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Figure 1.
Grouped values of relaxed motor threshold, intracortical inhibition, and intracortical facilitation. A, The relaxed motor threshold was significantly (P<.05) higher in the whole Prader-Willi syndrome (PWS) group than in controls. B, Intracortical inhibition was similar in both the PWS group and the control group. Intracortical facilitation was significantly reduced among patients with PWS (P<.001). C, The PWS group is split into patients with a deletion and patients with a uniparental disomy. Intracortical inhibition was significantly less (that is, its nominal value was higher) in patients with a deletion than in those with a uniparental disomy (P<.05). For intracortical facilitation, both subgroups showed a similar reduction as compared with controls (P< .01). White column indicates patients with PWS and a deletion; gray column, patients with PWS and a uniparental disomy; black column, controls; bar, standard deviation; and asterisk, statistically significant differences.

Grouped values of relaxed motor threshold, intracortical inhibition, and intracortical facilitation. A, The relaxed motor threshold was significantly (P<.05) higher in the whole Prader-Willi syndrome (PWS) group than in controls. B, Intracortical inhibition was similar in both the PWS group and the control group. Intracortical facilitation was significantly reduced among patients with PWS (P<.001). C, The PWS group is split into patients with a deletion and patients with a uniparental disomy. Intracortical inhibition was significantly less (that is, its nominal value was higher) in patients with a deletion than in those with a uniparental disomy (P<.05). For intracortical facilitation, both subgroups showed a similar reduction as compared with controls (P< .01). White column indicates patients with PWS and a deletion; gray column, patients with PWS and a uniparental disomy; black column, controls; bar, standard deviation; and asterisk, statistically significant differences.

Figure 2.
Typical example of the paired transcranial magnetic stimulation effects in a control subject, in a patient with Prader-Willi syndrome and a deletion, and in a patient with Prader-Willi syndrome and a uniparental disomy. Each tracing represents the average of at least 12 control (dotted line) and 12 conditioned (black line) motor evoked potentials. A, Interstimulus interval, 3 ms; the patient with a deletion shows less inhibition than the remaining 2 subjects. B, Interstimulus interval, 16 ms; facilitation is depressed in both patients as compared with the control.

Typical example of the paired transcranial magnetic stimulation effects in a control subject, in a patient with Prader-Willi syndrome and a deletion, and in a patient with Prader-Willi syndrome and a uniparental disomy. Each tracing represents the average of at least 12 control (dotted line) and 12 conditioned (black line) motor evoked potentials. A, Interstimulus interval, 3 ms; the patient with a deletion shows less inhibition than the remaining 2 subjects. B, Interstimulus interval, 16 ms; facilitation is depressed in both patients as compared with the control.

