 in 2 million people. Over the 20 years of study, there was a mean incidence rate of 0.18 per live births, range 0 to 0.5. INTERPRETATION To our knowledge, this study is the first to provide details of the prevalence and incidence of LND in the UK. The data highlight that clinical profiles, at the time of diagnosis, and management of the disease are variable. There is the need for ongoing monitoring of allopurinol dosage and metabolic screening. Lesch Nyhan disease (LND) is a very rare inherited disorder of purine salvage metabolism caused by congenital deficiency of the enzyme hypoxanthine guanine phosphoribosyl transferase (HPRT). Lesch and Nyhan first described the syndrome in 1964 when they recognized a recurring pattern of neurological abnormalities in two brothers who had hyperuricaemia, an extra-pyramidal motor disorder, and compulsive self-injurious behaviour, the combination of features suggesting a metabolic disorder. 1 Within a short time further cases were described, and in 1967 Seegmiller et al. 2 demonstrated absence of HPRT as the cause of the syndrome. Jolly et al. 3 cloned the human HPRT gene in Since then a steady increase in genetic mutations has been recognized: 218 mutations in 271 families by The condition is X-linked recessive but seven cases in females have been reported, including a female with a clinically normal twin. 5 Between classic LND and Kelley Seegmiller syndrome a spectrum of clinical features occurs. Attenuated variants of LND associated with intermediate levels of HPRT deficiency have recently been reviewed. 6 They were associated with varying but milder neurological symptoms. None exhibited selfinjurious behaviour but many exhibited behaviours that were maladaptive. Partial HPRT deficiency, or Kelley Seegmiller syndrome, is not associated with neurological symptoms. The diagnosis of LND depends upon measurement of HPRT, as uric acid levels may not be elevated in some young children. Early clues to diagnosis of LND are crystals in the diaper, irritability, hypotonia, and difficulties with feeding, sucking, and swallowing. Abnormal motor development becomes apparent by the end of the first year, evolving into dystonia in the second year. Self-injurious behaviour may start as the teeth erupt but does not usually emerge until later. 7 It is compulsive and distressing; the lips, tongue, and fingers may be damaged with permanent scarring. Arm splints need to be used to protect the hands and extraction of teeth is commonly performed. Other forms of self-injury may develop and children with the disease may be aggressive towards their carers. 8 Renal failure may be a presenting feature, even occurring in utero, and is a cause of early death. Additional complications caused by the metabolic disease are cognitive impairment and behavioural problems. 9,10 Life expectancy is reduced in LND. Sudden, unexplained death occurs possibly because of neurological dysfunction or acute respiratory problems from hiatus hernia or gastro-oesophageal reflux and inhalation. 11 The combination of metabolic and neurological abnormalities in LND has led to in-depth research, including evaluation of the metabolic abnormalities and careful observation of the neurological picture, and efforts to manage the associated complex difficulties. In a recent paper, Jinnah et al. 7 present a scholarly overview of the disorder, including a study of the motor disorder and a literature review describing 254 cases of LND. 34 DOI: /j x ª The Authors. Journal compilation ª Mac Keith Press 2010

2 In the UK the metabolic investigation of LND has been performed in two specialist purine pyrimidine laboratories in London and Glasgow. As this was a paediatric review, the primary aim of this study was to identify all people with LND in the UK born after 1 June 1988 and to obtain their profile. This included details of the age at diagnosis, genetic testing, family history, neurological signs, complications, drug treatment, management of existing problems, and distribution of cases in the country. A secondary aim was to improve awareness of the condition in the UK. METHOD The study was designed with anonymous participants who were identified by members of the