182
individuals from 23 families. Cases of schizophrenia, schizoaffective disorder, and atypical functional psychosis (82 individuals, according to Research Diagnostic criteria) were defined as affected.4 LOD scores (logarithm of the relative odds of linkage) were analysed with the assumption of autosomal dominant inheritance with incomplete penetrance, with age-related liability classes for unaffected individuals.’ Summated LOD scores were: Recombination fraction (0)
LODscore
0-00 -13-58
0-05 -5-51
0-10 -3-16
0-20 -0-97
030 -0-16
Dominant model, f1 =0.001, f2=0.85 and fj=0 99 refer to penetrances of genotypes A,A,, A,A, and A2A2, respectively, where A,
=
normal allele and
A2= abnormal allele and q(gene frequency of A2) = 0.02 One family gave a score of 1-25 at &thgr;=0, but there was no formal evidence of linkage heterogeneity. In addition, we did sibling-pair analysis with the ESPA program" and found no evidence for non-random sharing of alleles by affected sibling-pairs. We conclude that mutations at the debrisoquine 4-hydroxylase gene are not a major factor in determining susceptibility to schizophrenia in our families. However, examination of the various mutations in a large number of patients with schizophrenia is needed to determine if mutations at this locus contribute in a minor way to development of the disorder. Indeed, such an effect may be confined to a subset of schizophrenic patients, such as those resistant to, or those who develop parkinsonian side-effects in response to neuroleptics. Genetics Section, Institute of Psychiatry, London SE5 8AF, UK, Department of Psychological Medicine, University of Wales College of Medicine,
Cardiff, and Department of Psychiatry, Teikyo University School of Medicine,
Tokyo, Japan
HOMERO VALLADA DAVID COLLIER ELISABETH DAWSON MIKE OWEN SHIN NANKO ROBIN MURRAY MIKE GILL
Armstrong M, Daly AK, Cholerton S, Bateman DM, Idle JR. Mutant debrisoquine hydroxylation genes in Parkinson’s disease. Lancet 1992; 339: 1017-18. 2. Smith CAD, Gough AC, Leigh PN, et al. Debrisoquine hydroxylase gene polymorphism and susceptibilty to Parkinson’s disease. Lancet 1992; 339: 1375-77. 3 McGuffin P. Genetics of schizophrenia. In: Bebbington P, McGuffin P, eds. Schizophrenia, the major issues. London Heinemann Medical, 1988: 107-26. 4. O’Callaghan E, Sham P, Takei N, Glover G, Murray RM. Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet 1991; 337: 1248-50. 5. Mackay AVP, Iversen LL Neurotransmitters and schizophrenia. In. Weller M, Eysenck M, eds The scientific basis of psychiatry. London. WB Saunders, 1992: 1.
558-81.
6. Tyndale RF, Sunahara R, Inaba T, et al. Neuroanal cytochrome P45011D1 (debrisoquine/spateine-type): potent inhibition of activity by (-)-cocaine and nucleotide sequence identify to human hepatic P450 gene CYP2D6. Mol 7.
8.
9. 10.
Pharmacol 1991; 40: 63-68 Nisnik HB, Tyndale RF, Salle FR, et al. The dopamine transporter and cytochrome P450 IID1 (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distint [’H]GBR-12935 binding proteins. Arch Biochem Biophys 1990; 276: 424-32. Trofatter JA, Gusella JF, Haines JL. Dinucleotide repeat polymorphism at the debrisoquine 4-hydroxylase (CYP2D) locus. Nucleic Acids Res 1991; 19: 2802. Gill M, McGuffin P, Parfitt E, et al. A linkage study of schizophrenia with DNA markers from the long arm of chromosome 11 Psychol Med (in press). Sandkuijl LA Analysis of affected sib-pairs using information from extend families. In: Elston RC, Spence MA, Hodge SE, MacCluer JW, eds Multipoint mapping and linkage based upon affected pedigree members: genetic analysis workshop 6. New York: Alan R. Liss, 1989.