Table. 
Average Height and Transcranial Magnetic Stimulation Results in Patients With Prader-Willi Syndrome and Controls*
Average Height and Transcranial Magnetic Stimulation Results in Patients With Prader-Willi Syndrome and Controls*
1.
Nativio  DG The genetics, diagnosis, and management of Prader-Willi syndrome. J Pediatr Health Care 2002;16298- 303
PubMedArticle
2.
Roy  MSMilot  JAPolomeno  RCBarsoum-Homsy  M Ocular findings and visual evoked potential response in the Prader-Willi syndrome. Can J Ophthalmol 1992;27307- 312
PubMed
3.
Stauder  JEABrinkman  MJRCurfs  LMG Multi-modal P3 deflation of event-related brain activity in Prader-Willi syndrome. Neurosci Lett 2002;32799- 102
PubMedArticle
4.
Prader  ALabhart  AWilli  H Ein syndrom von adipositas, kleinwuchs, kryptorchismus und oligofrenic nach myalonieartigen zustand im neugeborenenalter. Schweiz Med Wochenschr 1956;861260- 1261
5.
Jay  PRouguelle  CMassacrier  A  et al.  The human necdine gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region. Nat Genet 1997;17357- 361
PubMedArticle
6.
Leonard  CMWilliams  CANicholls  RD  et al.  Angelman and Prader-Willi syndrome: a magnetic resonance imaging study of differences in cerebral structure. Am J Med Genet 1993;4626- 33
PubMedArticle
7.
Wagstaff  JKnoll  JHMFleming  J  et al.  Localization of gene encoding the GABA-A receptor beta-3 subunit to the Angelman/Prader-Willi region of human chromosome 15. Am J Hum Genet 1991;49330- 337
PubMed
8.
Ebert  MHSchmidt  DEThompson  TButler  MG Elevated plasma gamma-aminobutyric acid (GABA) levels in individuals with either Prader-Willi syndrome or Angelman syndrome. J Neuropsychiatry Clin Neurosci 1997;975- 80
PubMed
9.
Dimitropoulos  AFeurer  IDRoof  E  et al.  Appetitive behaviour, compulsivity, and neurochemistry in Prader-Willi syndrome. Ment Retard Dev Disabil Res Rev 2000;6125- 130
PubMedArticle
10.
Akefeldt  AEkman  RGillberg  CManson  JE Cerebrospinal fluid monoamines in Prader-Willi syndrome. Biol Psychiatry 1998;441321- 1328
PubMedArticle
11.
Abbruzzese  GTrompetto  C Clinical and research methods for evaluating cortical excitability. J Clin Neurophysiol 2002;19307- 321
PubMedArticle
12.
Boroojerdi  B Pharmacologic influences on TMS effects. J Clin Neurophysiol 2002;19255- 271
PubMedArticle
13.
Nicholls  RD Genomic imprinting candidate genes in the Prader-Willi and Angelman syndromes. Curr Opin Genet Dev 1993;3445- 456
PubMedArticle
14.
Khan  NLWood  NW Prader-Willi and Angelman syndrome: update on genetic mechanisms and diagnostic complexities. Curr Opin Neurol 1999;12149- 154
PubMedArticle
15.
Holm  VACassidy  SBButler  MG  et al.  Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 1993;91398- 402
PubMed
16.
ASHG/ACMG Report, Diagnostic testing for Prader-Willi and Angelman syndromes: report of the ASHG/ACMG test and technology transfer committee. Am J Hum Genet 1996;581085- 1089
PubMed
17.
Rothwell  JCHallett  MBerardelli  AEisen  ARossini  PMPaulus  W Magnetic stimulation: motor evoked potentials: guidelines of the International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl 1999;52(suppl)97- 103
PubMed
18.
Kujirai  TCaramia  MDRothwell  JC  et al.  Corticocortical inhibition in the human motor cortex. J Physiol 1993;471501- 519
PubMed
19.
Ziemann  ULonnecker  SSteinhoff  BJPaulus  W Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol 1996;40367- 378
PubMedArticle
20.
Guerrini  RDe Lorey  TMBonanni  P  et al.  Cortical myoclonus in Angelman syndrome. Ann Neurol 1996;4039- 48
PubMedArticle
21.
Cantello  R Applications of transcranial magnetic stimulation in movement disorders. J Clin Neurophysiol 2002;19272- 293
PubMedArticle
22.
Tassinari  CACincotta  MZaccara  GMichelucci  R Transcranial magnetic stimulation and epilepsy. Clin Neurophysiol 2003;114777- 798
PubMedArticle
23.
Olsen  RWHomanics  GE Function of GABA-A receptors: insight from mutant and knockout mice.  In: Martin  DL, Olsen  RW, eds. GABA in the Nervous System: The View at Fifty Years. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000:81-96
24.
Whiting  PJWafford  KAMcKernan  RM Pharmacologic subtypes of GABAA receptors based on subunit composition.  In: Martin  DL, Olsen  RW, eds. GABA in the Nervous System: The View at Fifty Years. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000:113-126
25.
Cantello  RGianelli  MCivardi  CMutani  R Magnetic brain stimulation: the silent period after the motor evoked potential. Neurology 1992;421951- 1959
PubMedArticle
26.
Greenberg  BDZiemann  UCora-Locatelli  G  et al.  Altered cortical excitability in obsessive-compulsive disorder. Neurology 2000;54142- 147
PubMedArticle
27.
Schwenkreis  PTegenthoff  MWitscher  K  et al.  Motor cortex activation by transcranial magnetic stimulation in ataxia patients depends on the genetic defect. Brain 2002;125301- 309
PubMedArticle
28.
Gillessen-Kaesbach  GRobinson  WLohmann  DKaya-Westerloh  SPassage  EHorsthemke  B Genotype-phenotype correlation in a series of 167 deletion and non deletion patients with Prader-Willi syndrome. Hum Genet 1995;96638- 643
PubMedArticle
29.
Cassidy  SBForsythe  MHeeger  S  et al.  Comparison of phenotype between patients with Prader-Willi syndrome due to deletion 15q and uniparental disomy 15. Am J Med Genet 1997;68433- 440
PubMedArticle
Original Contribution
October 2004