British Paediatric Neurology Association, under the auspices of the British Paediatric Neurology Surveillance Unit. Members of the British Paediatric Neurology Association were targeted by a monthly that directed them to an online questionnaire, which asked if they had seen a case of LND in the past month or had treated a male child born after 1 June If confirmation was received, a request was sent to them by to complete an anonymized patient questionnaire. The only identifiers were date of birth and the first part of the postcode. Ethical approval was obtained from the South West Multi-centre Research Ethics Committee, which designated the study as having no local investigators. Parental approval was not required as the participants were anonymous. To improve the identification of all individuals with the disease in the UK, the results were cross-referenced using dates of birth with the two purine laboratories in London and Glasgow where diagnostic HPRT levels are performed. Also, members of the British Paediatric Neurology Association identified individuals who had been passed on to adult services. RESULTS The data are reported in two groups: group A, males with LND aged between 0 and 20 years; group B, males with LND aged over 20 years. Group A (males with LND aged between 0 and 20y) Twenty-six males with LND born between 1 June 1988 and 1June2008wereidentifiedintheUK;allwerediagnosedin one of two purine laboratories in Glasgow or London. All had classic LND with HPRT enzyme levels of less than 1.5%. Seventeen questionnaires were received from six consultant paediatric neurologists, five consultant paediatricians, four specialists in neurodisability, one consultant in metabolic paediatrics, and one community paediatrician. Two new participants diagnosed at the end of the study period were brothers; only limited information about them was obtained. Four children had only metabolic information at diagnosis available. Twochildrenaged14and10yearsdiedbeforethestudy started. One participant, aged 4 years, died during the study; an ante-mortem questionnaire was completed about him. One further child born in 2007 was identified in What this paper adds It identifies a UK prevalence of Lesch Nyhan disease of 1 in 2 million people. Initially, uric acid levels should be measured in both plasma and urine. Measurement of the enzyme hypoxanthine guanine phosphoribosyl transferase is the definitive test for Lesch Nyhan disease. A multi-specialist approach is required to manage the complex problems associated with the disease. Twenty-three male children were alive at the time of the study. Eleven mothers were known to be carriers, and in 15 instances carrier status was unknown. Over the 20 years of the study, there was a mean incidence rate of 0.18 per live births (range 0 0.5) or approximately 1 in This equates to 0.68 per live births (range 0 1.9). The age at diagnosis was identified for 23 participants: 17 from the questionnaires and six from additional information from the metabolic laboratories. The age at diagnosis ranged from 2 months to 9 years (mean 2y 10mo, SD 2y 4mo). Figure 1 shows the participants numbered 1 to 23. Two children were diagnosed after the age of 8 years; for one, with severe self-injurious behaviour, his diagnosis was delayed as plasma uric acid was not markedly raised and the HPRT level was not analysed. Three participants were diagnosed after the age of 4 years, one when a younger brother aged 3 years 6 months presented with dystonia and self-injurious behaviour. Table I shows the clinical presentation at first diagnosis obtained from the 17 questionnaires returned. Levels of plasma uric acid were available for a further nine participants from the purine laboratories; these are included in Table I. The mean level of plasma uric acid for all children not on allopurinol treatment was 616umol L, range 300 to 1059umol L. Presenting symptoms and signs were developmental delay in 16 out of 17 children, a movement disorder in 14 out of 16, and hypotonia in 10 out of 15. The diagnosis of cerebral palsy was made in 13 out of 17 children; seven were older than 3 years when diagnosed with LND and 13 had a movement disorder. Eating problems