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Histidinaemia: a Benign Metabolic Disorder Arch Dis Child: First Published As 10.1136/Adc.74.4.343 on 1 April 1996

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Histidinaemia: a Benign Metabolic Disorder Arch Dis Child: First Published As 10.1136/Adc.74.4.343 on 1 April 1996 Archives ofDisease in Childhood 1996; 74: 343-346 343 Histidinaemia: a benign metabolic disorder Arch Dis Child: first published as 10.1136/adc.74.4.343 on 1 April 1996. Downloaded from W K Lam, M A Cleary, J E Wraith, J H Walter Abstract We have undertaken a prospective study in Histidinaemia is a relatively common 104 patients with histidinaemia over a 28 year inherited metabolic disorder with an period to determine the impact of histidi- incidence similar to phenylketonuria. This naemia on their growth, development, and paper reports the long term outcome of health, and to establish whether there was any patients diagnosed by newborn screening benefit from a low histidine diet given for the in the north west ofEngland. Between 1966 first 2 years of life. and 1990, 108 infants were diagnosed as having histidinaemia by a regional neo- natal screening programme (incidence Methods 1:11083). A firther five children were All children diagnosed as having histidinaemia detected following diagnosis in a sibling. Of by the Willink Biochemical Genetics Unit the 113, nine were lost to follow up. Infants between 1966 and 1990 were entered into this diagnosed before 1981 (n=47) were placed study. Most of these were first detected by our on a low histidine diet (225 mglkgld) for an newborn amino acid screening programme average period of 21 months (SD 4.5). All using paper chromatography. The diagnosis of patients were reviewed regularly, Griffiths histidinaemia was based on finding persis- developmental quotients (DQ) were tently raised plasma histidine concentrations assessed at 2 and 4 years, and WISC-R (>0 3 mmol/l) and on the presence of intelligence quotients (IQ) at 8, 12, and 18 histidine and urine imidazole metabolites in years. IQ data were converted to standard the urine. deviation scores (IQ SDS) to account for increasing IQ norms with time. Neither DQ nor IQ correlated with plasma LOW HISTIDINE DIET histidine at diagnosis or with the mean Until 1981, given the uncertainty of the out- plasma histidine throughout life. Growth come of the disorder and with the possibility was normal in all patients. There was no that mental retardation might be linked to apparent benefit from a low histidine diet high blood histidine levels, this unit's policy in early childhood. In contrast to other was to start patients who were diagnosed on http://adc.bmj.com/ studies, there was no excess of clinical newborn screening on a low histidine diet. symptoms. On the basis of these findings, The main protein requirement was provided histidinaemia is a benign metabolic dis- by a synthetic food substitute which was order that does not require treatment. histidine-free (for example, HF2, Cow & (Arch Dis Child 1996; 74: 343-346) Gate), while the daily histidine allowance (225 mglkg/d) was given either in the form of Keywords: histidinaemia, histidase deficiency, histidine cow's milk or, after weaning, in exchange ammonia-lyase deficiency. on September 26, 2021 by guest. Protected copyright. portions of certain vegetables or cereals. The diet was usually discontinued after the age of 2 years. After 1981 this policy was abandoned Histidinaemia, one of the most common disor- and newborn infants were allowed a normal ders of amino acid metabolism, results from a diet. deficiency in histidase (histidine ammonia- lyase, E.C. 4.3.1.3), an enzyme responsible for the deamination of the essential amino acid GROWTH, DEVELOPMENT AND GENERAL histidine to form urocanoic acid. In this dis- HEALTH order histidine is transaminated by an alterna- Following diagnosis, patients were seen regu- tive pathway to form imidazole derivatives. larly in our clinic where their growth, general The biochemical phenotype is characterised health, and development were monitored. by an increase in blood, cerebrospinal fluid Griffiths developmental assessments were per- (CSF), and urine histidine and by the presence formed at 1, 2, 4, and 6 years, and WISC-R of imidazole metabolites in urine.1 2 intelligence assessments at 8, 12, and 18 years. Early reports ofhistidinaemia documented a Willink Biochemical high frequency of mental retardation and Genetics Unit, Royal Manchester Children's speech delay, but with the introduction of neo- PLASMA HISTIDINE CONCENTRATIONS Hospital, Pendlebury, natal screening it has become apparent that the Plasma histidine concentrations were measured Manchester M27 4HA majority of affected individuals have developed by amino acid analyser (Waters HPLC W K Lam M A Cleary normally.3-7 However, concern remains that in system using a lithium cation exchange col- J E Wraith some circumstances histidinaemia may cause umn, Pickering Laboratories). Measurements J H Walter damage to the central nervous system.8-'2 A were made once or twice yearly, except in Correspondence to: recent study of a large number of children with children on a low histidine diet in the first 2 Dr Walter. histidinaemia found various clinical problems years of life, where they were made every 3 Accepted 14 November 1995 in over 20%.13 months. 