Corticospinal Physiology in Patients With Prader-Willi SyndromeA Transcranial Magnetic Stimulation Study

Author Affiliations

Author Affiliations: Department of Medical Sciences, Section of Neurology, Università del Piemonte Orientale “A. Avogadro,” Novara (Drs Civardi, Vicentini, and Cantello) and Istituto Auxologico Italiano, Piancavallo, (Verbania) (Dr Grugni), Italy.

Arch Neurol. 2004;61(10):1585-1589. doi:10.1001/archneur.61.10.1585
Abstract

Background  Prader-Willi syndrome (PWS) is a genetic developmental disorder, mostly caused by a deletion on the paternal chromosome 15 or by a maternal uniparental disomy 15. Some PWS clinical and neurochemical features suggest an involvement of the corticospinal motor structures.

Objective  To explore the corticospinal physiology of PWS by transcranial magnetic stimulation.

Setting  A community-based hospital.

Methods  We studied motor evoked potentials in the first dorsal interosseous muscle of 21 young-adult patients with PWS. Thirteen patients had a deletion at chromosome 15; 8 had a uniparental disomy. We measured the following variables: relaxed motor threshold, central motor conduction time, duration of the central silent period, and short-interval intracortical inhibition and facilitation. We also recorded F waves in the first dorsal interosseous muscle. We had 11 normal controls.

Results  In the whole PWS group, motor threshold was higher as compared with controls (P<.05). The central motor conduction time, central silent period, and F waves were normal. Intracortical facilitation was reduced significantly (P<.001). Patients with PWS and a deletion had a weaker intracortical inhibition as compared with patients with PWS and a uniparental disomy (P<.05).

Conclusions  Transcranial magnetic stimulation changes in patients with PWS suggested a hypo-excitability of the motor cortical areas. Defective neurogenesis of the cortical tissue and multiple transmitter alterations are the putative causes. Impaired intracortical inhibition might represent an electrical marker for a deletion defect.

Prader-Willi syndrome (PWS) affects both sexes, all races, and 1 in every 10 000 to 15 000 live births.1 Its neurophysiology has been poorly investigated,2,3 although the central nervous system is one of the main targets of the underlying genetic defect.4 In fact, apart from the characteristic facial aspect, the main clinical features of PWS are hyperphagia, obesity, short stature, and hypogonadism. A hypothalamic involvement has been proposed to explain these features. Other features suggest an involvement of the central nervous system motor structures: central hypotonia in infancy, delayed psychomotor development, difficulties in motor aspects of language, and obsessive-compulsive behavior.1 The original PWS genetic defect leads to an altered coding for proteins that control the neuronal growth/differentiation in widespread brain regions, such as necdin.5 Cortical dysgenesis with atrophic aspects was also reported.6 Moreover, coding of some subunits (α-5, β-3, and γ-3) of the γ-aminobutyric acid type-A (GABAA) receptors is defective.7 These receptors become hyposensitive in many cortical and subcortical areas. In response, circulating GABA levels increase abnormally.8 Thus, a complex derangement of the neurotransmitter balance arises,9,10 which may well involve the motor cortical regions and their projections.

