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VERY EARLY DIAGNOSIS OF DUCHENNE MUSCULAR DYSTROPHY
90
Letters
to
the Editor
DUCHENNE CARRIER DETECTION
SIR,-As part of a general family-screening programme in North-East Italy,’ we have tested the efficacy of a new method in association with the creatine phosphokinase (C.P.K.) method for the detection of Duchenne muscular dystrophy carriers. The new method was the determination of hsEmopexin; this cglobulin has been found to be responsible for an abnormal immunoelectrophoretic pattern in the serum of Duchenne
patients.2 We studied 26 healthy female volunteers and 62 presumed Duchenne carriers classified according to the criteria of Walton and Gardner-Medwin3 as definite carriers (9), probable carriers (6), and possible carriers (47). All subjects were tested for serum-c.P.K. by Boehringer ’Monotest’ and for haemopexin concentration
by Behringwerke ’M-Partigen’ plates.
Results
summarised in accompanying table. The hsemopexin levels in recognised Duchenne carriers were significantly different from those in controls. Even if the confidence interval of the mean is calculated at the 99% level, the two distributions of values do not overlap. are
HAEMOPEXIN CONCENTRATIONS IN DUCHENNE CARRIERS AND CONTROLS
*Includes definite carriers, mal c.P.K. level.
probable
carriers, and
possible
carriers with abnor-
tp <0.001 (ttest).
Possible carriers who had abnormal C.P.K. levels also had a mean concentration ofhaemopexin (98-48 mg/dl) than did the group with normal C.P.K. (84.35 mg/dl). In addition, significantly abnormal haemopexin levels were found in 33% of the possible carriers who had normal C.P.K. levels. Haemopexin can bind myoglobin, haemin, and cytochrome c.4 Askanas2 attributed increased haemopexin levels in Duchenne patients to release of myoglobin from sick muscle; however, no myoglobin could be detected in the serum of Duchenne patients.s Alteration of the red-blood-cell membrane has been found in Duchenne patients and carriers.6 Perhaps this alteration results in abnormal release of haemin into the bloodstream inducing an increase in harmopexin concentration. Our results suggest that haemopexin determination can be a simple and sensitive method for carrier detection. There is no non-specific rise of this protein in other neuromuscular diseases7 nor in infectious states.8 The concomitant use of haemopexin and C.P.K. determination in our series of definite and probable carriers raised the level of carrier detection from 70%
higher
to
87%. This work
was
supported by
Department of Neurology, Institute of Animal Biology, University of Padua, Padua, Italy
an
MDA grant.
VERY EARLY DIAGNOSIS OF DUCHENNE MUSCULAR DYSTROPHY SIR,-In Duchenne muscular dystrophy, a genetically determined degenerative myopathic disease, abiotrophy, with subsequent atrophy and weakness of striated musculature (especially that of the limb girdles), is the major feature. Patients are commonly symptom-free until 3-5 years of age. Progression of weakness, disability, and deformity is unrelenting with wheelchair confinement and death secondary to cardiorespiratory complications usually before age 20.’ The classic form of Duchenne muscular dystrophy is transmitted by X-linked inheritance. This pattern is the same as that for hmmophilia-sons being at 50% risk of manifesting the disease and daughters being at an equal risk of carrying it.2 The carrier state can be determined in over 75% of suspect carriers. The earlier such testing is done, the greater its accu racy. Mothers and sisters of afflicted boys should know if they are carriers of the disease, so that future pregnancies can be planned; thus very early diagnosis is important to genetic
counselling. Because early motor development
is normal, the condition is often overlooked until the child shows signs of gross weakness.3 However, much earlier subtle, yet definite, expression of the disorder can be suspected on close examination. Determination of creatine-phosphokinase, which is always very high at this early stage, will confirm such a suspicion. In general, the muscles first formed in the embryo are those first affected in the dystrophic process. Axial and proximal muscles weaken before their distal counterparts. Among the first muscles to show clinical weakness are the extensor stabilisers of the shoulder girdle. However, because hip extensors play such an important role in maintaining pelvic-femoral.stability, functional loss in these muscles is often noted first. Patients weakened thus may walk normaUy, but when their lower extremities are stressed during a fast walk or run, they waddle. Even before displaying obvious difficulty ascending stairs, they tend to hesitate slightly before attempting each step, and although the quadriceps is not yet weak enough to demonstrate a positive Gowers’ sign (Gowers’ or tripod sign is climbing up oneself when rising from the seated position), they cannot rise directly from the floor or a low chair, but must shift their weight a little to one side, so as to enable. the movement by readjusting their balance.4 Boys with Duchenne dystrophy develop tight heel cords very early in life. Because of this, they cannot properly dorsiflex the supporting ankle during the stance phase of gait. They tend to roll over the foot, flexing at the mid-tarsal joints, thus depressing the long arch. Tight heel cords are a known cause of flat foot in otherwise normal children, and Duchenne dystrophics .