Over the next 3 years, proximal right arm weakness progressed and in 1991 the patient had difficulty in walking. Neurological examination disclosed a bilateral distal deficit in the lower limbs. Motor weakness in the right arm had worsened (abduction of right arm and flexion of right forearm were impossible). Mild amyotrophy was noticed in affected muscles. Right brachioradial, right biceps, and both ankle reflexes were abolished. Sensory examination was normal. Nerve conduction studies showed
multifocal, predominantly proximal, blocks, involving right median, ulnar,and radial nerves, to a lesser degree left ulnar and median nerves, and both tibial nerves. Motor conduction velocities, sensory conduction velocities, and sensory amplitudes were normal. Electromyography revealed sparse fibrillation and many fasciculation potentials in clinically affected muscles. Cerebrospinal fluid was cell-free, and protein concentration was 071 g/l. Biochemical and haematological screening and immuno-
electrophoresis were normal. Serum anti-GMlIgG antibody titre (ELISA) was high (315, normal < 20). The patient did not respond to oral prednisone 60 mg a day for 2 months. He was treated with IVIG 200 mg/kg daily for 5 days. Strength improved 15 days after this treatment. 6 weeks later we noticed a striking improvement in his right proximal arm strength and both legs, and reflexes were normal in all four limbs. Conduction blocks disappeared in the right median and radial nerves, in the left tibial nerve, and improved in the left median and ulnar, right ulnar, and tibial nerves (figure). This response lasted 6-7 weeks, when a proximal deficit in the right arm recurred, although to a smaller extent than before treatment. Our patient had all the diagnostic criteria for MMN. Several treatments have been proposed. Corticosteroids and plasmapheresis were unsuccessful in most studies;z cyclophosphamide has been proposed with beneficial effects.2 IVIG is effective in chronic inflammatory demyelinating polyneuropathy, which sometimes does not respond to corticosteroids or plasma exchange.3,4 Because MMN is also a demyelinating neuropathy and antiganglioside antibodies may be related to the process that induces the neuropathy, IVIG seems to be a logical treatment. Our case suggests that IVIG might be an alternative to cyclophosphamide, with more rapid effect and fewer side-effects. We thank Prof Steck for assay of anti-GM1
Electromyography Laboratory, Hôpital Neurologique P Weirtheimer, 69003 Lyon, France
antibody.
N. CHARLES
C. VIAL T. MOREAU
P. BENOIT T. BIERME B. BADY
A, Comblath DR, Ilya AA, et al. A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann Neurol 1988; 24: 73-78 2. Feldman EL, Bromberg MB, Albers JW, et al. Immunosuppressive treatment In multifocal motor neuropathy. Ann Neurol 1991; 30: 397-401 3. Van Doorm PA, Brand A, Meulstee J, et al. High-dose intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. Neurology 1990; 40: 209-12 4. Van Doom PA, Vermeulen A, Brand A, et al. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy. Arch Neurol 1. Pestronk
1991; 48: 217-20.
Ophthalmic artery velocimetry in pregnant women
Intravenous immunoglobulin treatment in multifocal motor neuropathy SIR,-Multifocal motor neuropathy (MMN) is characterised by weakness and fasciculations, by conduction blocks, and by high titres of antibodies against GM1 ganglioside in most cases.l We report a case treated with intravenous immunoglobulin (IVIG). A 62-year-old patient presented in 1988 with progressive right shoulder weakness. He had no sensory complaints. Examination revealed weakness in deltoid, supra and infra spinatus, biceps, and, to a lesser degree, brachioradialis. Right brachioradial and biceps reflexes were abolished. There were many fasciculations in right shoulder muscles. Electromyography showed a slightly reduced interference pattern in the clinically affected muscles, nerve conduction studies were normal. These findings were compatible with a C5-C6 radiculopathy. Magnetic resonance imaging of cervical spine was normal.