For these reasons, we explored the corticospinal system in a group of patients with PWS by means of transcranial magnetic stimulation (TMS). This is a noninvasive, safe, and painless probe of the corticospinal excitability and conductivity. Transcranial magnetic stimulation variables are sensitive to the transmitter balance in the cortex.11,12

Prader-Willi syndrome develops from a failure to express paternally derived genes in the q11-q13 region of chromosome 15.13 Deletion in the paternally derived chromosome 15 occurs in 60% to 70% of patients with PWS.14 Almost 20% to 30% of patients inherit 2 maternally derived (ie, inactive) chromosomes 15; this is termed uniparental disomy(UPD).13 Other rare genetic defects can occur.14 With the hypothesis that a different genotype might produce different changes in the corticospinal physiology, we analyzed the TMS findings as a function of this variable.

METHODS
PATIENTS

We examined 21 right-handed patients with PWS (9 men; mean ± SD age, 24.6 ± 6.2 years; range, 15-39 years). All met the clinical and genetic criteria for a PWS diagnosis (average Holmscore 15 ± SD, 10.4 ± 1; range, 9-12.5). Each case was initially studied with high-resolution chromosome analysis. The presence of a deletion was confirmed by fluorescent in situ hybridization. If fluorescent in situ hybridization studies did not show a deletion, UPD and methylation were investigated.16 Thirteen patients had a deletion (6 men); 8 had a UPD (3 men). None had other unusual molecular findings. Informed consent was obtained from the patients or from their parents or legal guardians if the patients were underaged. In no case was the patient’s IQ below 69. The experimental procedure, which had the approval of the local ethics committee, was explained in detail to the patient. No patient was taking neuroactive drugs. We had a normal control group of 11 subjects, matched for age and sex.

TRANSCRANIAL MAGNETIC STIMULATION

Transcranial magnetic stimulation was performed through a round coil (outer diameter, 14 cm) centered at the vertex. We used an anticlockwise current direction to stimulate the left hemisphere preferentially. Motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle by silver-silver chloride surface electrodes. Data were collected, amplified, stored, and analyzed by a Neuroscan machine (Neuroscan Laboratory, Sterling, Va). The signal was amplified with a bandpass of 3 Hz to 3 kHz, a sweep duration of 10 to 50 ms/division, and a gain of 0.1 to 1 mV/division. Patients sat comfortably in a chair. Muscle relaxation was essential for most recordings, but patients were kept awake. Motor evoked potential variables were assessed following the guidelines of the International Federation of Clinical Neurophysiology.17 Using a single stimulator (Magstim 200; Magstim Co, Whitland, Wales), we determined the relaxed motor threshold (rT) and the central motor conduction time. To estimate the peripheral conduction time, we used the F wave latency. The central silent period was the period of electromyographic silence produced by a TMS pulse set as 1.5 × rT, and the first dorsal interosseous muscle was activated at the maximum force level. The length of the central silent period extended from the stimulus artifact to the consistent reappearing of electromyographic activity. With the paired-pulse technique,18 we finally studied intracortical inhibition (ICI) and intracortical facilitation (ICF) during complete muscle relaxation. Two Magstim 200 stimulators were coupled with a Bistim device (Magstim Co). The intensity of the conditioning stimulus was 0.8 × rT. The test stimulus was 1.2 × rT, and it was slightly adjusted to evoke MEPs sized 0.5 to 1 mV. We studied 2 inhibitory (2 and 3 ms) and 2 facilitatory (14 and 16 ms) interstimulus intervals. For each interstimulus interval, we recorded at least 12 control and 12 conditioned MEPs at random. The effect of conditioning was the ratio of the average conditioned MEP to the average control MEP.

F WAVES

We evoked 16 F waves from the first dorsal interosseous muscle by supramaximum electrical stimulation of the ulnar nerve at the wrist (1Hz, 0.1 ms). We measured their minimum latency and average peak-to-peak size.