usually develop flat feet secondary to tight heel cords even becoming obvious toe walkers. It is not uncommon for a boy with Duchenne muscular dystrophy to have been diagnosed as a "clumsy child with flat feet" and treated with cor-
before
rective shoes when
a
closer look would have revealed pes
planus secondary to tight heel cords. Finally, youngsters with Duchenne muscular dystrophy can seldom perform a standing jump because of lack of strength in the hip, knee, and shoulder extensors. The child’s failure to perform this simple test should alert the examining physician to this diagnosis. Skeletal muscle can suffer approximately a 30% loss before decrease in function is clinically apparent. In the child with Duchenne muscular dystrophy, this usually does not happen until 3-5 years of age. By that time, other pregnancies, with the birth of additional children with the disease, may have occurred. Duchenne muscular dystrophy should be suspected if a male child demonstrates a hip waddle on walking fast or a
G. A. DANIELI C. ANGELINI
1 Danieli, G. A., Vecchi, C., Angelini, C. Soc. Biol. 1974, 21, 235. 2. Askanas, W. Life Sci 1966, 5, 1767. 3. Walton, J. N., Gardner-Medwin, D. in Disorders of Voluntary Muscle (edited by J. N. Walton); p. 561. Edinburgh, 1974. 4. Hayem-Levi, A., Havez, R. Clin. chim. Acta, 1973, 47, 113. 5. Rowland, L. P., Layzer, R. B., Kagen, L. J Archs Neurol. 1968, 18, 272. 6. Miller, S. E , Roses, A. D., Appel, S. H. ibid. 1976, 33, 172. 7 Askanas, W. J. Neurol Neurosurg. Psychiat. 1967, 30, 43. 8. Kushner, I., Edginton, T S., Trimble, C., Liem H. H., Muller-Eberhard, V. J. Lab. clin. Med. 1972, 80, 18.
1. Walton, J. N. Disorders of Voluntary Muscle; p. 567. Edinburgh. 1974. 2. Zundel, W., Tyler, F. New Engl. J. Med. 1965, 273, 537, 543. 3. Swaiman, K. F., Wright, F. S. Neuromuscular Diseases of Infancy and Childhood; p. 166. Springfield, Illinois, 1970. 4. Brooke, M. Personal communication.
91
running, hesitates for balance when ascending stairs, cannot rise directly from the seated position, but shifts his weight laterally in order to do so, presents with flat feet secondary to tight heel cords, or cannot perform a standing jump. Any of these subtle findings of "soft" weakness requires a serum muscle enzyme determination to confirm or rule out the diagnosis. Strauss Surgical Group, 4640 Marine Drive, Chicago, Illinois 60640, U.S.A.
IRWIN M. SIEGEL
Thus, in view of previous experimental findings, we suggest that alterations in the ST interval of the E.c.G. recorded post partum reveal information about accumulated hypoxic stress to which the newborn child was subjected. Department of Obstetrics and Gynæcology, Sahlgrenska Sjukhuset, and Department of Pœdiatrics, Ostra Sjukhuset, Göteborg, Sweden.
