Molecular cytogenetics of Prader-Willi and Angelman syndromes

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1276 diameter coil placed over the vertex. MTCS was started at 20% output intensity and augmented in increments of 20% up to 100%, corresponding to 2 T. After each increase, the implanted SCS system was checked with a radiofrequency link. MTCS neither turned on the SCS system nor caused any change in control settings. Patients 3 and 4 had MTCS studies with the systems turned on and off. No electrode displacement was noted and no SCS controls (or drug-delivery indices in patient 4) were altered. Normal operation of the implants was noted at the end of the study in all patients. MTCS at the vertex with a Cadwell MES-10 magnetic stimulator seems not to affect adversely the implants used in our study. Our findings allow further investigation of how neuroaugmentative interventions might alter the function of descending motor pathways. Extrapolation to other systems should be done cautiously. Division of Restorative Neurology and Human Neurobiology, Baylor College of Medicine, Houston, Texas 77030, USA MARKUS KOFLER A. ARTURO LEIS ARTHUR M. SHERWOOD J. SCOTT DELAPASSE JOHN A. HALTER 1. Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet 1985; i: 1106-07. 2. Claus D, Waddy HM, Harding AE, Murray NMF, Thomas PK. Hereditary motor and sensory neuropathies and hereditary spastic paraplegia: a magnetic stimulation study. Ann Neurol 1990; 28: 43-49. 3. Brouwer B, Ashby P. Altered corticospinal projection to lower limb motoneurons in subjects with cerebral palsy Brain 1991; 114: 1395-1407. 4. Cracco RQ. Evaluation of conduction in central motor pathways: techniques, pathophysiology, and clinical interpretation. Neurosurgery 1987; 20: 199-203. 5. Dimitrijevic MM, Dimitrijevic MR, Illis LS, Nakajima K, Sharkey PC, Sherwood AM. Spinal cord stimulation for the control of spasticity in patients with chronic spinal cord injury I. clinical observations. CNS Trauma 1986; 3: 129-44. 6. Dimitrijevic MR, Illis LS, Nakajima K, Sharkey PC, Sherwood AM. Spinal cord stimulation for the control of spasticity in patients with chronic spinal cord injury II neurophysiologic observations. CNS Trauma 1986; 3: 145-52. 7. Spiegelmann R, Friedman WA. Spinal cord stimulation a contemporary series Neurosurgery 1991; 28: 65-71. Molecular cytogenetics of Prader-Willi and Angelman syndromes SIR,-We read with interest Professor Hulten and colleagues’ letter (Sept 7, p 638) on genomic imprinting in an Angelman syndrome (AS) and Prader-Willi syndrome (PWS) translocation family. The two syndromes differ phenotypically but have similar chromosome 15q deletions, inherited from the father in PWSl and mother in AS.2 Hulten et al report an unbalanced 15;22 translocation in index children which was overlooked at first, the children being classified as having the 15q11-13 deletion typical of most patients with PWS and AS. The translocation was detected only after application of specialised cytogenetic techniques, including fluorescent in-situ hybridisation (FISH). Genomic imprinting for PWS and AS has important implications for counselling, and FISH with chromosome 15 probes should be undertaken on apparently sporadic PWS and AS patients to rule out subtle translocations of this chromosome involving the pericentromeric region. We have seen a second instance of genomic imprinting for PWS and AS, and report our experience with FISH with a pericentromeric chromosome 15 probe in this family and in several sporadic PWS and AS cases. During an evaluation for behaviour and schooling difficulties, a 10-year-old girl was diagnosed as having PWS, on the basis of physical features and history. High-resolution chromosome analysis was normal. Review of the family history revealed that an 11 -year-old male paternal cousin had been diagnosed at 4 years of age with AS. His chromosome analysis revealed the typical 15q deletion seen in AS, and G-banded chromosome 15 polymorphisms showed the deletion to be of maternal origin. Paternal high-resolution cytogenetic studies were normal. These cousins are related in a fashion consistent with the imprinting hypothesis-ie, the father of the PWS child and the mother of the AS child are brother and sister. Our molecular cytogenetic study was extended to 4 males and 7 females with PWS (9 with del [15q] and 2 with normal SUMMARY DATA FROM FISH STUDIES WITH D15Z1 *,tFlrst cousms ND = no detectable difference chromosomes), 1 female and 2 males with AS (all del [15q]), and the parents of the cousin with AS. We used D15Z1, a satellite non-isotopic probe localised to the pericentromeric area of chromosome 15 (Oncor). By FISH at least 20 cells were analysed; several metaphases were photographed from each case and the presence and size of the fluorescent area on each chromosome 15 was recorded. When possible, the size of the fluorescent body from the deleted chromosome 15 and the normal chromosome was compared (table). Our results indicate a difference in the size of the fluorescent area detected by FISH in 9 of 14 PWS or AS patients, but the smaller fluorescent area did not consistently correlate with the deleted chromosome previously identified by short-arm and stalk-length polymorphisms. A size difference was observed in 1 parent; thus, the technique may be useful for identification of chromosome 15 pericentromeric polymorphisms for parental origin studies. We did not identify any previously undetected translocations involving this region in either the PWS or AS patients or the parents of one of the AS patients. Our study indicates that previously undetectable translocations involving the pericentromeric region of chromosome 15 are rare as a cause of the 15q deletion in PWS or AS patients-but FISH may be a useful technique identifying chromosome 15 polymorphisms so that parental origin can be determined. We thank Pamela Grimm for secretarial help and Lora Miller for technical assistance. Supported by March of Dimes Birth Defects Foundation and Tennessee Department of Mental Health and Mental Retardation. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37237, USA MERLIN G. BUTLER Department of Pediatrics, University of Connecticut and St Francis Hospital and Medical Center, Hartford, Connecticut MARK A. GREENSTEIN 1. Butler MG, Palmer CG. Parental origin of chromosome 15 deletion in Prader-Willi syndrome Lancet 1983; ii: 1285-86. 2. Knoll JHM, Nicholls RD, Magenis RE, Graham JM, Lalande M, Latt SA. Angelman and Prader-Willi syndrome share a common chromosome 15 deletion, but differ in parental origin of the deletion. Am J Med Genet 1989; 32: 285-90. Thrombelastography in pregnant patients on low-dose aspirin SIR,-Dr Mallett and Dr Platt (Sept 21, p 765) report a lack of change on thrombelastography (TEG) after 14 days of daily aspirin 150 mg in 7 female and 18 male healthy volunteers. They also emphasise the many advantages of TEG, a bedside test that evaluates all phases of coagulation. Its variables have been reported to correlate well with the clinical setting. We have been using TEG in our delivery suite for several months to monitor coagulation

