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HISTIDINÆMIA: TO TREAT OR NOT TO TREAT?
1047
Letters
to
the Editor
HISTIDINÆMIA: TO TREAT OR NOT TO TREAT? SIR,-During the past six years the Willink Biochemical Genetics Laboratory at the Royal Manchester Children’s Hospital has detected 15 cases of histidinsemia in 260,000 newborn infants. -The diagnosis was confirmed as described by Popkin et all, and in 4 of the cases skin histidase was assayed. We were faced with the same question that confronted Professor Popkin and his colleagues and we decided to treat these children for the first two years of life. reasons for this decision were: In our hands the dietary treatment of certain inborn errors of aminoacid metabolism in the first two years of life has not proved difficult, and with reasonable care and supervision there is little likelihood of the dangerous situations suggested in your editorial (April 20, p. 719). (ii) We have the administrative arrangements and facilities for good health-visitor supervision and for laboratory control. In addition, the clinicians are prepared to spend time discussing the problem with each family and in this way reduce the considerable stresses imposed upon them. (iii) We believe the first two years of life to be the most significant period in neurological disturbance and
The
(i)
damage.
(iv) By
of age we are able to assess reliably speech development of these children.
two years
the mental and
So far our observations have been encouraging, the eldest child being 6t years of age and in good health. However, we would support wholeheartedly a collaborative study of histidinsemia detected in the newborn period, since we feel it would be the best way to clarify the role of treatment in this disorder.
the diet which resulted in episodes of diarrhcea which disappeared when the HF2 was discontinued. This was later reintroduced and administered as a thick paste with cream and sugar without recurrence of diarrhoea. One other child is a little reduced in stature. The oldest children (almost 4 years) were treated for 18 months to 2t years, and now appear quite normal. The fasting plasma-histidine levels in our patients before treatment vary from 7-9 to 21 8 mg. per 100 ml. and, even allowing for differing protein intakes, it does appear that some children with the condition do have much higher levels than others. Our first 2 children had periods of normal-diet challenge early in their treatment when dietary stocks of HF2 were temporarily exhausted. In both cases the G.I.A. histidine level rose to greater than 20 mg. per 100 ml., and one of the children returned to a pretreatment state of apparent lassitude. In phenylketonuria the fasting level of phenylalanine before treatment varies over wide limits up to, and in excess of, 60 mg. per 100 ml. Nearly all workers will start treatment if the initial level is greater than or equal to 20 mg. per 100 ml. Normally developed older histidinaemic children seldom have very high levels, and the retarded children with moderate increases may well have had much higher levels in the neonatal period. The range of initial levels in neonates with histidinaemia is much smaller, but there is probably a point, perhaps about 10 mg. per 100 ml., above which the risk of mental retardation can be considered sufficiently great to warrant treatment. We support a collaborative study of children with histidinaemia detected in the neonatal period. If appropriate biochemical and psychological studies are made in both treated and untreated cases, some presently unrecognised pattern may well become evident. Department of Community Health, School of Medicine, University of Auckland, New Zealand.
I. C. T. LYON A. M. O. VEALE.
Willink Biochemical Genetics
PATHOGENESIS OF OSTEOARTHROSIS
Laboratory, Royal Manchester Children’s Hospital GEORGE M. KOMROWER
Pendlebury,
Manchester M27 1HA.
SIR,-Your leading article1 comprehensively reviewed
I. B. SARDHARWALLA.
the
on
SIR,-We read with interest the reportand comment2 dietary treatment in histidinxniia of the neonate. In
of the New Zealand phenylketonuria screening programme included the Guthrie inhibition assay (G.I.A.) for histidine using dried blood spots collected on the 5th day of life. Approximately 60,000 samples are received each year and we reported the first 2 confirmed cases of histidinsemia in 1970.3 The information on histidinxmia and the possible need for dietary treatment was confusing at the time; however, in cooperation with a number of paediatricians, 13 cases have been treated. Until March 31, 1974, 257,035 babies have been tested and 15 " classical " histidinsemics (1/17,135) and 2 " variants " have been detected. In 2 cases the patient’s physician elected not to start treatment. In the treated cases, the low-histidine diet (Trufood HF2) has been monitored with regular G.I.A. histidine tests. A level of 2-4 mg. per 100 ml. was considered desirable for control and this was achieved with daily intakes of histidine of 16-40 mg. per kg. body-weight. Although the children have not had formal psychological assessments, growth and development have generally been good. One child may have had a period of intolerance to 1970
1.
an
expansion
Popkin, J. S., Clow, C. L., Scriver, C. R., Grove, J. Lancet, April 20,
1974, p. 721. 2. ibid. p. 719. 3. Lyon, I. C. T., 48, 68.