ULTRASOUND MONITORING OF FETAL MOVEMENTS
E.C.G. CHANGES AS SIGN OF HYPOXIA INTRA PARTUM an
SiR,—The fetal electrocardiogram (E.C.G.) is used mainly as indicator of fetal heart-rate in clinical practice. Although
alterations in the pattern of the fetal
E.C.G.
have been detected
during labour, these alterations are believed to be preceded by changes of the heart-rate. Our experiments in fetal lambs have shown progressive changes in the ST interval of the fetal E.C.G. (elevation of sT-segment, high and peaked T waves) as an early and constant sign of fetal asphyxia before deterioration of circulatory indices and well in advance of any bradycardia.’1 These changes are signs of myocardial glycolysis.2 We have now investigated in a consecutive series, E.c.. changes in immediately post partum in man. A CR-Iead with the precordial electrode placed between the nipple and the sternum was recorded within the first minute after birth. In twenty-four single births sixteen babies had normal Apgar scores (8-10) at 1 min and normal E.C.G., while in the other eight transient hypoxic altera-
KLAS-HENRY HÖKEGÅRD KARL GUSTAF ROSÉN
al.’ are to be congratulated for their fetal movements. However, their statement that "monitoring of fetal movements as an indicator of normal and abnormal fetal development appears to have been neglected" needs some correction. Also we feel that some of the questions they raised have already been answered. We are surprised that a group studying fetal movements so enthusiastically do not seem to realise that real-time scanning (practised throughout continental Europe) is the method of choice for investigation of fetal movements and are not familiar with work published on this subject.
SiR,—Higginbottom et
work
on
tions in the E.c.G. were recorded in six. The E.c.G. returned to normal within a few minutes. Three of these babies had an Apgar score of 6 or 7 at 1 min while the other three had normal Apgar scores. In two cases there was an Apgar score of 6 or 7 associated with a normal E.C.G. All newborn children had normal heart-rate. They had a normal neonatal period except for one child who had a mild hypoglycaemia. This baby had had an Apgar score of 7 at 1 min as well as E.c.G. changes (see
figure). 1. 2.
Rosén, K. G., Kjellmer, I. Acta physiol. scand. 1975, 93, Rosén, K. G., Isaksson, O. Biol. Neonate (in the press).
59.
Frequency of fetal movements detected by ultrasound. Shaded area: mean + s.D. for control population. 8
=
abnormal
0-0, -8, ae
(Source:
pregnancies.
=
Haller
serial studies et
ending
in fetal death.
al. 4)
Real-time sonar studies of fetal movements were reported in 1971 by Reinold.2 On the basis of 250 examinations done at 18-20 weeks’ gestation Reinold described different types of active movements (strong and slow) and their absence with fetal death. Reinold’s work has also been published in English.3 Since then in most departments ultrasound evaluation of fetal movements with regard to presence or absence, type, and frequency has become the most important single procedure in the management of threatened abortion. Whereas it is easy to detect the presence or absence of fetal movements, evaluation of their type is more difficult. As in other areas of perinatal biophysical monitoring the main problem is quantification. For frequency of movements, our group45has established the normal range in early pregnancy and has demonstrated the prognostic value of abnormal frequencies with impending early fetal death (see figure). QuanK. M., Harris, P. F., Slater, J. H., Porter, G A. Lancet, 1976, i, 719. 2. Reinold, E. Z. Geburtsh. Gynäk. 1971, 174, 220. 1.
Higginbottom, J., Bagnall,
3. 4.
Reinold, E. J. perinat. Med 1973, 1, 65. Haller, U., Rüttgers, H., Wille, F., Heinrich, D., Müller, P , Kubli, F. Gynäk. Rdsch 1973, 13, Suppl. 1, p. 118. Haller, U. Rüttgers, H., Wille, F., Müller, P, Heinrich, D, Kubli, F in Perinatale Medizin, (edited by J. W. Dudenhausen and E. Saling, vol. v, p 30. Stuttgart, 1974.
5.
E.C.G. changes 1, 3, 5, and 7 min post partum in full-term boy with the umbilical cord around the neck and Apgar score 7 at 1 min.