were reported in 10 of the 17. Crystals were noticed in the diaper in 8 out of 15 children. Post-diagnosis signs and symptoms from the questionnaire data are also shown in Table I. All children for whom questionnaire data were available had some form of self-injurious behaviour at the time the questionnaire was completed. The main types of behaviour were hyperextension, finger biting, lip biting, kicking, and head banging. Other types of self-injury were jamming arms in door, damage to nasal septum, dislocation of shoulders, putting fingers in spokes of wheelchair, and hitting out at parents. Speech problems and dystonia were described as severe or moderate in all children. Eating problems were common in 13 children, although only four had a gastrostomy. The teeth had been removed from 10 children. A hiatus hernia was diagnosed in three. Concerning medication after diagnosis, all participants were treated with allopurinol. Figure 2 shows the daily dose of allopurinol in milligrams per day compared with the weight (in kilograms) of each participant at the end of the study. The participants reported in Figure 2 are in order of descending age. This figure shows a wide variation in daily dosage. It was Population Study of LND in the UK Gillian T McCarthy et al. 35

3 Age (years) Age at diagnosis Age at end of study Cases Figure 1: Age at diagnosis and at the end of the study in male children with LND. not clear how many cases had regular metabolic screening to establish the effect of allopurinol. Nine of 17 children received potassium citrate mixture to alkalinize the urine and increase solubility of uric acid. Eleven of 17 children received baclofen, including one intrathecally to reduce muscle tone. Only two children received diazepam to alleviate muscle tone and anxiety, and two were on gabapentin. Other medications used were fluoxetine, carbidopa levodopa, omeprazole, diclofenac, trimethoprim, melatonin, and botulinum toxin injection, in separate children. S-adenosylmethionine had been given to one child for 1 year. Only one child suffered from minor epilepsy. Group B (males with LND aged over 20y) Nineteen males with LND born before 1 June 1988 were identified in the UK. Metabolic results were obtained from purine laboratories in Glasgow and London, or from members of the British Paediatric Neurology Association who passed care of these patients to adult services. Eight males were alive at the time of the study, age range 20 to 31 years. Eleven males had died: two died during the study (aged 31y and 35y); for the nine other deaths, ages ranged from 2 months to 23 years. Metabolic results were available for 13 males, including those who had died. The mean level of plasma uric acid was 358 umol L, range 141 to 580 umol L. Five levels were stated to be with allopurinol treatment, but it was not always clear from the historical records whether the level of uric acid stated was with or without allopurinol treatment Prevalence Thirty-one live cases of LND were identified in the UK in 2008, giving a prevalence of 1 in 2 million people. The total number of people with LND (group A [n=26] plus group B [n=19]) identified in the UK in an approximate 38-year timescale was 45. During the 2 years of the study, one child and two adult males died. Thirteen other individuals with LND were known to have died before the study started. Distribution of the individuals was investigated using the initial part of the postcode obtained from the completed questionnaires and the purine laboratories. The initial part of the postcode identifies a general area within the UK but does not pinpoint closely where the participants live. There appeared to be only one cluster of cases: in South Wales, where seven cases were identified. DISCUSSION This study reports the prevalence of LND in the UK using surveillance methods backed up by cross-referencing with the two diagnostic laboratories in the UK. Thirty-one live cases of LND were identified in 2008, giving a prevalence of 1 in 2 million people. The incidence of LND often cited internationally is taken from the report of Crawhall et al. 12 from Canada of 1 in live births in However, in Spain in 2007, Torres and Puig reported an estimated prevalence of 1 in live births, although this included all forms of HPRT enzyme deficiency. 