SIR,—The orbital circulation has been evaluated with colour doppler flow imaging.1-3 The most pathologically significant change in pre-eclampsia is arteriolar constriction in general organ systems. We postulated that pre-eclampsia could be associated with vascular constriction in the orbital circulation and hence with changes in the flow-velocity waveform in the maternal ophthalmic artery. Eight normotensive non-pregnant women (16 orbits), 17i normotensive pregnant women (16 to 40 weeks’ gestation, 34 orbits), and 2 pre-eclamptic women (3 orbits, 1 orbit was excluded because of previous ablatio retinae) were studied with colour doppler flow imaging and pulsed doppler ultrasonography (Aloka SSD-680) with a 5 MHz microconvex transducer. This system detects amplitude, phase, and frequency shift, resulting in real-time grey-scale/colour-flow imaging. Flow toward the transducer was selected as red and flow away as blue. Pre-eclampsia was defined as a blood pressure of at least 140/90 mm Hg, or a rise in systolic (more than 30 mm Hg) or diastolic (more than 15 mm Hg) values over
individuals from 23 families. Cases of schizophrenia, schizoaffective disorder, and atypical functional psychosis (82 individuals, according to Research Diagnostic criteria) were defined as affected.4 LOD scores (logarithm of the relative odds of linkage) were analysed with the assumption of autosomal dominant inheritance with incomplete penetrance, with age-related liability classes for unaffected individuals.’ Summated LOD scores were: Recombination fraction (0)
LODscore
0-00 -13-58
0-05 -5-51
0-10 -3-16
0-20 -0-97
030 -0-16
Dominant model, f1 =0.001, f2=0.85 and fj=0 99 refer to penetrances of genotypes A,A,, A,A, and A2A2, respectively, where A,
=
normal allele and
A2= abnormal allele and q(gene frequency of A2) = 0.02 One family gave a score of 1-25 at &thgr;=0, but there was no formal evidence of linkage heterogeneity. In addition, we did sibling-pair analysis with the ESPA program" and found no evidence for non-random sharing of alleles by affected sibling-pairs. We conclude that mutations at the debrisoquine 4-hydroxylase gene are not a major factor in determining susceptibility to schizophrenia in our families. However, examination of the various mutations in a large number of patients with schizophrenia is needed to determine if mutations at this locus contribute in a minor way to development of the disorder. Indeed, such an effect may be confined to a subset of schizophrenic patients, such as those resistant to, or those who develop parkinsonian side-effects in response to neuroleptics. Genetics Section, Institute of Psychiatry, London SE5 8AF, UK, Department of Psychological Medicine, University of Wales College of Medicine,
Cardiff, and Department of Psychiatry, Teikyo University School of Medicine,
Tokyo, Japan
HOMERO VALLADA DAVID COLLIER ELISABETH DAWSON MIKE OWEN SHIN NANKO ROBIN MURRAY MIKE GILL
Armstrong M, Daly AK, Cholerton S, Bateman DM, Idle JR. Mutant debrisoquine hydroxylation genes in Parkinson’s disease. Lancet 1992; 339: 1017-18. 2. Smith CAD, Gough AC, Leigh PN, et al. Debrisoquine hydroxylase gene polymorphism and susceptibilty to Parkinson’s disease. Lancet 1992; 339: 1375-77. 3 McGuffin P. Genetics of schizophrenia. In: Bebbington P, McGuffin P, eds. Schizophrenia, the major issues. London Heinemann Medical, 1988: 107-26. 4. O’Callaghan E, Sham P, Takei N, Glover G, Murray RM. Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet 1991; 337: 1248-50. 5. Mackay AVP, Iversen LL Neurotransmitters and schizophrenia. In. Weller M, Eysenck M, eds The scientific basis of psychiatry. London. WB Saunders, 1992: 1.
558-81.
6. Tyndale RF, Sunahara R, Inaba T, et al. Neuroanal cytochrome P45011D1 (debrisoquine/spateine-type): potent inhibition of activity by (-)-cocaine and nucleotide sequence identify to human hepatic P450 gene CYP2D6. Mol 7.
8.
9. 10.
Pharmacol 1991; 40: 63-68 Nisnik HB, Tyndale RF, Salle FR, et al. The dopamine transporter and cytochrome P450 IID1 (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distint [’H]GBR-12935 binding proteins. Arch Biochem Biophys 1990; 276: 424-32. Trofatter JA, Gusella JF, Haines JL. Dinucleotide repeat polymorphism at the debrisoquine 4-hydroxylase (CYP2D) locus. Nucleic Acids Res 1991; 19: 2802. Gill M, McGuffin P, Parfitt E, et al. A linkage study of schizophrenia with DNA markers from the long arm of chromosome 11 Psychol Med (in press). Sandkuijl LA Analysis of affected sib-pairs using information from extend families. In: Elston RC, Spence MA, Hodge SE, MacCluer JW, eds Multipoint mapping and linkage based upon affected pedigree members: genetic analysis workshop 6. New York: Alan R. Liss, 1989.