Letters
to
the Editor
DUCHENNE CARRIER DETECTION
SIR,-As part of a general family-screening programme in North-East Italy,’ we have tested the efficacy of a new method in association with the creatine phosphokinase (C.P.K.) method for the detection of Duchenne muscular dystrophy carriers. The new method was the determination of hsEmopexin; this cglobulin has been found to be responsible for an abnormal immunoelectrophoretic pattern in the serum of Duchenne
patients.2 We studied 26 healthy female volunteers and 62 presumed Duchenne carriers classified according to the criteria of Walton and Gardner-Medwin3 as definite carriers (9), probable carriers (6), and possible carriers (47). All subjects were tested for serum-c.P.K. by Boehringer ’Monotest’ and for haemopexin concentration
by Behringwerke ’M-Partigen’ plates.
Results
summarised in accompanying table. The hsemopexin levels in recognised Duchenne carriers were significantly different from those in controls. Even if the confidence interval of the mean is calculated at the 99% level, the two distributions of values do not overlap. are
HAEMOPEXIN CONCENTRATIONS IN DUCHENNE CARRIERS AND CONTROLS
*Includes definite carriers, mal c.P.K. level.
probable
carriers, and
possible
carriers with abnor-
tp <0.001 (ttest).
Possible carriers who had abnormal C.P.K. levels also had a mean concentration ofhaemopexin (98-48 mg/dl) than did the group with normal C.P.K. (84.35 mg/dl). In addition, significantly abnormal haemopexin levels were found in 33% of the possible carriers who had normal C.P.K. levels. Haemopexin can bind myoglobin, haemin, and cytochrome c.4 Askanas2 attributed increased haemopexin levels in Duchenne patients to release of myoglobin from sick muscle; however, no myoglobin could be detected in the serum of Duchenne patients.s Alteration of the red-blood-cell membrane has been found in Duchenne patients and carriers.6 Perhaps this alteration results in abnormal release of haemin into the bloodstream inducing an increase in harmopexin concentration. Our results suggest that haemopexin determination can be a simple and sensitive method for carrier detection. There is no non-specific rise of this protein in other neuromuscular diseases7 nor in infectious states.8 The concomitant use of haemopexin and C.P.K. determination in our series of definite and probable carriers raised the level of carrier detection from 70%
higher
to
87%. This work
was
supported by
Department of Neurology, Institute of Animal Biology, University of Padua, Padua, Italy
an
MDA grant.
VERY EARLY DIAGNOSIS OF DUCHENNE MUSCULAR DYSTROPHY SIR,-In Duchenne muscular dystrophy, a genetically determined degenerative myopathic disease, abiotrophy, with subsequent atrophy and weakness of striated musculature (especially that of the limb girdles), is the major feature. Patients are commonly symptom-free until 3-5 years of age. Progression of weakness, disability, and deformity is unrelenting with wheelchair confinement and death secondary to cardiorespiratory complications usually before age 20.’ The classic form of Duchenne muscular dystrophy is transmitted by X-linked inheritance. This pattern is the same as that for hmmophilia-sons being at 50% risk of manifesting the disease and daughters being at an equal risk of carrying it.2 The carrier state can be determined in over 75% of suspect carriers. The earlier such testing is done, the greater its accu racy. Mothers and sisters of afflicted boys should know if they are carriers of the disease, so that future pregnancies can be planned; thus very early diagnosis is important to genetic
counselling. Because early motor development
is normal, the condition is often overlooked until the child shows signs of gross weakness.3 However, much earlier subtle, yet definite, expression of the disorder can be suspected on close examination. Determination of creatine-phosphokinase, which is always very high at this early stage, will confirm such a suspicion. In general, the muscles first formed in the embryo are those first affected in the dystrophic process. Axial and proximal muscles weaken before their distal counterparts. Among the first muscles to show clinical weakness are the extensor stabilisers of the shoulder girdle. However, because hip extensors play such an important role in maintaining pelvic-femoral.stability, functional loss in these muscles is often noted first. Patients weakened thus may walk normaUy, but when their lower extremities are stressed during a fast walk or run, they waddle. Even before displaying obvious difficulty ascending stairs, they tend to hesitate slightly before attempting each step, and although the quadriceps is not yet weak enough to demonstrate a positive Gowers’ sign (Gowers’ or tripod sign is climbing up oneself when rising from the seated position), they cannot rise directly from the floor or a low chair, but must shift their weight a little to one side, so as to enable. the movement by readjusting their balance.4 Boys with Duchenne dystrophy develop tight heel cords very early in life. Because of this, they cannot properly dorsiflex the supporting ankle during the stance phase of gait. They tend to roll over the foot, flexing at the mid-tarsal joints, thus depressing the long arch. Tight heel cords are a known cause of flat foot in otherwise normal children, and Duchenne dystrophics .
