Eur Arch Psychiatr Neurol Sci ( 1988) 237:230-236 European Psychiatryand Neurological

Sciences© Springer-Verlag 1988

Autosomal Dominant Emery-Dreifuss Syndrome:Evidence of a Neurogenic Variant of the Disease*

Th N Witt 1 , C G Garner', D Pongratz 2 , and X Baur 3

'Neurologische Klinik, Klinikum Gro Bhadern, Marchioninistrasse 15, D-8000 Miinchen 70, Federal Republic of Germany2Friedrich Baur Stiftung, Medizinische Klinik Innenstadt, D-8000 Munchen, Federal Republic of Germany3Medizinische Klinik I, Klinikum Grofhadern der Universitat Muinchen, D-8000 M Unchen, Federal Republic of Germany

Summary The first German family with autosomaldominant Emery-Dreifuss syndrome (EDS) is de-scribed, with electrophysiologic and myopathologicresults providing evidence of a primary neurogenicdisease According to classification of the scapuloperoneal syndrome without cardiomyopathy, we con-clude that there are two variants of EDS: one myo-pathic, the other neurogenic in origin Therefore, theterm Emery-Dreifuss muscular dystrophy should beavoided Instead, each case of EDS should be classi-fied as myopathic or neurogenic with X chromosomerecessive or autosomal dominant inheritance.

Chakrabarti and Pearce ( 1981) first noted a simi-lar syndrome with autosomal dominant inheritance,and nine cases within four families with that transmis-sion have been examined and described in detail todate On the basis of conventional EMG and musclehistology most of these cases were classified as myo-pathic origin.

We report the results of an electrodiagnostic andmyopathologic study on three members of the firstGerman family with autosomal dominant Emery-Dreifuss syndrome (EDS).

Key words: Emery-Dreifuss syndrome Autosomaldominant inheritance Single-fiber EMG Fibertype-I atrophy Spinal muscular atrophy

Introduction

Dreifuss and Hogan ( 1961) and Emery and Dreifuss( 1966) first described a particular X-linked musculardisorder with early contractures and cardiomyopathy.Most further cases reported showed predominantatrophy of the scapulo humero peroneal muscles.Despite contradictory myopathic and neuropathicfindings obtained by electromyography (EMG) andmuscle histology, Rowland et al ( 1979) proposed theterm Emery-Dreifuss muscular dystrophy (Emery-Dreifuss disease) to define the unique clinical fea-tures and the X-linked recessive inheritance.

Offprint requests to: Th N Witt* The results of this study were presented in part at the 8thinternational congress of electromyography and related neuro-physiology, Sorrento, Italy 1987

Materials and Methods

The pedigree of the investigated family with EDS, showingautosomal dominant inheritance, is listed in Fig 1.

Case 1 and 2 are brothers, case 3 is the son of case one Thefather of cases 1 and 2, his sister and brother and one son ofthis brother died in middle age of sudden heart death This sonhad a pacemaker implanted 6 months before his death because

IIII

III

IV3

Fig 1 Pedigree of the investigated family with Emery-Dreifusssyndrome (EDS) Symbols: Circle = female, square = male,light symbols = normal members, dark symbols = patientswith EDS, ? = EDS possible, 1-3 = investigated patients

l Tf40 1-I

6 ? * 10

231

Table 1 Clinical data of three patients with EDS

Case 1 Case 2 Case 3a

Age 47 43 17Sex Male Male MaleAge of onset (decade) First Third SecondDistribution of weakness Humeroperoneal*** Humeroperoneal** No weaknessContractures Elbows, ankles, neck**** Elbows, ankles** Elbows***Creatine kinase (normal < 80 U/) Elevated ( 80-295 U/) Normal ( 39 U/l) Elevated ( 312 U/l)Cardiology AV-block III AV-block III Normal

1983 pace-maker 1986 pace-maker9/86 heart transplant

* Very mild** Mild

*** Moderate**** Severea Son of case 1

of an AV-block III Because of a progressive therapy-resistant Resultsmyocardiac insufficiency case 1 received a heart transplant inSeptember 1986 The clinical findings of the three cases are Electrod nost Resultssummarized in Table 1 For further details see Baur et al ag( 1987) Motor and sensory NCV of the median nerve, motor