Over the next 3 years, proximal right arm weakness progressed and in 1991 the patient had difficulty in walking. Neurological examination disclosed a bilateral distal deficit in the lower limbs. Motor weakness in the right arm had worsened (abduction of right arm and flexion of right forearm were impossible). Mild amyotrophy was noticed in affected muscles. Right brachioradial, right biceps, and both ankle reflexes were abolished. Sensory examination was normal. Nerve conduction studies showed
multifocal, predominantly proximal, blocks, involving right median, ulnar,and radial nerves, to a lesser degree left ulnar and median nerves, and both tibial nerves. Motor conduction velocities, sensory conduction velocities, and sensory amplitudes were normal. Electromyography revealed sparse fibrillation and many fasciculation potentials in clinically affected muscles. Cerebrospinal fluid was cell-free, and protein concentration was 071 g/l. Biochemical and haematological screening and immuno-
electrophoresis were normal. Serum anti-GMlIgG antibody titre (ELISA) was high (315, normal < 20). The patient did not respond to oral prednisone 60 mg a day for 2 months. He was treated with IVIG 200 mg/kg daily for 5 days. Strength improved 15 days after this treatment. 6 weeks later we noticed a striking improvement in his right proximal arm strength and both legs, and reflexes were normal in all four limbs. Conduction blocks disappeared in the right median and radial nerves, in the left tibial nerve, and improved in the left median and ulnar, right ulnar, and tibial nerves (figure). This response lasted 6-7 weeks, when a proximal deficit in the right arm recurred, although to a smaller extent than before treatment. Our patient had all the diagnostic criteria for MMN. Several treatments have been proposed. Corticosteroids and plasmapheresis were unsuccessful in most studies;z cyclophosphamide has been proposed with beneficial effects.2 IVIG is effective in chronic inflammatory demyelinating polyneuropathy, which sometimes does not respond to corticosteroids or plasma exchange.3,4 Because MMN is also a demyelinating neuropathy and antiganglioside antibodies may be related to the process that induces the neuropathy, IVIG seems to be a logical treatment. Our case suggests that IVIG might be an alternative to cyclophosphamide, with more rapid effect and fewer side-effects. We thank Prof Steck for assay of anti-GM1
Electromyography Laboratory, Hôpital Neurologique P Weirtheimer, 69003 Lyon, France
antibody.
N. CHARLES
C. VIAL T. MOREAU
P. BENOIT T. BIERME B. BADY
A, Comblath DR, Ilya AA, et al. A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann Neurol 1988; 24: 73-78 2. Feldman EL, Bromberg MB, Albers JW, et al. Immunosuppressive treatment In multifocal motor neuropathy. Ann Neurol 1991; 30: 397-401 3. Van Doorm PA, Brand A, Meulstee J, et al. High-dose intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. Neurology 1990; 40: 209-12 4. Van Doom PA, Vermeulen A, Brand A, et al. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy. Arch Neurol 1. Pestronk
1991; 48: 217-20.
Ophthalmic artery velocimetry in pregnant women
Intravenous immunoglobulin treatment in multifocal motor neuropathy SIR,-Multifocal motor neuropathy (MMN) is characterised by weakness and fasciculations, by conduction blocks, and by high titres of antibodies against GM1 ganglioside in most cases.l We report a case treated with intravenous immunoglobulin (IVIG). A 62-year-old patient presented in 1988 with progressive right shoulder weakness. He had no sensory complaints. Examination revealed weakness in deltoid, supra and infra spinatus, biceps, and, to a lesser degree, brachioradialis. Right brachioradial and biceps reflexes were abolished. There were many fasciculations in right shoulder muscles. Electromyography showed a slightly reduced interference pattern in the clinically affected muscles, nerve conduction studies were normal. These findings were compatible with a C5-C6 radiculopathy. Magnetic resonance imaging of cervical spine was normal.
SIR,—The orbital circulation has been evaluated with colour doppler flow imaging.1-3 The most pathologically significant change in pre-eclampsia is arteriolar constriction in general organ systems. We postulated that pre-eclampsia could be associated with vascular constriction in the orbital circulation and hence with changes in the flow-velocity waveform in the maternal ophthalmic artery. Eight normotensive non-pregnant women (16 orbits), 17i normotensive pregnant women (16 to 40 weeks’ gestation, 34 orbits), and 2 pre-eclamptic women (3 orbits, 1 orbit was excluded because of previous ablatio retinae) were studied with colour doppler flow imaging and pulsed doppler ultrasonography (Aloka SSD-680) with a 5 MHz microconvex transducer. This system detects amplitude, phase, and frequency shift, resulting in real-time grey-scale/colour-flow imaging. Flow toward the transducer was selected as red and flow away as blue. Pre-eclampsia was defined as a blood pressure of at least 140/90 mm Hg, or a rise in systolic (more than 30 mm Hg) or diastolic (more than 15 mm Hg) values over