STATISTICAL ANALYSIS

We used the software package SPSS 6.0 for Windows (SPSS Inc, Chicago, Ill) to analyze the TMS variables. First, we compared the whole PWS group with controls. Intracortical inhibition was the average inhibition (percentage of control MEP) at interstimulus intervals of 2 and 3 ms. Intracortical facilitation was the average facilitation at interstimulus intervals of 14 and 16 ms. We used unpaired t tests with a Bonferroni correction of P values. We then split patients into 2 subgroups (deletion and UPD) according to their genotype. These were compared with controls by a 1-way analysis of variance model. Post hoc Bonferroni tests were performed to determine significant (P < .05) differences.

RESULTS
ALL PATIENTS VS CONTROLS

The Table shows numerical data. The average rT value was higher in the PWS group than in the control group (P < .05) (Figure 1A). The central motor conduction time (corrected by height) was normal in the PWS group. The average central silent period duration and ICI values did not differ between patients and controls as well. Intracortical facilitation showed an average reduction in the PWS group (P<.001) (Figure 1B). The F wave size of patients with PWS was normal.

DELETION SUBGROUP VS UPD SUBGROUP VS CONTROLS

The threshold was enhanced, and ICF was decreased to a similar extent in both PWS subgroups in comparison with controls (P<.05). Intracortical inhibition was weaker (ie, its nominal value was higher) in the deletion subgroup (24.1% ± 11.9%) than in the UPD subgroup (11.4% ± 5.6%) (P<.05) (Figure 1C and Figure 2).

COMMENT

The main findings of the present study are an increased rT and a reduced ICF in patients with PWS. Physiologically, these findings correspond to an overall corticospinal hypo-excitability.11

Many factors may affect the rT to transcranial magnetic stimulation.11 To extract the cortical responsibility in a given threshold change, many authors evaluated the spinal excitability by means of F waves.19 This method, however, has some limitations.17 In our PWS group, F waves were of normal size. Thus, we suggest that hypo-excitability was mainly a motor cortical phenomenon. Changes in rT reflect changes in the voltage-gated ion channel function in the neuron membrane.12 In PWS, some of the pivotal genetic defects interfere with neural differentiation in the cortex.6 This may well cause abnormalities in the membrane properties of the area 4 neurons targeted by TMS shocks.11 Interestingly, threshold is also increased in the Angelman syndrome,20 a disorder that results from a genetic defect in the maternally inherited chromosome 15.13

Paired-pulse TMS is now used to test neurotransmission within the motor cortex11,12 in health and disease.21,22 Reportedly, dopaminergic drugs increase ICI, while antidopaminergic, anticholinergic, and serotonergic drugs reduce it. Antidopaminergic and anticholinergic drugs increase ICF. Moreover, N-methyl D-aspartate receptor blockers can increase ICI and reduce ICF. In turn, enhancement of GABAergic transmission mainly decreases ICF and, to a lesser extent, strengthens ICI. However, not all GABAergic drugs have the same action on ICF. Vigabatrin and the benzodiazepines, the typical GABAA receptor antagonists, reduce ICF when given acutely. Conversely, tiagabine leads to an ICF increase through presynaptic GABAB receptors.12

Neurochemically, the PWS genetic defect would imply a malfunction of GABAAergic inhibition, due to hyposensitivity of GABAA receptors. This, in turn, would release an excess serotonergic, dopaminergic, glutamatergic, and peptidergic transmission.9,10 Moreover, the PWS genetic defect would imply, as a feedback response, enhanced GABA plasma levels.8 On this basis, we should have expected an excess ICF (and a weaker ICI) in our patients. The actual data went in the opposite direction, denying the validity of the model. In addition, the complex nature and distribution of the GABAA receptors do not support simplistic explanations.23 Prader-Willi syndrome affects 3 subunits (α-5, β-3, and γ-3) of the GABAA receptor. They aggregate into isoforms, which represent no more than one third of the overall GABAA receptors in the brain.24 Thus, high levels of circulating GABA might even result in a paradoxical overstimulation of the surviving GABAA (or GABAB) receptors. Overstimulation of GABAA would nicely explain our finding of a defective ICF.