13 The Spanish individuals were diagnosed from 1984 to 2007, a 23-year period. Out of a total of 36 individuals with HPRT deficiency, 25 had LND. The results of that study are closer to those found in the UK. As the number of questionnaires completed in the UK study was relatively small, it has been useful to make comparisons with the data of Jinnah et al. 7 In both studies the most common presenting problems were motor delay, abnormalities of muscle tone, or cerebral palsy. An incorrect diagnosis of cerebral palsy, as shown in 13 of 17 male children, allows the doctor to stop questioning. If there is no reason for a perinatal brain insult, other neurological causes must be sought. In our study the age at diagnosis varies widely and does not appear to have improved in recent years (mean age 2y 10mo). The age at diagnosis was consistent with earlier studies. In the study of Jinnah et al., 7 the age at onset of self-injurious behaviour was known for 31 individuals, the mean being 2 years 9 months. Robey et al. 8 reported a mean age of 2 years 6monthswhenself-injuriousbehaviourwasfirstidentifiedin 36 Developmental Medicine & Child Neurology 2011, 53: 34 39

4 Table I: Presenting signs and symptoms at (A) time of diagnosis and (B) after diagnosis Age at diagnosis Plasma uric acid (lmol L) Developmental delay Eating problems Selfinjurious behaviour CP Hypotonia Movement disorder Irritability Renal failure Crystals in diaper Family history DNA Mother carrier Dystonia Speech problem Hiatus hernia Gastrostomy Teeth removed A A A A B A B A A A A A A B B B B B B B B 2mo 300 N N Y N Y N N N N N Y Y U Y Y Y N N Y 7mo 560 Y Y Y Y Y N Y U Y N Y U Y U Y Y U Y Y 8mo 860 Y N Y N Y Y Y Y Y N N U Y Y Y Y N N N 10mo 619 Y Y N N Y N Y Y N Y Y U Y Y Y Y N N N 11mo U Y Y Y N Y Y N Y U N Y U U U Y Y Y N Y 1y 710 U U U U U U U U U U U U U U U U U U U 1y 292 a U U U U U U U U U U U U U U U U U U U 1y 6mo 1003 Y Y Y N Y Y U Y U N N U Y Y Y Y Y N Y 1y 9mo 600 Y N Y N Y Y Y Y Y N N U Y Y Y Y N N Y 1y 11mo 487 Y N Y N Y Y Y Y Y N N U Y Y Y Y Y Y Y 2y 401 U U U U U U U U U U U U U U U U U U U 2y 540 Y N U N Y Y Y Y Y N N U Y U Y Y N N N 2y 631 Y Y Y Y Y N N N Y N Y Y Y Y Y Y N N Y 2y 5mo 681 U U U U U U U U U U U U U U U U U U U 3y 529 Y Y Y N Y Y N Y N N Y U Y Y Y Y N Y Y 3y 6mo 510 Y N N Y Y Y Y Y Y N Y U Y Y Y Y N N Y 4y 1mo 514 Y Y Y Y Y Y Y Y Y N N U N U Y Y N Y N 4y 5mo 570 U U U U U U U U U U U U U U U U U U U 4y 9mo 548 Y Y Y Y Y Y N Y N N U U U U Y Y N N Y 4y 9mo 1059 Y Y Y Y Y Y Y Y Y N U U Y Y Y Y U N U 5y 670 Y N N Y Y Y Y Y U N Y U N U Y Y N N N 8y 6mo 550 U U U U U U U U U U U U U U U U U U U 9y 10mo 377 Y Y Y N Y Y U Y U N N U Y Y Y Y N N N Unknown 637 U U U U U U U U U U U U U U U U U U U Unknown 170 a U U U U U U U U U U U U U U U U U U U Unknown 830 U U U U U U U U U U U U U U U U U U U Mean=616 b Y=16 Y=10 Y=13 Y=7 Y=17 Y=13 Y=10 Y=14 Y=9 Y=1 Y=8 Y=2 Y=12 Y=11 Y=17 Y=17 Y=3 Y=4 Y=10 Range= N=1 N=7 N=3 N=10 N=0 N=4 N=5 N=2 N=4 N=16 N=7 N=0 N=2 N=0 N=0 N=0 N=12 N=13 N=6 U=9 U=9 U=10 U=9 U=9 U=9 U=11 U=10 U=13 U=9 U=11 U=24 U=12 U=15 U=9 U=9 U=11 U=9 U=10 a On allopurinol. b Mean value (excluding those on allopurinol). Normal range of plasma uric acid is less than 230 lmol L. CP, cerebral palsy; Y, yes; N, no; U, unknown. Population Study of LND in the UK Gillian T McCarthy et al. 37

5 Weight (kg) & allopurinol dose (mg) Weight (kg) Allopurinol (mg) Cases Figure 2: Weight and daily dosage of allopurinol in male children with LND. 64 individuals. In our UK study, early diagnosis was associated with renal problems including renal failure and gout with a tophus in two instances. Onset of self-injury was a factor in making the definitive diagnosis in several cases. A family history was present for two individuals, and in two families there was a history of cerebral palsy in the mother s brothers. All cases had levels of HPRT less than 1.5%. It is important that diagnosis is not delayed so that appropriate management starts from an early age. This benefits the infant and the parents and may prevent the birth of another affected child by promoting genetic counselling