Transcript of Molecular cytogenetics of Prader-Willi and Angelman syndromes

Page 1: Molecular cytogenetics of Prader-Willi and Angelman syndromes

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diameter coil placed over the vertex. MTCS was started at 20%output intensity and augmented in increments of 20% up to 100%,corresponding to 2 T. After each increase, the implanted SCSsystem was checked with a radiofrequency link. MTCS neitherturned on the SCS system nor caused any change in controlsettings. Patients 3 and 4 had MTCS studies with the systemsturned on and off. No electrode displacement was noted and noSCS controls (or drug-delivery indices in patient 4) were altered.Normal operation of the implants was noted at the end of the studyin all patients.MTCS at the vertex with a Cadwell MES-10 magnetic

stimulator seems not to affect adversely the implants used in ourstudy. Our findings allow further investigation of how

neuroaugmentative interventions might alter the function of

descending motor pathways. Extrapolation to other systems shouldbe done cautiously.

Division of Restorative Neurologyand Human Neurobiology,

Baylor College of Medicine,Houston, Texas 77030, USA

MARKUS KOFLERA. ARTURO LEISARTHUR M. SHERWOOD

J. SCOTT DELAPASSEJOHN A. HALTER

1. Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of humanmotor cortex. Lancet 1985; i: 1106-07.

2. Claus D, Waddy HM, Harding AE, Murray NMF, Thomas PK. Hereditary motorand sensory neuropathies and hereditary spastic paraplegia: a magnetic stimulationstudy. Ann Neurol 1990; 28: 43-49.

3. Brouwer B, Ashby P. Altered corticospinal projection to lower limb motoneurons insubjects with cerebral palsy Brain 1991; 114: 1395-1407.

4. Cracco RQ. Evaluation of conduction in central motor pathways: techniques,pathophysiology, and clinical interpretation. Neurosurgery 1987; 20: 199-203.

5. Dimitrijevic MM, Dimitrijevic MR, Illis LS, Nakajima K, Sharkey PC, SherwoodAM. Spinal cord stimulation for the control of spasticity in patients with chronicspinal cord injury I. clinical observations. CNS Trauma 1986; 3: 129-44.

6. Dimitrijevic MR, Illis LS, Nakajima K, Sharkey PC, Sherwood AM. Spinal cordstimulation for the control of spasticity in patients with chronic spinal cord injuryII neurophysiologic observations. CNS Trauma 1986; 3: 145-52.

