4Med Genet 1998;35:94-98

"Cataplexy" and muscle ultrasound abnormalitiesin Coffin-Lowry syndrome

Y J Crow, S M Zuberi, R McWilliam, J L Tolmie, A Hollman, K Pohl, J B P Stephenson

AbstractThe Coffin-Lowry syndrome is a rarecause ofmental retardation recognised byits distinctive facial and digital features.We have observed an unusual, non-epileptic, cataplexy-like phenomenon inthree subjects with the syndrome and wespeculate that this feature may go unrec-ognised. We also provide evidence of neu-romuscular dysfunction as part of thephenotype by showing abnormalities onmuscle ultrasound in four gene carriers.(iMed Genet 1998;35:94-98)

Keywords: Coffin-Lowry syndrome; cataplexy; muscleultrasound abnormalities

Department of ClinicalGenetics, YorkhillHospitals NHS Trust,Glasgow G3 8SJ, UKY J CrowJ L Tolmie

Department ofPaediatric Neurology,Yorkhill Hospitals NHSTrust, Glasgow G3 8SJ,UKS M ZuberiR McWilliamJ B P Stephenson

Department ofRadiology, YorkhillHospitals NHS Trust,Glasgow G3 8SJ, UKA Hollman

Department ofPaediatric Neurology,Guy's and St Thomas'sHospital Trust, StThomas's Street,London SEI 9RT, UKK Pohl

Correspondence to:Professor Stephenson, Fraserof Allander Unit (Neurologyand Child Development),Yorkhill Hospitals NHSTrust, Glasgow G3 8SJ, UK.

Received 30 July 1997Revised version accepted forpublication 21 October 1997

Coffin et al' in 1966 and Lowry et af in 1971independently described patients with themental handicap syndrome which now bearstheir names. They recognised a phenotypecomprising moderate to severe mental retarda-tion, facial dysmorphism, tapering digits, andskeletal deformity.3 Linkage analysis subse-quently mapped the gene locus to Xp22.2,supporting the clinical impression that the syn-drome is an X linked trait with variable clinicalmanifestations in female heterozygotes. Re-cently, mutations have been identified in theRsk-2 gene in affected subjects.4 Here wereport five patients with Coffin-Lowry syn-drome from four families. Three of themexhibit episodes of sudden, non-epilepticcollapse with atonia which we describe as aform of cataplexy. Four patients show signifi-cant changes on muscle ultrasound indicativeof undefined neuromuscular dysfunction. Nei-ther of these features has been previouslyrecognised in this syndrome.

Case reportsCASE 1 (MALE)Scoliosis was evident by the age of 6 monthsand significant developmental delay was obvi-ous by 9 months of age. When 6 years old, hedeveloped episodes of sudden loss of tonecausing his legs to give way under him resultingin recurrent falls to the ground. These episodeswere reported to be precipitated by a loud noiseand could also occur at times ofexcitement andafter being "told off". Tone was regained withina few seconds. There were no associatedjerking movements. The frequency of theattacks subsequently necessitated the use of awheelchair from the age of 10 years. At 14 yearsof age he was referred for detailed neurologicalassessment. It was felt that his facial featuresand fingers were in keeping with a diagnosis ofCoffin-Lowry syndrome (figs 1 and 2). Investi-

gation of urinary glycosaminoglycans, chromo-somes, and DNA for fragile X syndrome wasunremarkable. Close examination of videorecordings of the episodes suggested a loss oftone spreading from the head downwards withan initial drooping of his eyelids, followed bysagging of the jaw, dropping of the headtowards the chest, and finally a falling forwardof his body so that he appeared to "slump" intohis chair. Although muscle power appearednormal, muscle ultrasound (recorded using anAcuson 128XP 10 ultrasound system with 7MHz probe) showed increased muscle echo-genicity, reduced bone echogenicity, a reduc-tion in muscle bulk, and an increase in subcu-taneous fat (fig 3). These changes wereclassified as grade 3 according to the systemsuggested by Heckmatt et al.5 Serum creatinekinase was normal. Motor and sensory nerveconduction velocities measured in the rightmedian nerve were normal. Limited needleEMG examination of the right first dorsalinterosseous muscle showed normal wave formmorphology although of lower than expectedamplitude (<1 mvolt). A full interferencepattern was obtained but again the amplitudewas lower than expected at 2.5 mvolts. Therewas no spontaneous activity or increased inser-tional activity. Needle muscle biopsy of theright vastus lateralis, including electron micro-scopy and dystrophin immunocytochemistry,was unremarkable. EEG during one of these

Figure 1 Case I showing typicalfacialfeatures ofCoffin-Lowry syndrome. (Photograph reproduced withpermission.)