for family members. The metabolic diagnosis depends upon measuring raised levels of uric acid in blood plasma and urine compared with healthy male children of similar age. However, raised levels of uric acid are found in other conditions. Consequently, levels of HPRT must be measured in blood cells as well. Renal clearance of uric acid is better in children than in adults. Therefore the uric acid in plasma may be normal, but that in urine will be grossly elevated. Thus both must be measured with enzyme activity when making the diagnosis. The multiple clinical problems of LND are best managed by a local multi-specialist team (rehabilitation engineers, occupational and physiotherapists, speech and language therapists, teachers and carers, as well as psychologists, dieticians, nurses, doctors, and social workers) working with the child and family at home and at school. Owing to the high level of sleep problems (e.g. noisy breathing, sleep apnoea), correct positioning at night can help to prevent hyperextension and sleep deprivation, and reduce self-injury. Self-injurious behaviour is the most distressing aspect of LND. Its management depends on teaching good communication skills, relaxation techniques, and consistent handling by family, teachers, and carers. Protective devices are necessary when self-injurious behaviour is severe. These include padding of bed sides and wheelchairs, helmets, gloves, arm splints, gum shields, straps to restrain arm and hand movement, and waistcoats for sleeping. Managing self-injurious behaviour is a lifelong task and may need consultation and support from a specialist centre where behavioural management can be facilitated. The decision to extract the teeth to avoid risk of self-injury is a very difficult personal decision for the family and the child. Consultants in paediatric dentistry can provide beneficial advice and help families in this situation. Other problems such as eating and swallowing difficulties need careful evaluation, including the use of a gastrostomy for enteral feeding and the giving of medication or fluids. The use of a low purine, low caffeine diet is recommended. 14 Ahigh fluid intake is also recommended. Paediatric dieticians can offer dietary advice as caloric supplements may be required. Although in the past a variety of descriptions have been used, dystonia was recognized as the major motor disorder in this UK study. The treatment of dystonia needs further investigation; a variety of medications have been tried including dopamine replacement with levodopa, a direct-acting dopamine agonist bromcriptine, and a dopamine-depleting agent, tetrabenazine. 15 Jinnah et al. 7 commented that the value of baclofen in the management of dystonia is unclear. Its main indication is for severe spasticity. In patients with this disorder it is difficult to ascertain side effects, which are known to be anxiety, agitation, and headaches. The use of baclofen was proportionally higher in the UK: 11 out of 17 individuals compared with 7 out of 44. Benzodiazepines were used less in the UK: in 2 out of 17 individuals compared with 19 out of 44 in the study of Jinnah et al. 7 Deep brain stimulation using neurosurgical techniques has been tried in several instances, 16,17 but long-term outcome and complications are uncertain at present. One child had been given S-adenosylmethionine for 1 year to reduce his self-injurious behaviour. Both the child and his parents thought this treatment had been helpful, which is in agreement with a short report by Glick. 18 Allopurinol lowers the level of uric acid in blood, thus preventing kidney stones and gout. In this study all participants were receiving allopurinol to treat the raised urate levels. However, the dose varied considerably and did not relate to the weight or age of the children. Details of regular monitor- 38 Developmental Medicine & Child Neurology 2011, 53: 34 39