Veale, A. M. O. Proc. Univ. Otago med. Sch. 1970,
primary aetiology of the pre-arthritic lesion. Although possibility that proteoglycan depletion could be the primary event in idiopathic osteoarthrosis, it you discussed the
apparently discarded in favour of the view that failure collagen network was the more likely primary event.
was
of
Work in
laboratories has demonstrated that proteocan, in fact, be regularly demonstrated in the absence of cartilage fibrillation in areas which later develop the characteristic changes of osteoarthrosis. By studying serial sections of normal young and adult rabbit hip-joints, cut in both the coronal and sagittal planes and stained with a series of cationic dyes, we have demonstrated that, whereas the cartilage in the loadbearing areas of the normal femoral head contains large quantities of sulphated proteoglycan, the cells in the relatively unloaded parts of the cartilage around the fovea and in the peripheral parts of the femoral head, away from the site of loadbearing, have different morphological characteristics and produce smaller amounts of sulphated proteoglycan. Moreover, we have demonstrated that connective-tissue cells in parts of a tendon which are subject to pressure rather than tension produce unusually large quantities of the sulphated glycosaminoglycan, keratan sulphate.2 In these compression areas, the extracellular collagen associated with the keratan sulphate is deposited in a cartilagelike network in contradistinction to the closely packed our
glycan depletion
1. 2.
Lancet, 1973, ii, 1131. Flint, M. H. in The Hand (edited by R. Tubiana); London and Philadelphia (in the press).
chap. 53.
Letters
to
the Editor
HISTIDINÆMIA: TO TREAT OR NOT TO TREAT? SIR,-During the past six years the Willink Biochemical Genetics Laboratory at the Royal Manchester Children’s Hospital has detected 15 cases of histidinsemia in 260,000 newborn infants. -The diagnosis was confirmed as described by Popkin et all, and in 4 of the cases skin histidase was assayed. We were faced with the same question that confronted Professor Popkin and his colleagues and we decided to treat these children for the first two years of life. reasons for this decision were: In our hands the dietary treatment of certain inborn errors of aminoacid metabolism in the first two years of life has not proved difficult, and with reasonable care and supervision there is little likelihood of the dangerous situations suggested in your editorial (April 20, p. 719). (ii) We have the administrative arrangements and facilities for good health-visitor supervision and for laboratory control. In addition, the clinicians are prepared to spend time discussing the problem with each family and in this way reduce the considerable stresses imposed upon them. (iii) We believe the first two years of life to be the most significant period in neurological disturbance and
The
(i)
damage.
(iv) By
of age we are able to assess reliably speech development of these children.
two years
the mental and
So far our observations have been encouraging, the eldest child being 6t years of age and in good health. However, we would support wholeheartedly a collaborative study of histidinsemia detected in the newborn period, since we feel it would be the best way to clarify the role of treatment in this disorder.