Conventional EMG, including motor unit potential analy NCV of the peroneal nerve, SE Ps of median and ti-sis, single fiber EMG and turns/s versus amplitude/turn analy-sis in at least 10 recording sites according to the method de bial nerves, and VE Ps were within normal ranges inscribed by Stalberg et al ( 1983) was done in the m biceps all three cases.brachii in all three cases, and additionally in the m tibialisanterior in cases 1 and 2 The motor and sensory nerve conduc Concentric Needle EMG The results of the concen-tion velocity (NCV) of the median nerve, the motor NCV of tric needle EMG-recorded motor unit potentials inthe peroneal nerve, and the visual (VEP) and somatosensory the m biceps brachii (cases 1 to 3) and the m tibialisevoked potentials (SEP) of the median and tibial nerves weremeasured in all cases The EMG and NCV studies were per anterior (cases 1 and 2) are given in Table 2.formed using a Medelec Mystro device, the VEP and SEP with With low effort innervation the activity patterna Nihon Kohden Neuropac 8 A muscle specimen was taken had a low amplitude and relative full appearance,from the m biceps brachii in cases 1 and 2 Standard histologic suggesting early recruitment of motor unit potentials,stains and histochemical preparations were used on deep whereas with increasing effort there was a lack offrozen material Histometric analysis with regard to fiber typedistribution and calculation of atrophy and hypertrophy factors further recruitment, showing mostly reduced inter-were performed (Brooke and Engel 1969 a and b; Brenni et al ference patterns at maximum effort with increased1981 ; Dubowitz 1985) amplitudes.

Table 2 Results of concentric needle EMG

Case 1 Case 2 Case 3

Biceps Tibialis Biceps Tibialis Bicepsbrachii anterior brachii anterior brachii

Spontaneous activity Fibrillation potentials (+), complex repetition discharges (+)

Motor unit potential analysis:Mean duration 8 9 ms 6 3 ms 8 1 ms 10 3 ms 6 4 msRange 3 6-19 6 ms 4 3-11 5 ms 3 4-15 4 ms 5 5-16 9 ms 2 8-13 4 msPolyphasic potentials 55 % 65 % 60 % 60 % 35 %

Interference Reduced Full Reduced Full ReducedPattern High amplitude Low High

amplitude amplitude

Missing(+) Occasionally

232

E

E

E

a o

ECX

E

E

500 1000

Turns/s

b O 500 1000

Turns/sFig 2 a and b Amplitude/turn versus turns/s analysis in case 1(m biceps brachii) a Medium effort; normal values b Maxi-mum effort; increase in amplitude/turn in 5 of 10 recordingsites, suggesting a neuropathic lesion

Automatic Analysis of the EMG Interference Pattern.Turns/s versus amplitude/turn were analyzed at 10different recording sites of the m biceps brachii inall cases and in m tibialis anterior in cases 1 and 2with medium and high voluntary effort Abnormal highamplitudes/turn are seen in neurogenic diseases, ab-normal low amplitudes/turn and an increased ratio ofturns/s are typical findings for a myopathic lesion.

With medium effort, normal values were seen inall tests An increase in amplitude/turn above thenormal range occurred during high voluntary effortin all examined muscles An increase of turns/s withnormal amplitude was seen rarely In none of the 60registration sites within the investigated muscles

Table 3 Results of single-fiber EMG

Case 1 Case 2 Case 3

Biceps brachiiMCD 71 S 68 S 78 tsBlocking + (+) +Fiber density 2 3 2 8 2 8

Tibialis anterior:

MCD 36 Ls 45 ps Not doneBlocking + Not doneFiber density 2 3 2 8 Not done

Missing(+) Rarely+ FrequentMCD, mean consecutive difference

Fig 3 Example of a single-fiber electromyography (EMG)recording in m tibialis anterior of case 2 Markedly increasedjitter of at least 4 different fibers, frequent blocking and highfiber density, as typically seen in chronic denervation

Table 4 Myopathologic and histometric results of muscle biop-sy in case 1 (left m biceps brachii) and case 2 (right m bicepsbrachii)

Case 1 Case 2

Fiber size variation + +Type-I atrophy + + + +Type-II hypertrophy + +Group atrophy (+) +Fiber type grouping +Increased internal nuclei (+)Necrotic fibersConnective tissue proliferation (+)Target fibers (+) (+)

