1361
injection of 1 mg autoclaved M vaccae over the deltoid muscle. Most patients improved symptomatically within a week and 12 became sputum-negative for acid-fast bacillus (AFB). Except for 4 who remained sputum-negative, the improvement did not last. 6 months later, during which 4 patients had died and 4 had returned to Afghanistan, the 29 remaining AFB-positive patients received a second injection, with little bacteriological improvement. A third injection was given 2 months later to 27 patients (1more had died and 1 more had departed), after which 4 further patients became sputum-negative. 9 of the remaining patients with AFB in their sputum were given a fourth injection 2 months later, after which 3 more became sputum-negative. 15 months after the last injection, 11 patients remain sputumnegative. Throughout the study chemotherapy was continued although previous experience of only 1 out of more than 100 such patients being cured with chemotherapy alone leads us to think that none of our patients would have been cured without immunotherapy. The patients remaining sputum-positive for AFB have continued to deteriorate slowly and 2 more have died, whereas the 11 becoming sputum-negative show steady clinical and radiological improvement. All 11 have returned home, and perhaps we have been conservative in continuing their chemotherapy. Immunotherapy with M vaccae may be the first step towards successful treatment for multiply drug-resistant tuberculosis. Tahleghani Pulmonary Diseases Hospital, Mashad, Iran Mashad
A. ETEMADI
University of Medical Sciences,
Mashad, Iran
R. FARID
Division of Bacteriology, Department of Medical Microbiology, University College London Medical School, London W1 P 7LD, UK 1. Stanford JL, Grange JM, Pozniak A. Is Africa lost? Lancet
J. L. STANFORD 1991; 338: 557-58.
Abnormal chromosome complement after normal amniocentesis result SIR,-Chromosome-banding techniques continue to improve so that finer and finer detail can be observed, which has the advantage of providing a diagnosis for an increasing number of children with developmental delay, many of whom may have only very few dysmorphic features. Amniocenteses are generally done for women at risk of Down’s syndrome or other trisomies, and fine analysis (routinely carried out on blood lymphocyte chromosome preparations) is not warranted or practicable. Fetuses karyotyped and reported as chromosomally normal at amniocentesis may turn out to be children with a clinically significant chromosome abnormality associated with undetected small rearrangements. The
following three case-reports are illustrative. Case 1 (amniocentesis in 1986, mother aged 38, normal male chromosome complement). The infant was bom at 34 weeks, birthweight 1 -8 kg. Bilateral talipes and unusual face were noted. He had developmental delay and at age 3 his face showed arched eyebrows, antimongoloid slant to palpebral fissures, anteverted nostrils, and thick lips. At age 5 he had speech delay and coarse facial features. Lymphocyte chromosome analysis was done to exclude fragile X and revealed a microdeletion of 17p with chromosome
complement 46,XY,deI(17)(pll-2 pi 1-2 or pl2) (Smith-Magenis syndrome). This was detected on routine 450-550 band preparations. Parental chromosomes were normal. Case 2 (amniocentesis in 1990, mother aged 40, normal male chromosome complement). The baby had omphalocele at birth. A neonatal blood sample was karyotyped and poor preparations confirmed a 46,XY complement. By age 9 months he showed motor delay with poor head control and inability to sit unsupported. Examination showed strabismus, plagiocephaly, deep set eyes, asymmetric helices to ears, and a small mouth. Neurological examination showed evidence of cerebral palsy. The karyotype was repeated and with standard G-banded preparations a small terminal deletion of the long arm of chromosome 10 was found. With high resolution banding the karyotype was 46,XY,del(10)(q?26-1). Parental chromosomes were normal. Case 3 (amniocentesis in 1991, mother aged 37, normal male
chromosome complement). The baby was bom at 34 weeks, birthweight 1-5 kg. There was a history of maternal alcohol abuse and the infant’s facial features and intrauterine growth retardation suggested fetal alcohol syndrome. He failed to thrive and showed microcephaly and developmental delay. At 7 months (after birth) he had an unusual face with ptosis, short palpebral fissures, and hypertelorism. The philtrum was long and upper lip smooth, all features compatible with fetal alcohol syndrome. However, his failure to thrive seemed disproportionate to his minor dysmorphic features so a blood sample was karyotyped with standard G-banded preparations. An abnormality of chromosome 9 short arm was identified which, with high resolution banding analysis, was shown to be due to loss of the terminal part and replacement with material from an unidentified chromosome, 46,XY,-9 + der(9)?t(9;?)(p23;?). Parental chromosomes were normal. These three cases occurred over 6 years, during which time about 10 500 amniotic fluid samples from mothers older than 35 years were referred to our laboratory, with 240 abnormal results being
reported. Although the missed abnormalities could be seen in the amniotic fluid preparations in retrospect, they were very subtle and not easily detectable in the quality of preparations acceptable for routine amniotic screening. These cases serve as a warning to all those caring for pregnant women and their children. The low index of suspicion in laboratories screening large numbers of predominantly normal or trisomic prenatal samples inevitably leads to a less than perfect detection rate of minor chromosome anomalies. Women need to become aware that a normal amniocentesis result excludes trisomies and other major chromosome anomalies but does not guarantee a normal complement. Paediatricians need to karyotype babies whose features warrant chromosome analysis even if amniocentesis during pregnancy was normal. SE Thames Regional Genetics Centre, Division of Medical and Molecular Genetics, 7th and 8th Floors Guy’s Tower, London SE1 9RT, UK
A. CAROLINE BERRY ZOE DOCHERTY MARTIN BOBROW
Possible role for COMT in psychosis associated with velo-cardio-facial syndrome SiR,—In the velo-cardio-facial syndrome (VCF, Shprintzen syndrome, McKusick 19243), patients commonly present with cleft palate, craniofacial abnormalities, cardiac defects, and leaming difficulties. VCF syndrome is sporadic or inherited as a dominant disorder, and is associated with interstitial deletions of chromosome 22q11.’It is not known which gene or genes mapping within these deletions are important for the development of the dysmorphology.