usually develop flat feet secondary to tight heel cords even becoming obvious toe walkers. It is not uncommon for a boy with Duchenne muscular dystrophy to have been diagnosed as a "clumsy child with flat feet" and treated with cor-
before
rective shoes when
a
closer look would have revealed pes
planus secondary to tight heel cords. Finally, youngsters with Duchenne muscular dystrophy can seldom perform a standing jump because of lack of strength in the hip, knee, and shoulder extensors. The child’s failure to perform this simple test should alert the examining physician to this diagnosis. Skeletal muscle can suffer approximately a 30% loss before decrease in function is clinically apparent. In the child with Duchenne muscular dystrophy, this usually does not happen until 3-5 years of age. By that time, other pregnancies, with the birth of additional children with the disease, may have occurred. Duchenne muscular dystrophy should be suspected if a male child demonstrates a hip waddle on walking fast or a
G. A. DANIELI C. ANGELINI
1 Danieli, G. A., Vecchi, C., Angelini, C. Soc. Biol. 1974, 21, 235. 2. Askanas, W. Life Sci 1966, 5, 1767. 3. Walton, J. N., Gardner-Medwin, D. in Disorders of Voluntary Muscle (edited by J. N. Walton); p. 561. Edinburgh, 1974. 4. Hayem-Levi, A., Havez, R. Clin. chim. Acta, 1973, 47, 113. 5. Rowland, L. P., Layzer, R. B., Kagen, L. J Archs Neurol. 1968, 18, 272. 6. Miller, S. E , Roses, A. D., Appel, S. H. ibid. 1976, 33, 172. 7 Askanas, W. J. Neurol Neurosurg. Psychiat. 1967, 30, 43. 8. Kushner, I., Edginton, T S., Trimble, C., Liem H. H., Muller-Eberhard, V. J. Lab. clin. Med. 1972, 80, 18.
1. Walton, J. N. Disorders of Voluntary Muscle; p. 567. Edinburgh. 1974. 2. Zundel, W., Tyler, F. New Engl. J. Med. 1965, 273, 537, 543. 3. Swaiman, K. F., Wright, F. S. Neuromuscular Diseases of Infancy and Childhood; p. 166. Springfield, Illinois, 1970. 4. Brooke, M. Personal communication.
91
running, hesitates for balance when ascending stairs, cannot rise directly from the seated position, but shifts his weight laterally in order to do so, presents with flat feet secondary to tight heel cords, or cannot perform a standing jump. Any of these subtle findings of "soft" weakness requires a serum muscle enzyme determination to confirm or rule out the diagnosis. Strauss Surgical Group, 4640 Marine Drive, Chicago, Illinois 60640, U.S.A.
IRWIN M. SIEGEL
Thus, in view of previous experimental findings, we suggest that alterations in the ST interval of the E.c.G. recorded post partum reveal information about accumulated hypoxic stress to which the newborn child was subjected. Department of Obstetrics and Gynæcology, Sahlgrenska Sjukhuset, and Department of Pœdiatrics, Ostra Sjukhuset, Göteborg, Sweden.