the diet which resulted in episodes of diarrhcea which disappeared when the HF2 was discontinued. This was later reintroduced and administered as a thick paste with cream and sugar without recurrence of diarrhoea. One other child is a little reduced in stature. The oldest children (almost 4 years) were treated for 18 months to 2t years, and now appear quite normal. The fasting plasma-histidine levels in our patients before treatment vary from 7-9 to 21 8 mg. per 100 ml. and, even allowing for differing protein intakes, it does appear that some children with the condition do have much higher levels than others. Our first 2 children had periods of normal-diet challenge early in their treatment when dietary stocks of HF2 were temporarily exhausted. In both cases the G.I.A. histidine level rose to greater than 20 mg. per 100 ml., and one of the children returned to a pretreatment state of apparent lassitude. In phenylketonuria the fasting level of phenylalanine before treatment varies over wide limits up to, and in excess of, 60 mg. per 100 ml. Nearly all workers will start treatment if the initial level is greater than or equal to 20 mg. per 100 ml. Normally developed older histidinaemic children seldom have very high levels, and the retarded children with moderate increases may well have had much higher levels in the neonatal period. The range of initial levels in neonates with histidinaemia is much smaller, but there is probably a point, perhaps about 10 mg. per 100 ml., above which the risk of mental retardation can be considered sufficiently great to warrant treatment. We support a collaborative study of children with histidinaemia detected in the neonatal period. If appropriate biochemical and psychological studies are made in both treated and untreated cases, some presently unrecognised pattern may well become evident. Department of Community Health, School of Medicine, University of Auckland, New Zealand.
I. C. T. LYON A. M. O. VEALE.
Willink Biochemical Genetics
PATHOGENESIS OF OSTEOARTHROSIS
Laboratory, Royal Manchester Children’s Hospital GEORGE M. KOMROWER
Pendlebury,
Manchester M27 1HA.
SIR,-Your leading article1 comprehensively reviewed
I. B. SARDHARWALLA.
the
on
SIR,-We read with interest the reportand comment2 dietary treatment in histidinxniia of the neonate. In
of the New Zealand phenylketonuria screening programme included the Guthrie inhibition assay (G.I.A.) for histidine using dried blood spots collected on the 5th day of life. Approximately 60,000 samples are received each year and we reported the first 2 confirmed cases of histidinsemia in 1970.3 The information on histidinxmia and the possible need for dietary treatment was confusing at the time; however, in cooperation with a number of paediatricians, 13 cases have been treated. Until March 31, 1974, 257,035 babies have been tested and 15 " classical " histidinsemics (1/17,135) and 2 " variants " have been detected. In 2 cases the patient’s physician elected not to start treatment. In the treated cases, the low-histidine diet (Trufood HF2) has been monitored with regular G.I.A. histidine tests. A level of 2-4 mg. per 100 ml. was considered desirable for control and this was achieved with daily intakes of histidine of 16-40 mg. per kg. body-weight. Although the children have not had formal psychological assessments, growth and development have generally been good. One child may have had a period of intolerance to 1970
1.
an
expansion
Popkin, J. S., Clow, C. L., Scriver, C. R., Grove, J. Lancet, April 20,
1974, p. 721. 2. ibid. p. 719. 3. Lyon, I. C. T., 48, 68.
Veale, A. M. O. Proc. Univ. Otago med. Sch. 1970,
primary aetiology of the pre-arthritic lesion. Although possibility that proteoglycan depletion could be the primary event in idiopathic osteoarthrosis, it you discussed the
apparently discarded in favour of the view that failure collagen network was the more likely primary event.
was
of
Work in
laboratories has demonstrated that proteocan, in fact, be regularly demonstrated in the absence of cartilage fibrillation in areas which later develop the characteristic changes of osteoarthrosis. By studying serial sections of normal young and adult rabbit hip-joints, cut in both the coronal and sagittal planes and stained with a series of cationic dyes, we have demonstrated that, whereas the cartilage in the loadbearing areas of the normal femoral head contains large quantities of sulphated proteoglycan, the cells in the relatively unloaded parts of the cartilage around the fovea and in the peripheral parts of the femoral head, away from the site of loadbearing, have different morphological characteristics and produce smaller amounts of sulphated proteoglycan. Moreover, we have demonstrated that connective-tissue cells in parts of a tendon which are subject to pressure rather than tension produce unusually large quantities of the sulphated glycosaminoglycan, keratan sulphate.2 In these compression areas, the extracellular collagen associated with the keratan sulphate is deposited in a cartilagelike network in contradistinction to the closely packed our
glycan depletion
1. 2.
Lancet, 1973, ii, 1131. Flint, M. H. in The Hand (edited by R. Tubiana); London and Philadelphia (in the press).
chap. 53.