6 ing of plasma urate and levels of urinary urate and xanthine were not obtained. Allopurinol needs to be carefully monitored as xanthine levels may rise, which may cause stones to form. Members of the British Paediatric Neurology Association completed the questionnaires; parents were not involved in providing data. Elements of the questionnaire were subjective so that a variety of responses were received. Although every effort was made to identify all individuals with LND, it is possible that an underestimate of cases in the UK may have occurred as the youngest child in the study was born in Although LND is a rare condition, it causes significant morbidity for the patient and cost to the UK s National Health Service. This study highlights the significant variation in management and suggests an opportunity for multicentre trials or audits in several areas. Regular metabolic screening and reviews by specialists (paediatric neurologists, nephrologists, and geneticists) for neurological and other problems are required. CONCLUSION In this 2-year study, 26 male children with LND were identified in the UK; 23 were alive at the end of the study. The mean incidence rate over the 20-year period was 0.18 per live births, range 0 to 0.5. Eight males with LND over the age of 22 years were alive at the end of the study. Thirty-one individuals in a population of 61.4 million gives a 2008 prevalence of 1 in 2 million people. This report confirms the rarity of LND and suggests a need for more collaboration in its management. ACKNOWLEDGEMENTS The Purine Metabolic Patients Association (PUMPA) supported the study. We acknowledge Dr Gordon Graham, for advice on historical cases and assistance in locating possible Scottish cases. ONLINE MATERIAL SUPPORTING INFORMATION Additional material and supporting information may be found in the online version of this article. REFERENCES 1. Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function. Am J Med 1964; 36: Seegmiller JE, Rosenbloom FM, Kelley WN. Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 1967; 155: Jolly DJ, Esty AC, Bernard HU, Friedmann T. Isolation of a genomic clone partially encoding human hypoxanthine phosphoribosyltransferase. Proc Natl Acad Sci USA 1982; 79: Jinnah HA, Harris JC, O Neill JP. The spectrum of mutations causing HPRT deficiency; an update. Nucleotides Nucleosides Nucleic Acids 2004; 23: De Gregorio L, Jinnah HA, Harris JC, et al. Lesch-Nyhan disease in a female with a clinically normal monozygotic twin. Mol Genet Metab 2005; 85: Jinnah HA, Ceballos-Picot I, Torres RJ, et al. Attenuated variants of Lesch-Nyhan disease. Brain 2010; 133: Jinnah HA, Visser JE, Harris JC, et al. Delineation of the motor disorder in Lesch-Nyhan disease. Brain 2006; 129: Robey KL, Reck JF, Giacomini KD, Barabas G, Eddey GE. Modes and patterns of self-mutilation in persons with Lesch- Nyhan disease. Dev Med Child Neurol 2003; 45: Schretlen DJ, Harris JC, Park KS, Jinnah HA, Ojeda del Pozo N. Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine phosphoribosyltransferase deficiency. J Int Neuropsychol Soc 2001; 7: Schretlen DJ, Ward J, Meyer SM, et al. Behavioural aspects of Lesch-Nyhan disease and its variants. Dev Med Child Neurol 2005; 47: Neychev VK, Jinnah HA. Sudden death in Lesch-Nyhan disease. Dev Med Child Neurol 2006; 48: Crawhall JC, Henderson JF, Kelley WN. Diagnosis and treatment of Lesch-Nyhan syndrome. Pediatr Res 1972; 6: Torres RJ, Puig JG. Hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency: Lesch-Nyhan syndrome. Orphanet J Rare Dis 2007; 2: McCarthy GT, editor. Caring for children wtih Lesch Nyhan disease a guide for parents and professionals. 2nd edn. London: PUMPA in conjuction with Chailey Heritage Clinical Services, Taira T, Kabayashi T, Hori T. Disappearance of selfmutilating behavior in a patient with Lesch-Nyhan syndrome after bilateral chronic stimulation of the globus pallidus internus. J Neurosurg 2003; 98: Pralong E, Pollo C, Coubes P, et al. Electrophysiological characteristics of limbic and motor globus pallidus internus (GPI) neurons in two cases of Lesch-Nyhan syndrome. Neurophysiol Clin 2005; 35: Cif L, Biolsi B, Gavarini S, et al. Antero-ventral internal pallidum stimulation improves behavioral disorders in Lesch- Nyhan disease. Mov Disord 2007; 22: Glick N. Dramatic reduction in self-injury in Lesch-Nyhan disease following S-adenosylmethionine administration. J Inherit Metab Dis 2006; 29: 687. Population Study of LND in the UK Gillian T McCarthy et al. 39