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"Cataplexy"and muscle ultrasound abnormalities in Coffin-Lowry syndrome

Figure 2 Case I showing typical digitalfeatures ofCoffin-Lowry syndrome.

induced falls did not show any epilepticdischarges (fig 4). Changes in paraspinal mus-cle activity were assessed using surface elec-trodes placed 2 cm either side of the midline atC5 level with a ground electrode on the rightforearm. Collapses could be induced bysudden and unexpected sound or electricalstimulation of a peripheral nerve above themotor threshold. Following successful stimula-tion, there was an abrupt reduction in surfaceEMG activity with a latency of approximately76 msec. This reduction was transient, 4 msec,and was followed by an increase in EMG activ-ity to greater than pre-stimulus levels.

CASE 2 (MALE)At the age of 1 year he was noted to bedysmorphic and by 16 months was showingsigns of global developmental delay. Chromo-somal analysis was normal. He was diagnosedwith Coffin-Lowry syndrome when 5 years old.At the age of 7 years, it was noted that a suddennoise would make him fall: "if startled his legsswitch off". He would then get up and walkagain as normal. An EEG was unremarkable.By the age of 10 years these episodes wereoccurring up to 12 times per day. When stand-ing or walking he would suddenly drop, alwaysin a forwards direction, and never from a sittingposition. On occasion, he would "half-dropthen freeze", being able to recover beforecollapsing completely. On other occasions hisfalls were so instantaneous that he hurthimself, dislocating his jaw and fracturing his

F_~~Figure 3 Muscle ultrasound of thigh. Appearance in case 1 (right) shows a reduction inbone echo (B), a reduction in muscle bulk with increased echogenicity (M), and an increasein subcutaneous fat (F) compared to normal control (left).

nose. He recovered spontaneously from theseepisodes which were not accompanied by con-fusion or loss of consciousness. EEG, MRI ofthe brain, cerebral angiography, and ECG wereall normal. Muscle ultrasound was unremark-able. A therapeutic trial of clobazam did notproduce any clear benefit.

CASE 3 (FEMALE)Unfortunately, few details are available for thispatient regarding family history and earlydevelopment. However, it is known that shehad significant developmental retardation froma young age and was placed in a psychiatricinstitution. Frequent attacks of falling downwere recognised from the age of 13 years.When placed on her feet she was said to"buckle at the knees" and fall to the ground.Initially it was felt that her walking difficultieswere non-organic in nature. At the age of 35years she was reassessed. Facial and digital fea-tures were consistent with a diagnosis ofCoffin-Lowry syndrome (fig 5). Muscle ultra-sound showed generalised increase in muscleechogenicity and reduction in muscle bulk(grade 4, Heckmatt). These changes were moststriking in the calves and thighs. The arms andforearms were least affected. Serum creatinekinase was normal. X ray of the hands showedtypical tufting of the terminal phalanges.Attempts at recording surface EMG activityduring an episode of collapse were unsuccess-ful.

CASE 4 (MALE)Developmental delay was first noted at the ageof 11 months with an inability to sit unsup-ported. At 17 months of age there was nounderstanding of spoken language and nosymbolic play. He was still unsteady whensitting and was unable to roll or stand. HisOFC was 47 cm (10-50th centile). He wasnoted to have plagiocephaly, tapering fingers,and a dysmorphic facies consistent withCoffin-Lowry syndrome. Muscle ultrasoundshowed a marked increase in muscle echo-genicity and a reduction in bone echogenicity(grade 3, Heckmatt) particularly affecting thethighs and calves but also, to a lesser extent, thearms and forearms. Serum creatine kinase andchromosomal analysis were both normal. At 30months he is making some developmentalprogress, is now able to walk unsteadily, andshows limited understanding of symbolic play.