344 Lam, Cleary, Wraith, Walter 2.0 913 infants were screened by the Willink o Treated Biochemical Genetics Unit. Histidinaemia was 1.8 K * Non-treated diagnosed in 108 infants, an incidence of 1: 11 Arch Dis Child: first published as 10.1136/adc.74.4.343 on 1 April 1996. Downloaded from 1.6 F- 083. An additional five children were identified 1,4 e following the diagnosis in a sibling on newborn 0 screening. Nine of these 113 patients either E 1.2 F- moved from E away the region or failed to return 1.0 r- to the clinic after the initial diagnosis, so were -0C excluded from this study, leaving a total of 104 0.8 H children, of whom 51 were female and 53 I 06 I male. The mean age at diagnosis of those patients detected by newborn screening was 11 0.4 44 1 If I days (range 9-18). Forty seven patients were 0.2 placed on a low histidine diet for an average period of 21 (4 5) months. 0-0 0 2 4 6 8 10 12 14 16 18 20 Age (years) PLASMA HISTIDINE CONCENTRATIONS Figure 1 Histidine concentrations from diagnosis plotted against age. Patients in the treated group were given a low histidine dietfrom diagnosis for a period ofmean 21 months Figure 1 shows the mean plasma histidine con- (SD 4.5 months). Error bars=SD. centrations from the time of diagnosis. The histidine concentration at diagnosis was signifi- cantly higher in those born before 1981, and STATISTICAL ANALYSIS who were subsequently treated with a low his- Standard statistical methods were used to tidine diet (treated group), than in those begun compare the data from the intellectual assess- on a normal diet (non-treated group): 1 29 ments at the various ages with the histidine (0-58) v 0-61 (0 22) mmol/, p<0001. levels obtained at diagnosis and at the age of Following the institution of a low histidine testing. In order to compare intellectual perfor- diet in the treated group, the mean plasma his- mance in histidinaemia patients with that of tidine concentration was maintained at a the general population, IQ scores, obtained significantly lower level than that of the non- from the age of 8 years onwards, were con- treated group [0 3 (0 19) v 0 59 (0 23) mmol/l, verted to standard deviation scores (SDS) to p<0 001], although histidine concentrations account for the rise in IQ norms with time.'4 were still much higher than those ofthe normal Analyses were carried out to determine population (0.061-0.119 mmol/l). After the whether there was any difference in develop- diet was stopped, the mean plasma concentra- ment or intellectual performance between tion for the treated group rose to 0-52 (0 23) those given a low histidine diet for the first 2 mmol/l, comparable to that of the untreated http://adc.bmj.com/ years and those started on a normal protein group (p=0 55). intake. Subscores of the developmental assess- ments were examined to establish whether there was an increased frequency in delayed GROWTH speech or language development. Mean weight and height were normal for patients at all ages when compared with Tanner and Whitehouse growth charts. There Results was no statistical significance between the two on September 26, 2021 by guest. Protected copyright. Between 1966, when the newborn amino acid dietary groups (figs 2-5). disorder screening programme using the Scriver technique started in the Northwest Region of England, and 1990, a total of 1 196 GENERAL HEALTH We were unable to identify any increased 90 problems in the general health of either group. Two patients had mild asthma, one had an age 80 related behavioural disorder, and one had mild 70 hyperactivity. 60 'a 50 1j1 DEVELOPMENT AND IQ 0s Developmental scores and IQ SD scores were ._ 40 normal for both groups at all ages (tables 1 and 2). Concern was raised about the intellec- 30 tual development of only two patients (1 9%), 20 a brother and sister. The boy, who was treated o Treated from birth with a low histidine diet, had a DQ 10 * Non-treated of 86 at 2 years falling to 61 at 7 years. His I I I sister, who was untreated, had a DQ of 87 at 0 2 4 6 8 10 12 14 16 18 2 years and 78 at 4 years. There were no Age (years) particular differences, either in their age of Figure 2 The mean weight of male patients plotted on Tan?rzer and Whitehouse growth diagnosis or in their plasma levels or treat- charts (97th, 50th, and 3rd centiles).
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