7. Spiegelmann R, Friedman WA. Spinal cord stimulation a contemporary seriesNeurosurgery 1991; 28: 65-71.

Molecular cytogenetics of Prader-Willi andAngelman syndromes

SIR,-We read with interest Professor Hulten and colleagues’letter (Sept 7, p 638) on genomic imprinting in an Angelmansyndrome (AS) and Prader-Willi syndrome (PWS) translocationfamily. The two syndromes differ phenotypically but have similarchromosome 15q deletions, inherited from the father in PWSl andmother in AS.2 Hulten et al report an unbalanced 15;22translocation in index children which was overlooked at first, thechildren being classified as having the 15q11-13 deletion typical ofmost patients with PWS and AS. The translocation was detectedonly after application of specialised cytogenetic techniques,including fluorescent in-situ hybridisation (FISH). Genomicimprinting for PWS and AS has important implications for

counselling, and FISH with chromosome 15 probes should beundertaken on apparently sporadic PWS and AS patients to rule outsubtle translocations of this chromosome involving the

pericentromeric region.We have seen a second instance of genomic imprinting for PWS

and AS, and report our experience with FISH with a

pericentromeric chromosome 15 probe in this family and in severalsporadic PWS and AS cases. During an evaluation for behaviourand schooling difficulties, a 10-year-old girl was diagnosed ashaving PWS, on the basis of physical features and history.High-resolution chromosome analysis was normal. Review of thefamily history revealed that an 11 -year-old male paternal cousin hadbeen diagnosed at 4 years of age with AS. His chromosome analysisrevealed the typical 15q deletion seen in AS, and G-bandedchromosome 15 polymorphisms showed the deletion to be ofmaternal origin. Paternal high-resolution cytogenetic studies werenormal. These cousins are related in a fashion consistent with the

imprinting hypothesis-ie, the father of the PWS child and themother of the AS child are brother and sister.Our molecular cytogenetic study was extended to 4 males and 7

females with PWS (9 with del [15q] and 2 with normal

SUMMARY DATA FROM FISH STUDIES WITH D15Z1

*,tFlrst cousmsND = no detectable difference

chromosomes), 1 female and 2 males with AS (all del [15q]), and theparents of the cousin with AS. We used D15Z1, a satellite

non-isotopic probe localised to the pericentromeric area ofchromosome 15 (Oncor). By FISH at least 20 cells were analysed;several metaphases were photographed from each case and thepresence and size of the fluorescent area on each chromosome 15was recorded. When possible, the size of the fluorescent body fromthe deleted chromosome 15 and the normal chromosome was

compared (table). Our results indicate a difference in the size of thefluorescent area detected by FISH in 9 of 14 PWS or AS patients,but the smaller fluorescent area did not consistently correlate withthe deleted chromosome previously identified by short-arm andstalk-length polymorphisms. A size difference was observed in 1

parent; thus, the technique may be useful for identification ofchromosome 15 pericentromeric polymorphisms for parental originstudies. We did not identify any previously undetectedtranslocations involving this region in either the PWS or ASpatients or the parents of one of the AS patients.Our study indicates that previously undetectable translocations

involving the pericentromeric region of chromosome 15 are rare as acause of the 15q deletion in PWS or AS patients-but FISH may bea useful technique identifying chromosome 15 polymorphisms sothat parental origin can be determined.

We thank Pamela Grimm for secretarial help and Lora Miller for technicalassistance. Supported by March of Dimes Birth Defects Foundation andTennessee Department of Mental Health and Mental Retardation.

Department of Pediatrics,Vanderbilt University Medical Center,Nashville, Tennessee 37237, USA MERLIN G. BUTLER

Department of Pediatrics,University of Connecticutand St Francis Hospital and Medical Center,

Hartford, Connecticut MARK A. GREENSTEIN

1. Butler MG, Palmer CG. Parental origin of chromosome 15 deletion in Prader-Willisyndrome Lancet 1983; ii: 1285-86.

2. Knoll JHM, Nicholls RD, Magenis RE, Graham JM, Lalande M, Latt SA. Angelmanand Prader-Willi syndrome share a common chromosome 15 deletion, but differ inparental origin of the deletion. Am J Med Genet 1989; 32: 285-90.

Thrombelastography in pregnant patients onlow-dose aspirin

SIR,-Dr Mallett and Dr Platt (Sept 21, p 765) report a lack ofchange on thrombelastography (TEG) after 14 days of daily aspirin150 mg in 7 female and 18 male healthy volunteers. They alsoemphasise the many advantages of TEG, a bedside test thatevaluates all phases of coagulation. Its variables have been reportedto correlate well with the clinical setting. We have been using TEGin our delivery suite for several months to monitor coagulation