The central silent period is an index of motor cortical inhibition, and GABA transmission might affect it.25 However, its pharmacology turned out to be contradictory.12 Perhaps this is why we found no significant central silent period changes in our patients, even if GABA changes were expected.

Incidentally, the TMS features of our patients with PWS were nearly opposite to those of patients with obsessive-compulsive disorder.26 Yet, PWS reportedly implies a proneness to obsessive-compulsive behavior,1 whose physiology would thus seem peculiar.

Finally, the amount of ICI was less in patients with PWS and a deletion than in patients with PWS and a UPD. Deletion, as compared with UPD, would thus imply a lower cortical GABAergic tone and possibly an enhanced serotonergic/glutamatergic tone.12 This neurochemical change would be more akin to the proposed model of PWS.9,10 A similar, selective involvement of ICI was found in patients with subtypes 2 and 3 of spinocerebellar ataxia. Selective involvement of ICI was seen as a typical genotype-related electrophysiological difference because of the expression of the mutant protein in the cortex.27 We then hypothesize that impaired ICI is a candidate electrical marker for patients with PWS and a deletion as opposed to patients with PWS and a UPD. Reportedly, seizures are more common in patients with a deletion,28,29 which would fit the lessened inhibition nicely.22 However, this is a preliminary observation, which awaits reproduction in larger patient cohorts.

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Article Information

Correspondence: Roberto Cantello, MD, PhD, Dipartimento di Scienze Mediche, Via Solaroli 17, 28100 Novara, Italy (cantello@med.unipmn.it).

Accepted for Publication: March 2, 2004.

Author Contributions:Study concept and design:Civardi, Grugni, and Cantello. Acquisition of data: Civardi andVicentini. Analysis and interpretation of data:Civardi and Cantello. Drafting of the manuscript: Civardi and Cantello. Critical revision of the manuscript for important intellectual content: Civardi, Vicentini, and Grugni. Statistical expertise: Civardi and Cantello. Administrative, technical, and material support: Cantello. Study supervision: Cantello.

Funding/Support: Drs Civardi and Cantello were supported by a research grant from the Istituto Auxologico Italiano, Milano, Italy.