Missing(+) Mild

+ Moderate+ + Severe

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No of type I fibers

Fig 4 Histogram of fiber typedistribution in case 2 (rightm biceps brachii): severe fibertype-I atrophy and moderate fibertype-II hypertrophy x = meanfiber diameter, SD = standarddeviation, AF = atrophy factor,HF = hypertrophy factor, VAR= variation coefficient (AF andHF calculated according to themethod described by Brooke andEngel 1969 a and b)

70

40

30

20

10

a

20

30

HO

50

70

No of type II fiber:

TYP I SE 25

X 37,39ED IE 38RF 11 77HF IH VHVRR H 38 07

fiber diameter

TYP II H 3 BS

-ED RF -HF -VRR

77 00

13.9 H9.01

603 60l o

s

Fig Sa and b Case 2, NADH reaction, m biceps brachii.Fiber type-i dark, fiber type-II light a small and large groupatrophy of fiber type-I, pathologic grouping of type-I fibers( 120 x) b Small group atrophy, single target fibers, type-IIhypertrophy ( 200 x) + Muscle spindle

there was a reduced amplitude/turn A typical ex-ample is shown in Fig 2.

Single-fiber EMG Single-fiber EMG recordingswere carried out in the m biceps brachii in all threecases, additionally in the m tibialis anterior in cases 1and 2 In the m biceps brachii significantly increasedjitter and moderate blocking were seen in all cases Inthe m tibialis anterior, only case 2 showed increasedjitter in 4 of 20 single-fiber recordings Fiber densitywas moderately increased in all muscles For detailssee Tables 3 and Fig 3.

Histologic Results

The histopathologic and morphometric results of amuscle biopsy performed near the site examined inthe EMG from the right m biceps brachii in cases 1and 2 are summarized in Table 4 Case 3 refused amuscle biopsy Histometric analysis of fiber type dis-tribution and the calculation of atrophy and hyper-trophy factors is shown in Fig 4 Figure 5 a and brepresent typical histological findings In both casesexamined histologically the most striking findingswere marked fiber type-I atrophy along with fibertype-II hypertrophy and scattered small group atro-phy Additionally a slight predominance of type-Ifibers was seen Degenerative fiber anomalies and in-terstitial connective tissue proliferation were onlyminor findings.

.

234

Discussion

Emery-Dreifuss syndrome is a well-defined clinicalentity with slow progressive scapulohumeroperonealatrophic paresis, early contractures, and severecardiomyopathy The majority of the cases reportedfollowed a X-linked transmission (Merlini et al.1986), autsomal dominant inheritance of the syn-drome is a rare finding Rotthauwe et al ( 1972) andCamman et al ( 1974) reported two German familieswith X-linked EDS, we present a quantitative elec-trodiagnostic and myopathologic study of the firstGerman family with autosomal dominant EDS (Bauret al 1987).

All three cases showed typical features of the syn-drome to varying degrees Two cases suffered fromsevere cardiomyopathy with conduction heart block.Because of progressive heart failure a heart trans-plant was done in case 1 in autumn 1986 Pathologicinvestigation of the explanted heart showed a dilata-tive cardiomyopathy with marked fibrosis of the mus-cle, especially in the septum of the ventricles Themacroscopic and microscopic findings were the sameas those in common dilatative cardiomyopathy (Bauret al 1987) More than 1 year after heart transplanta-tion this patient is clinically in good condition.

In the literature the origin of the disease is regard-ed to be myopathic Most authors suggest classifyingthe disease as a certain type of the muscular dys-trophies (Emery and Dreifuss 1966 ; Rotthauwe et al.1972 ; Thomas et al 1972 ; Camman et al 1974 ; Row-land et al 1979 ; Hopkins et al 1981 ; Fenichel et al.1982 ; Miller et al 1985) However, the EMG resultsdescribed do not strictly correspond to a myopathy.Some authors described a mixed or even a pureneurogenic EMG pattern (Emery and Dreifuss 1966 ;Mawatari and Katayama 1973 ; Takahashi et al 1974 ;Waters et al 1975 ; Rowland et al 1981 ; Sulaiman etal 1981 ; Hopkins et al 1981 ; Fenichel et al 1982 ;Takamato et al 1984 ; Petty et al 1986 ; Witt et al.1987) Most reports only included a qualitative EMGreport of motor unit potentials and activity patterns,quantitative methods were only seldom used (Thomaset al 1972 ; Rowland et al 1979 ; Lin 1982) We alsofound a reduced mean duration and an increased rateof polyphasic motor unit potentials, findings regard-ed to suggest a myopathic disease Surprisingly,quantitative analysis of the activity pattern showednormal values for amplitudes per turn and turns persecond with medium innervation; but with strong in-nervation, amplitudes per turn were significantly in-creased, suggesting neurogenic muscular changes Inall cases the m biceps brachii showed a reduced in-terference pattern, also indicating a neurogenic typeof disease Similar findings myopathic motor unit