Psychotic illness is also a feature of VCF syndrome in adolescents or adults.z During experiments aimed at building a contiguous group of yeast artificial chromosomes (YACs) spanning 22qll, we found that the HP500 sequence often deleted in VCF syndrome1 was located within the same 450 kb YAC as the catechol-O-methyl transferase (COMT) gene previously mapped to 22qll.*Both direct hybridisation to ordered arrays of YACs and polymerase chain reaction of sequence tagged sites were used in mapping. COMT metabolises catecholamines, such as noradrenaline, adrenaline, and dopamine, occurs in soluble and membrane-bound forms, but is found predominantly in the cytoplasm. This soluble form (S-COMT) has high and low activity alleles. Although the molecular basis for this variation is not known, heat-labile forms of the enzyme suggest that a structural alteration may be responsible. Presence of COMT activity may serve as a functional barrier for catecholamines in the brainS and placentaand variation in COMT activity has an important influence on the response ofparkinsonian patients to L-dopa.7 Low COMT activity has been reported in women with primary affective disorder.8 It is therefore conceivable that individuals hemizygous for COMT and carrying a low metabolising allele on their non-deleted chromosome would be predisposed to development of the psychotic features of VCF syndrome. This event could occur either via decreased inactivation of catecholamines in the brain, increased placental transfer of catecholamines, or both. 23% of a randomly selected population were classified as "low" metabolisers,9 so the frequency of the low activity allele(s) would be a considerable proportion of the VCF
injection of 1 mg autoclaved M vaccae over the deltoid muscle. Most patients improved symptomatically within a week and 12 became sputum-negative for acid-fast bacillus (AFB). Except for 4 who remained sputum-negative, the improvement did not last. 6 months later, during which 4 patients had died and 4 had returned to Afghanistan, the 29 remaining AFB-positive patients received a second injection, with little bacteriological improvement. A third injection was given 2 months later to 27 patients (1more had died and 1 more had departed), after which 4 further patients became sputum-negative. 9 of the remaining patients with AFB in their sputum were given a fourth injection 2 months later, after which 3 more became sputum-negative. 15 months after the last injection, 11 patients remain sputumnegative. Throughout the study chemotherapy was continued although previous experience of only 1 out of more than 100 such patients being cured with chemotherapy alone leads us to think that none of our patients would have been cured without immunotherapy. The patients remaining sputum-positive for AFB have continued to deteriorate slowly and 2 more have died, whereas the 11 becoming sputum-negative show steady clinical and radiological improvement. All 11 have returned home, and perhaps we have been conservative in continuing their chemotherapy. Immunotherapy with M vaccae may be the first step towards successful treatment for multiply drug-resistant tuberculosis. Tahleghani Pulmonary Diseases Hospital, Mashad, Iran Mashad
A. ETEMADI
University of Medical Sciences,
Mashad, Iran
R. FARID
Division of Bacteriology, Department of Medical Microbiology, University College London Medical School, London W1 P 7LD, UK 1. Stanford JL, Grange JM, Pozniak A. Is Africa lost? Lancet