CASE 5 (FEMALE)This was the mother of case 4. She had a pooreducational record associated with learningdifficulties. She has tapering fingers withprominence of the terminal phalanges on x rayconsistent with carrier status for Coffin-Lowrysyndrome. Muscle ultrasound showed general-ised increase in muscle echogenicity withreduction in muscle bulk predominantly affect-ing the thighs and calves (grade 3, Heckmatt).Her mother was also said to have fingers whichwere broad proximally but tapering towards theends.

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Figure 4(A) Serialframes at 400 msec intervals after sound startle. (B) ERG duning sound startle induced collapsedisplays large motion artefact and scalp muscle potential but neither epileptic discharges nor background suppression wereevident. Interictal ERG was also normal.

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"Cataplexy"and muscle ultrasound abnormalities in Coffin-Lowry syndrome

Figure 5 Typical digital changes seen in a manifestingfemale (case 3).

DiscussionIn this report we describe three subjects withCoffin-Lowry syndrome who show an unusualphenomenon characterised by a sudden andreversible loss of muscle tone without loss ofconsciousness. This developed in two malesbeginning at 6 and 7 years of age and in one

manifesting female heterozygote beginning atthe age of 13 years. The frequency of attackshas resulted in all three patients being confinedto a wheelchair to reduce the risk of injury,although there is no evidence to suggest thatcollapses become more frequent or severe withtime. We could find only one other descriptionof a person with Coffin-Lowry syndrome andrecurrent collapses that may be similar to thoseseen in three of our patients. Ishida et at

describe a male (case 2) who "occasionally lostconsciousness, but electrocardiogram and elec-troencephalogram showed normal patterns".The major differential diagnosis of collapse

in these three patients includes an epilepticphenomenon, hyperekplexia, negative myo-clonus, and cataplexy.

"Seizures" have been described in patientswith Coffin-Lowry syndrome,278 althoughdescriptions of the episodes and documenta-tion of the EEG findings are frequentlyinadequate. The normal EEG recorded duringepisodes in two of our cases suggests that theyare not epileptic in origin. Although startleprovoked epileptic seizures (SPES) can occur

in the absence of EEG changes, the clinicalfeatures are quite distinct. In particular, inSPES, seizures are almost always also seen inthe absence of startle provocation and arecharacterised by focal or generalised tonicmotor activity.9 Neither of these features wasseen in the subjects we describe.

Hyperekplexia is characterised by an exag-gerated motor response to a sudden and unex-

pected noise, a tap to the body or, less

frequently, a visual stimulus. Typically, thepatients will "startle" and if standing may falland injure themselves. This exaggeration of thenormal startle reflex is accompanied by hyper-tonia and a marked increase of muscle activityon EMG recording,'0 which features differenti-ate it completely from the episodes reportedhere.

Negative myoclonus, asterixis, is character-ised by arrhythmic lapses of sustained posturewith periods ofEMG silence lasting up to 400msec. It is not associated with startle provoca-tion and is usually seen in the context of meta-bolic and toxic encephalopathies."

Cataplexy comprises an abrupt, complete, orpartial loss of voluntary muscle tone and isusually seen in response to strong emotion butcan be precipitated by startle. It is rare inchildhood and has previously only beendescribed in association with narcolepsy,'2Niemann-Pick type C,'3 Prader-Willisyndrome,'4 and Norrie disease.'5 Cataplexy inassociation with the narcolepsy syndrome ischaracterised by typical EEG correlates ofREM sleep which were not seen in our cases.We also looked for the HLA DR2/DQ616 hap-lotype in two patients and this was positive incase 1 only. Vossler et all5 described cataplexy inboys with Norrie disease and a reduction inmonoamine oxidase type B (MAO-B). Wemeasured platelet monamine oxidase activityin case 1 and the level was unremarkable. Guil-leminault and Gelb'7 have described theelectrophysiological characteristics ofcataplexywhich include an abolition of the H reflex dur-ing attacks of atonia. In view of the very shortduration of the episodes seen in our patients wewere unable to replicate these studies. We were,however, able to show changes in paraspinalmuscle activity which suggest that, in responseto a sudden and unexpected stimulus, theinitial event is a loss of muscle tone followedthereafter by a very rapid increase in muscleactivity.The short duration ofthe attacks we describe