potentials in combination with reduced recruitmentwith maximum effort with high amplitudes havebeen described several times and usually regarded asmixed pattern (Takahashi et al 1974 ; Rowland et al.1979 ; Sulaiman et al 1981 ; Chakrabarti and Pearce1981 ; Takamoto et al 1984) According to Engel( 1975), brief, small, and abundant motor unit actionpotentials are not pathognomonic for a myopathy,but can also be found in certain primary neurogenicsituations, e g , in acquired selective fiber type-Iatrophy It is well-known that type-I fibers fire firstwith light voluntary effort (Warmolts and Engel1972) So, our findings of so-called myopathic motorunit potentials with low effort and neurogenic activitypattern can be explained by the histologically provenselective fiber type-I atrophy.

Increased jitter and fiber density in the single-fiber EMG was a nonspecific result, which is found inneurogenic and myopathic disorders However, withrespect to the histologically well-preserved muscletissue with lack of dystrophic changes and fiber split-ting these results may better be interpreted as a signof a neurogenic lesion In particular the increasedfiber density can be explained by fiber type-I atro-phy The entirely normal motor and sensory conduc-tion velocity tests and the unimpaired evoked poten-tial latencies disclose a demyelinating neuropathy aspreviously described (Rotthauwe et al 1972 ; Row-land et al 1979 ; Fenichel et al 1982 ; Miller et al.1985 ; Hara et al 1987) The histologic and myo-pathologic results with marked fiber type-I atrophy,slight fiber type-II hypertrophy, small group atrophy,and fiber type grouping are strong arguments for aprimary chronic, slow progressive neurogenic disease(Sulaiman et al 1981) The pathologic fiber typegrouping together with the rare incidence of targetfibers indicates an accompanying reinnervation pro-cess.

Finally, fiber type-I atrophy and myopathic mus-cle unit potentials have also been described in theneurogenic scapuloperoneal syndrome of type Kaeser(Ricker et al 1968 ; Scarlato et al 1978 ; Mercelis etal 1980 ; Reiter et al 1984), a neuromuscular dis-order, generally accepted to be a variant of spinalmuscular atrophy on the basis of autoptic investiga-tions of the spinal cord (Kaeser 1964, 1975 ; Probstet al 1977) To date the histologic results of postmor-tem examination of the spinal cord in four patientswith clinically proven EDS have been published(Takahashi et al 1974 ; Charkabarti and Pearce 1981 ;Kudo et al 1982 ; Hara et al 1987), and the resultsare contradictory Whereas Charkrabarti and Pearce( 1981) and Hara et al ( 1987) disclosed no abnormal-ity of the spinal cord, Tagahashi et al ( 1974) de-scribed a large number of lipofuscin granules in the

235

anterior horn cells with no reduction in the totalnumber of these cells Kudo et al ( 1982) reveiledfocal neuronal and axonal changes in lower cervicaland lumbar spinal segments in combination with a re-duction in the number of anterior horn cells.

On the basis of the presented electrodiagnosticand myopathologic data, we conclude, that there aretwo variants of autosomal dominant transmittedEDS, one myopathic, the other neurogenic in origin.This concept corresponds to the classification of thescapuloperoneal syndrome without cardiomyopathyand contractures, where a spinal scapuloperonealmuscular atrophy with dominant inheritance (typeKaeser) is established For the EDS further postmor-tem examinations of the spinal cord are necessary toconfirm this hypothesis In agreement with Serratriceand Pouget ( 1986) we suggest avoiding the termEmery-Dreifuss disease Instead, each case of EDSshould be classified as myopathic or neurogenic EDSwith X chromosome recessive or autosomal domi-nant inheritance.

Acknowledgement We are indebted to Mrs Franziska Anneserfor her expert assistence with the histology stainings and histo-chemistry preparations.

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Received December 10, 1987