ULTRASOUND MONITORING OF FETAL MOVEMENTS
E.C.G. CHANGES AS SIGN OF HYPOXIA INTRA PARTUM an
SiR,—The fetal electrocardiogram (E.C.G.) is used mainly as indicator of fetal heart-rate in clinical practice. Although
alterations in the pattern of the fetal
E.C.G.
have been detected
during labour, these alterations are believed to be preceded by changes of the heart-rate. Our experiments in fetal lambs have shown progressive changes in the ST interval of the fetal E.C.G. (elevation of sT-segment, high and peaked T waves) as an early and constant sign of fetal asphyxia before deterioration of circulatory indices and well in advance of any bradycardia.’1 These changes are signs of myocardial glycolysis.2 We have now investigated in a consecutive series, E.c.. changes in immediately post partum in man. A CR-Iead with the precordial electrode placed between the nipple and the sternum was recorded within the first minute after birth. In twenty-four single births sixteen babies had normal Apgar scores (8-10) at 1 min and normal E.C.G., while in the other eight transient hypoxic altera-
KLAS-HENRY HÖKEGÅRD KARL GUSTAF ROSÉN
al.’ are to be congratulated for their fetal movements. However, their statement that "monitoring of fetal movements as an indicator of normal and abnormal fetal development appears to have been neglected" needs some correction. Also we feel that some of the questions they raised have already been answered. We are surprised that a group studying fetal movements so enthusiastically do not seem to realise that real-time scanning (practised throughout continental Europe) is the method of choice for investigation of fetal movements and are not familiar with work published on this subject.
SiR,—Higginbottom et
work
on
tions in the E.c.G. were recorded in six. The E.c.G. returned to normal within a few minutes. Three of these babies had an Apgar score of 6 or 7 at 1 min while the other three had normal Apgar scores. In two cases there was an Apgar score of 6 or 7 associated with a normal E.C.G. All newborn children had normal heart-rate. They had a normal neonatal period except for one child who had a mild hypoglycaemia. This baby had had an Apgar score of 7 at 1 min as well as E.c.G. changes (see
figure). 1. 2.
Rosén, K. G., Kjellmer, I. Acta physiol. scand. 1975, 93, Rosén, K. G., Isaksson, O. Biol. Neonate (in the press).
59.
Frequency of fetal movements detected by ultrasound. Shaded area: mean + s.D. for control population. 8
=
abnormal
0-0, -8, ae
(Source:
pregnancies.
=
Haller
serial studies et
ending
in fetal death.
al. 4)
Real-time sonar studies of fetal movements were reported in 1971 by Reinold.2 On the basis of 250 examinations done at 18-20 weeks’ gestation Reinold described different types of active movements (strong and slow) and their absence with fetal death. Reinold’s work has also been published in English.3 Since then in most departments ultrasound evaluation of fetal movements with regard to presence or absence, type, and frequency has become the most important single procedure in the management of threatened abortion. Whereas it is easy to detect the presence or absence of fetal movements, evaluation of their type is more difficult. As in other areas of perinatal biophysical monitoring the main problem is quantification. For frequency of movements, our group45has established the normal range in early pregnancy and has demonstrated the prognostic value of abnormal frequencies with impending early fetal death (see figure). QuanK. M., Harris, P. F., Slater, J. H., Porter, G A. Lancet, 1976, i, 719. 2. Reinold, E. Z. Geburtsh. Gynäk. 1971, 174, 220. 1.
Higginbottom, J., Bagnall,
3. 4.
Reinold, E. J. perinat. Med 1973, 1, 65. Haller, U., Rüttgers, H., Wille, F., Heinrich, D., Müller, P , Kubli, F. Gynäk. Rdsch 1973, 13, Suppl. 1, p. 118. Haller, U. Rüttgers, H., Wille, F., Müller, P, Heinrich, D, Kubli, F in Perinatale Medizin, (edited by J. W. Dudenhausen and E. Saling, vol. v, p 30. Stuttgart, 1974.
5.
E.C.G. changes 1, 3, 5, and 7 min post partum in full-term boy with the umbilical cord around the neck and Apgar score 7 at 1 min.