and their association with sound/startle provo-cation are not typical of cataplexy. However,the features seen on the video recording of case1 are very similar to those seen in cataplexy andit is important to note that emotional stress isalso described as a trigger in case 1. We regardthe observation in case 2 that, on occasion, hewould "half drop then freeze" as typical ofsome episodes seen in cataplexy where thereappears to be a successful voluntary attempt toovercome the atonic attack. For these reasonswe feel that cataplexy is the best description ofthese collapses. Moreover, the occurrence ofthis unusual cataplexy-like phenomenon inthree subjects with Coffin-Lowry syndromesuggests to us that it might be a relatively com-mon feature of the condition and that episodespreviously described as epileptic may, in fact,be similar to those we report.Heckmatt et al'8 in 1980 first described the

use of ultrasound imaging to detect pathologi-cal changes in the muscles of boys with Duch-enne muscular dystrophy. They reported in-creased echogenicity of damaged muscle, as aconsequence of progressive infiltration and

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Crow, Zuberi, McWilliam, et al

replacement of muscle by adipose and connec-tive tissue, and later extended these observa-tions to other neuromuscular conditions.5Importantly, they found that controls showedclear delineation of bone and fascia, appearingas strongly echogenic structures, while musclewas only weakly echogenic.We have observed abnormalities on muscle

ultrasound in four of our patients with increasein muscle echogenicity (especially in the thighsand calves), variable attenuation of bone echo,reduction in muscle bulk, and increase in sub-cutaneous fat. These changes are similar tothose seen in spinal muscular atrophy. Grade 3changes were seen in a 2 year old male andgrade 4 abnormalities were present in a mani-festing female at the age of 35 years. It is diffi-cult to determine the degree of functionalweakness and whether or not it is progressive,but it is well recognised that the severity of thechanges observed on ultrasound do not neces-sarily relate to the degree of functional disabil-ity. Abnormalities of muscle on ultrasoundwere not seen in case 2 and are presumably notrelated to the cataplexy-like episodes.Muscle wasting and weakness are not

commonly referred to as a part of the clinicalphenotype in Coffin-Lowry syndrome. How-ever, Fryns et af described two brothers withCoffin-Lowry syndrome who showed markeddistal muscle wasting. Other authors have alsocommented on this aspect of the condition.'9 21Kyphoscoliosis, pes planus, and pectus de-formities are well recognised and it is possiblethat these features may be the result, at least inpart, of neuromuscular dysfunction. Investiga-tions to elucidate the nature of any nerve ormuscle disorder have included creatine kinaseestimation, electromyography, muscle biopsy,and nerve conduction studies. Vine et a!'0reported "diminished amplitude and pro-longed latency of nerve conduction" in a 22year old male and suggested that the muscleweakness was more likely to be the result of aneurogenic rather than myopathic process.Procopis and Turner2' showed mild myopathicchanges on EMG in one patient. Musclebiopsy and nerve conduction studies were nor-mal. Muscle biopsy from a sib was said to showa pattern of neurogenic muscle atrophy. In thepresent study, creatine kinase was normal in allthree patients tested. A muscle biopsy in case 1was normal although the EMG findings wereinterpreted as possibly myopathic in origin. Wefeel that the clinical features and ultrasoundfindings certainly seem to indicate neuromus-cular disease but supplementary investigationshave failed to determine the nature of theunderlying abnormality.

In summary, we have observed an unusualcataplexy-like phenomenon in three subjectswith the Coffin-Lowry syndrome and we alsodescribe muscle ultrasound changes suggestiveof neuromuscular dysfunction in four cases.Recently, mutations in the Rsk-24 gene havebeen reported in subjects with Coffin-Lowrysyndrome. Rsk-2 is a member of a family ofgrowth factor regulated serine-threonine ki-nases, but at present the known functions ofRsk-2 provide no clues as to the nature of thesephenomena and we are uncertain as to theunderlying mechanisms.

We would like to thank Mrs Jean Hyslop of the Department ofMedical Illustration for preparation of the clinical photographs.

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