References
1.
Nativio  DG The genetics, diagnosis, and management of Prader-Willi syndrome. J Pediatr Health Care 2002;16298- 303
PubMedArticle
2.
Roy  MSMilot  JAPolomeno  RCBarsoum-Homsy  M Ocular findings and visual evoked potential response in the Prader-Willi syndrome. Can J Ophthalmol 1992;27307- 312
PubMed
3.
Stauder  JEABrinkman  MJRCurfs  LMG Multi-modal P3 deflation of event-related brain activity in Prader-Willi syndrome. Neurosci Lett 2002;32799- 102
PubMedArticle
4.
Prader  ALabhart  AWilli  H Ein syndrom von adipositas, kleinwuchs, kryptorchismus und oligofrenic nach myalonieartigen zustand im neugeborenenalter. Schweiz Med Wochenschr 1956;861260- 1261
5.
Jay  PRouguelle  CMassacrier  A  et al.  The human necdine gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region. Nat Genet 1997;17357- 361
PubMedArticle
6.
Leonard  CMWilliams  CANicholls  RD  et al.  Angelman and Prader-Willi syndrome: a magnetic resonance imaging study of differences in cerebral structure. Am J Med Genet 1993;4626- 33
PubMedArticle
7.
Wagstaff  JKnoll  JHMFleming  J  et al.  Localization of gene encoding the GABA-A receptor beta-3 subunit to the Angelman/Prader-Willi region of human chromosome 15. Am J Hum Genet 1991;49330- 337
PubMed
8.
Ebert  MHSchmidt  DEThompson  TButler  MG Elevated plasma gamma-aminobutyric acid (GABA) levels in individuals with either Prader-Willi syndrome or Angelman syndrome. J Neuropsychiatry Clin Neurosci 1997;975- 80
PubMed
9.
Dimitropoulos  AFeurer  IDRoof  E  et al.  Appetitive behaviour, compulsivity, and neurochemistry in Prader-Willi syndrome. Ment Retard Dev Disabil Res Rev 2000;6125- 130
PubMedArticle
10.
Akefeldt  AEkman  RGillberg  CManson  JE Cerebrospinal fluid monoamines in Prader-Willi syndrome. Biol Psychiatry 1998;441321- 1328
PubMedArticle
11.
Abbruzzese  GTrompetto  C Clinical and research methods for evaluating cortical excitability. J Clin Neurophysiol 2002;19307- 321
PubMedArticle
12.
Boroojerdi  B Pharmacologic influences on TMS effects. J Clin Neurophysiol 2002;19255- 271
PubMedArticle
13.
Nicholls  RD Genomic imprinting candidate genes in the Prader-Willi and Angelman syndromes. Curr Opin Genet Dev 1993;3445- 456
PubMedArticle
14.
Khan  NLWood  NW Prader-Willi and Angelman syndrome: update on genetic mechanisms and diagnostic complexities. Curr Opin Neurol 1999;12149- 154
PubMedArticle
15.
Holm  VACassidy  SBButler  MG  et al.  Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 1993;91398- 402
PubMed
16.
ASHG/ACMG Report, Diagnostic testing for Prader-Willi and Angelman syndromes: report of the ASHG/ACMG test and technology transfer committee. Am J Hum Genet 1996;581085- 1089
PubMed
17.
Rothwell  JCHallett  MBerardelli  AEisen  ARossini  PMPaulus  W Magnetic stimulation: motor evoked potentials: guidelines of the International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl 1999;52(suppl)97- 103
PubMed
18.
Kujirai  TCaramia  MDRothwell  JC  et al.  Corticocortical inhibition in the human motor cortex. J Physiol 1993;471501- 519
PubMed
19.
Ziemann  ULonnecker  SSteinhoff  BJPaulus  W Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol 1996;40367- 378
PubMedArticle
20.
Guerrini  RDe Lorey  TMBonanni  P  et al.  Cortical myoclonus in Angelman syndrome. Ann Neurol 1996;4039- 48
PubMedArticle
21.
Cantello  R Applications of transcranial magnetic stimulation in movement disorders. J Clin Neurophysiol 2002;19272- 293
PubMedArticle
22.
Tassinari  CACincotta  MZaccara  GMichelucci  R Transcranial magnetic stimulation and epilepsy. Clin Neurophysiol 2003;114777- 798
PubMedArticle
23.
Olsen  RWHomanics  GE Function of GABA-A receptors: insight from mutant and knockout mice.  In: Martin  DL, Olsen  RW, eds. GABA in the Nervous System: The View at Fifty Years. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000:81-96
24.
Whiting  PJWafford  KAMcKernan  RM Pharmacologic subtypes of GABAA receptors based on subunit composition.  In: Martin  DL, Olsen  RW, eds. GABA in the Nervous System: The View at Fifty Years. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000:113-126
25.
Cantello  RGianelli  MCivardi  CMutani  R Magnetic brain stimulation: the silent period after the motor evoked potential. Neurology 1992;421951- 1959
PubMedArticle
26.
Greenberg  BDZiemann  UCora-Locatelli  G  et al.  Altered cortical excitability in obsessive-compulsive disorder. Neurology 2000;54142- 147
PubMedArticle
27.
Schwenkreis  PTegenthoff  MWitscher  K  et al.  Motor cortex activation by transcranial magnetic stimulation in ataxia patients depends on the genetic defect. Brain 2002;125301- 309
PubMedArticle
28.
Gillessen-Kaesbach  GRobinson  WLohmann  DKaya-Westerloh  SPassage  EHorsthemke  B Genotype-phenotype correlation in a series of 167 deletion and non deletion patients with Prader-Willi syndrome. Hum Genet 1995;96638- 643
PubMedArticle
29.
Cassidy  SBForsythe  MHeeger  S  et al.  Comparison of phenotype between patients with Prader-Willi syndrome due to deletion 15q and uniparental disomy 15. Am J Med Genet 1997;68433- 440
PubMedArticle
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