J. L. STANFORD 1991; 338: 557-58.
Abnormal chromosome complement after normal amniocentesis result SIR,-Chromosome-banding techniques continue to improve so that finer and finer detail can be observed, which has the advantage of providing a diagnosis for an increasing number of children with developmental delay, many of whom may have only very few dysmorphic features. Amniocenteses are generally done for women at risk of Down’s syndrome or other trisomies, and fine analysis (routinely carried out on blood lymphocyte chromosome preparations) is not warranted or practicable. Fetuses karyotyped and reported as chromosomally normal at amniocentesis may turn out to be children with a clinically significant chromosome abnormality associated with undetected small rearrangements. The
following three case-reports are illustrative. Case 1 (amniocentesis in 1986, mother aged 38, normal male chromosome complement). The infant was bom at 34 weeks, birthweight 1 -8 kg. Bilateral talipes and unusual face were noted. He had developmental delay and at age 3 his face showed arched eyebrows, antimongoloid slant to palpebral fissures, anteverted nostrils, and thick lips. At age 5 he had speech delay and coarse facial features. Lymphocyte chromosome analysis was done to exclude fragile X and revealed a microdeletion of 17p with chromosome
complement 46,XY,deI(17)(pll-2 pi 1-2 or pl2) (Smith-Magenis syndrome). This was detected on routine 450-550 band preparations. Parental chromosomes were normal. Case 2 (amniocentesis in 1990, mother aged 40, normal male chromosome complement). The baby had omphalocele at birth. A neonatal blood sample was karyotyped and poor preparations confirmed a 46,XY complement. By age 9 months he showed motor delay with poor head control and inability to sit unsupported. Examination showed strabismus, plagiocephaly, deep set eyes, asymmetric helices to ears, and a small mouth. Neurological examination showed evidence of cerebral palsy. The karyotype was repeated and with standard G-banded preparations a small terminal deletion of the long arm of chromosome 10 was found. With high resolution banding the karyotype was 46,XY,del(10)(q?26-1). Parental chromosomes were normal. Case 3 (amniocentesis in 1991, mother aged 37, normal male
chromosome complement). The baby was bom at 34 weeks, birthweight 1-5 kg. There was a history of maternal alcohol abuse and the infant’s facial features and intrauterine growth retardation suggested fetal alcohol syndrome. He failed to thrive and showed microcephaly and developmental delay. At 7 months (after birth) he had an unusual face with ptosis, short palpebral fissures, and hypertelorism. The philtrum was long and upper lip smooth, all features compatible with fetal alcohol syndrome. However, his failure to thrive seemed disproportionate to his minor dysmorphic features so a blood sample was karyotyped with standard G-banded preparations. An abnormality of chromosome 9 short arm was identified which, with high resolution banding analysis, was shown to be due to loss of the terminal part and replacement with material from an unidentified chromosome, 46,XY,-9 + der(9)?t(9;?)(p23;?). Parental chromosomes were normal. These three cases occurred over 6 years, during which time about 10 500 amniotic fluid samples from mothers older than 35 years were referred to our laboratory, with 240 abnormal results being
reported. Although the missed abnormalities could be seen in the amniotic fluid preparations in retrospect, they were very subtle and not easily detectable in the quality of preparations acceptable for routine amniotic screening. These cases serve as a warning to all those caring for pregnant women and their children. The low index of suspicion in laboratories screening large numbers of predominantly normal or trisomic prenatal samples inevitably leads to a less than perfect detection rate of minor chromosome anomalies. Women need to become aware that a normal amniocentesis result excludes trisomies and other major chromosome anomalies but does not guarantee a normal complement. Paediatricians need to karyotype babies whose features warrant chromosome analysis even if amniocentesis during pregnancy was normal. SE Thames Regional Genetics Centre, Division of Medical and Molecular Genetics, 7th and 8th Floors Guy’s Tower, London SE1 9RT, UK
A. CAROLINE BERRY ZOE DOCHERTY MARTIN BOBROW
Possible role for COMT in psychosis associated with velo-cardio-facial syndrome SiR,—In the velo-cardio-facial syndrome (VCF, Shprintzen syndrome, McKusick 19243), patients commonly present with cleft palate, craniofacial abnormalities, cardiac defects, and leaming difficulties. VCF syndrome is sporadic or inherited as a dominant disorder, and is associated with interstitial deletions of chromosome 22q11.’It is not known which gene or genes mapping within these deletions are important for the development of the dysmorphology.
Psychotic illness is also a feature of VCF syndrome in adolescents or adults.z During experiments aimed at building a contiguous group of yeast artificial chromosomes (YACs) spanning 22qll, we found that the HP500 sequence often deleted in VCF syndrome1 was located within the same 450 kb YAC as the catechol-O-methyl transferase (COMT) gene previously mapped to 22qll.*Both direct hybridisation to ordered arrays of YACs and polymerase chain reaction of sequence tagged sites were used in mapping. COMT metabolises catecholamines, such as noradrenaline, adrenaline, and dopamine, occurs in soluble and membrane-bound forms, but is found predominantly in the cytoplasm. This soluble form (S-COMT) has high and low activity alleles. Although the molecular basis for this variation is not known, heat-labile forms of the enzyme suggest that a structural alteration may be responsible. Presence of COMT activity may serve as a functional barrier for catecholamines in the brainS and placentaand variation in COMT activity has an important influence on the response ofparkinsonian patients to L-dopa.7 Low COMT activity has been reported in women with primary affective disorder.8 It is therefore conceivable that individuals hemizygous for COMT and carrying a low metabolising allele on their non-deleted chromosome would be predisposed to development of the psychotic features of VCF syndrome. This event could occur either via decreased inactivation of catecholamines in the brain, increased placental transfer of catecholamines, or both. 23% of a randomly selected population were classified as "low" metabolisers,9 so the frequency of the low activity allele(s) would be a considerable proportion of the VCF
